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1
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Krattiger LA, Moser LO, Odabasi R, Odriozola A, Simona BR, Djonov V, Tibbitt MW, Ehrbar M. Recovery of Therapeutically Ablated Engineered Blood-Vessel Networks on a Plug-and-Play Platform. Adv Healthc Mater 2024; 13:e2301142. [PMID: 37946678 DOI: 10.1002/adhm.202301142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Revised: 10/13/2023] [Indexed: 11/12/2023]
Abstract
Limiting the availability of key angiogenesis-promoting factors is a successful strategy to ablate tumor-supplying blood vessels or to reduce excessive vasculature in diabetic retinopathy. However, the efficacy of such anti-angiogenic therapies (AATs) varies with tumor type, and regrowth of vessels is observed upon termination of treatment. The ability to understand and develop AATs remains limited by a lack of robust in vitro systems for modeling the recovery of vascular networks. Here, complex 3D micro-capillary networks are engineered by sequentially seeding human bone marrow-derived mesenchymal stromal cells and human umbilical vein endothelial cells (ECs) on a previously established, synthetic plug-and-play hydrogel platform. In the tightly interconnected vascular networks that form this way, the two cell types share a basement membrane-like layer and can be maintained for several days of co-culture. Pre-formed networks degrade in the presence of bevacizumab. Upon treatment termination, vessel structures grow back to their original positions after replenishment with new ECs, which also integrate into unperturbed established networks. The data suggest that this plug-and-play platform enables the screening of drugs with blood-vessel inhibiting functions. It is believed that this platform could be of particular interest in studying resistance or recovery mechanisms to AAT treatment.
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Affiliation(s)
- Lisa A Krattiger
- Department of Obstetrics, University Hospital Zurich, University of Zurich, Schmelzbergstrasse 12, Zurich, 8091, Switzerland
- Macromolecular Engineering Laboratory, Department of Mechanical and Process Engineering, ETH Zurich, Sonneggstrasse 3, Zürich, 8092, Switzerland
| | - Lukas O Moser
- Department of Obstetrics, University Hospital Zurich, University of Zurich, Schmelzbergstrasse 12, Zurich, 8091, Switzerland
| | - Rodi Odabasi
- Department of Obstetrics, University Hospital Zurich, University of Zurich, Schmelzbergstrasse 12, Zurich, 8091, Switzerland
| | - Adolfo Odriozola
- Institute of Anatomy, University of Bern, Baltzerstrasse 2, Bern, 3012, Switzerland
| | - Benjamin R Simona
- Ectica Technologies AG, Raeffelstrasse 24, Zurich, 8045, Switzerland
| | - Valentin Djonov
- Institute of Anatomy, University of Bern, Baltzerstrasse 2, Bern, 3012, Switzerland
| | - Mark W Tibbitt
- Macromolecular Engineering Laboratory, Department of Mechanical and Process Engineering, ETH Zurich, Sonneggstrasse 3, Zürich, 8092, Switzerland
| | - Martin Ehrbar
- Department of Obstetrics, University Hospital Zurich, University of Zurich, Schmelzbergstrasse 12, Zurich, 8091, Switzerland
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2
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The Long Telling Story of "Endothelial Progenitor Cells": Where Are We at Now? Cells 2022; 12:cells12010112. [PMID: 36611906 PMCID: PMC9819021 DOI: 10.3390/cells12010112] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Revised: 12/21/2022] [Accepted: 12/23/2022] [Indexed: 12/29/2022] Open
Abstract
Endothelial progenitor cells (EPCs): The name embodies years of research and clinical expectations, but where are we now? Do these cells really represent the El Dorado of regenerative medicine? Here, past and recent literature about this eclectic, still unknown and therefore fascinating cell population will be discussed. This review will take the reader through a temporal journey that, from the first discovery, will pass through years of research devoted to attempts at their definition and understanding their biology in health and disease, ending with the most recent evidence about their pathobiological role in cardiovascular disease and their recent applications in regenerative medicine.
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3
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Plasma protein biomarkers for primary graft dysfunction after lung transplantation: a single-center cohort analysis. Sci Rep 2022; 12:16137. [PMID: 36167867 PMCID: PMC9515157 DOI: 10.1038/s41598-022-20085-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Accepted: 09/08/2022] [Indexed: 11/08/2022] Open
Abstract
The clinical use of circulating biomarkers for primary graft dysfunction (PGD) after lung transplantation has been limited. In a prospective single-center cohort, we examined the use of plasma protein biomarkers as indicators of PGD severity and duration after lung transplantation. The study comprised 40 consecutive lung transplant patients who consented to blood sample collection immediately pretransplant and at 6, 24, 48, and 72 h after lung transplant. An expert grader determined the severity and duration of PGD and scored PGD at T0 (6 h after reperfusion), T24, T48, and T72 h post-reperfusion using the 2016 ISHLT consensus guidelines. A bead-based multiplex assay was used to measure 27 plasma proteins including cytokines, growth factors, and chemokines. Enzyme-linked immunoassay was used to measure cell injury markers including M30, M65, soluble receptor of advanced glycation end-products (sRAGE), and plasminogen activator inhibitor-1 (PAI-1). A pairwise comparisons analysis was used to assess differences in protein levels between PGD severity scores (1, 2, and 3) at T0, T24, T48, and T72 h. Sensitivity and temporal analyses were used to explore the association of protein expression patterns and PGD3 at T48-72 h (the most severe, persistent form of PGD). We used the Benjamini-Hochberg method to adjust for multiple testing. Of the 40 patients, 22 (55%) had PGD3 at some point post-transplant from T0 to T72 h; 12 (30%) had PGD3 at T48-72 h. In the pairwise comparison, we identified a robust plasma protein expression signature for PGD severity. In the sensitivity analysis, using a linear model for microarray data, we found that differential perioperative expression of IP-10, MIP1B, RANTES, IL-8, IL-1Ra, G-CSF, and PDGF-BB correlated with PGD3 development at T48-72 h (FDR < 0.1 and p < 0.05). In the temporal analysis, using linear mixed modeling with overlap weighting, we identified unique protein patterns in patients who did or did not develop PGD3 at T48-72 h. Our findings suggest that unique inflammatory protein expression patterns may be informative of PGD severity and duration. PGD biomarker panels may improve early detection of PGD, predict its clinical course, and help monitor treatment efficacy in the current era of lung transplantation.
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4
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Gender differences and pharmacological regulation of angiogenesis induced by synovial fluids in inflammatory arthritis. Biomed Pharmacother 2022; 152:113181. [PMID: 35653890 DOI: 10.1016/j.biopha.2022.113181] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Revised: 05/10/2022] [Accepted: 05/22/2022] [Indexed: 11/27/2022] Open
Abstract
Several mediators including cytokines, growth factors and metalloproteinases (MMP) modulate pathological angiogenesis associated with inflammatory arthritis. The biological factors underlying sex disparities in the incidence and severity of rheumatic musculoskeletal diseases are only partially understood. We hypothesized that synovial fluids (SFs) from rheumatoid arthritis (RA) and psoriatic arthritis (PsA) patients would impact on endothelial biology in a sexually dimorphic fashion. Immune cell counts and levels of pro-angiogenic cytokines found in SFs from RA and PsA patients (n = 17) were higher than in osteoarthritis patients (n = 6). Synovial VEGF concentration was significantly higher in male than in female RA patients. Zymography revealed that SFs comprised solely MMP-9 and MMP-2, with significantly higher MMP-9 levels in male than female RA patients. Using in vitro approaches that mimic the major steps of the angiogenic process, SFs from RA and PsA patients induced endothelial migration and formation of capillary-like structures compared to control. Notably, endothelial cells from female donors displayed enhanced angiogenic response to SFs with respect to males. Treatment with the established anti-angiogenic agent digitoxin prevented activation of focal adhesion kinase and SF-induced in vitro angiogenesis. Thus, despite higher synovial VEGF and MMP-9 levels in male patients, the responsiveness of vascular endothelium to SF priming was higher in females, suggesting that gender differences in angiogenic responses were mainly related to the endothelial genotype. These findings may have implications for pathogenesis and targeted therapies of inflammatory arthritis.
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5
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Taylor DA, Chacon-Alberty L, Sampaio LC, Del Hierro MG, Perin EC, Mesquita FCP, Henry TD, Traverse JH, Pepine CJ, Hare JM, Murphy MP, Yang PC, March KL, Vojvodic RW, Ebert RF, Bolli R. Recommendations for Nomenclature and Definition Of Cell Products Intended for Human Cardiovascular Use. Cardiovasc Res 2021; 118:2428-2436. [PMID: 34387303 DOI: 10.1093/cvr/cvab270] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Accepted: 08/10/2021] [Indexed: 12/15/2022] Open
Abstract
Exogenous cell-based therapy has emerged as a promising new strategy to facilitate repair of hearts damaged by acute or chronic injury. However, the field of cell-based therapy is handicapped by the lack of standardized definitions and terminology, making comparisons across studies challenging. Even the term "stem cell therapy" is misleading because only a small percentage of cells derived from adult bone marrow, peripheral blood, or adipose tissue meets the accepted hematopoietic or developmental definition of stem cells. Furthermore, cells (stem or otherwise) are dynamic biological products, meaning that their surface marker expression, phenotypic and functional characteristics, and the products they secrete in response to their microenvironment can change. It is also important to point out that most surface markers are seldom specific for a cell type. In this article, we discuss the lack of consistency in the descriptive terminology used in cell-based therapies and offer guidelines aimed at standardizing nomenclature and definitions to improve communication among investigators and the general public.
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Affiliation(s)
- Doris A Taylor
- Regenerative Medicine Research, Texas Heart Institute, Houston, Texas.,RegenMedix Consulting LLC, Houston, Texas
| | | | - Luiz C Sampaio
- Regenerative Medicine Research, Texas Heart Institute, Houston, Texas
| | | | - Emerson C Perin
- Regenerative Medicine Research, Texas Heart Institute, Houston, Texas
| | | | - Timothy D Henry
- The Carl and Edyth Lindner Center for Research and Education, The Christ Hospital, Cincinnati, Ohio
| | - Jay H Traverse
- Minneapolis Heart Institute Foundation at Abbott Northwestern Hospital, and University of Minnesota School of Medicine, Minneapolis, Minnesota
| | - Carl J Pepine
- University of Florida College of Medicine, Gainesville, Florida
| | - Joshua M Hare
- University of Miami School of Medicine, Miami, Florida
| | | | - Phillip C Yang
- Stanford University School of Medicine, Stanford, California
| | - Keith L March
- University of Florida College of Medicine, Gainesville, Florida
| | - Rachel W Vojvodic
- University of Texas Health Science Center at Houston School of Public Health, Houston, Texas
| | - Ray F Ebert
- National Heart, Lung, and Blood Institute, Bethesda, Maryland
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Association between [ 68Ga]NODAGA-RGDyK uptake and dynamics of angiogenesis in a human cell-based 3D model. Mol Biol Rep 2021; 48:5347-5353. [PMID: 34213709 PMCID: PMC8318966 DOI: 10.1007/s11033-021-06513-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Accepted: 06/25/2021] [Indexed: 12/22/2022]
Abstract
Radiolabeled RGD peptides targeting expression of αvβ3 integrin have been applied to in vivo imaging of angiogenesis. However, there is a need for more information on the quantitative relationships between RGD peptide uptake and the dynamics of angiogenesis. In this study, we sought to measure the binding of [68Ga]NODAGA-RGDyK to αvβ3 integrin in a human cell-based three-dimensional (3D) in vitro model of angiogenesis, and to compare the level of binding with the amount of angiogenesis. Experiments were conducted using a human cell-based 3D model of angiogenesis consisting of co-culture of human adipose stem cells (hASCs) and of human umbilical vein endothelial cells (HUVECs). Angiogenesis was induced with four concentrations (25%, 50%, 75%, and 100%) of growth factor cocktail resulting in a gradual increase in the density of the tubule network. Cultures were incubated with [68Ga]NODAGA-RGDyK for 90 min at 37 °C, and binding of radioactivity was measured by gamma counting and digital autoradiography. The results revealed that tracer binding increased gradually with neovasculature density. In comparison with vessels induced with a growth factor concentration of 25%, the uptake of [68Ga]NODAGA-RGDyK was higher at concentrations of 75% and 100%, and correlated with the amount of neovasculature, as determined by visual evaluation of histological staining. Uptake of [68Ga]NODAGA-RGDyK closely reflected the amount of angiogenesis in an in vitro 3D model of angiogenesis. These results support further evaluation of RGD-based approaches for targeted imaging of angiogenesis.
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7
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Wang X, Chacon LI, Derakhshandeh R, Rodriguez HJ, Han DD, Kostyushev DS, Henry TD, Traverse JH, Moyé L, Simari RD, Taylor DA, Springer ML. Impaired therapeutic efficacy of bone marrow cells from post-myocardial infarction patients in the TIME and LateTIME clinical trials. PLoS One 2020; 15:e0237401. [PMID: 32841277 PMCID: PMC7446972 DOI: 10.1371/journal.pone.0237401] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Accepted: 07/25/2020] [Indexed: 01/07/2023] Open
Abstract
Implantation of bone marrow-derived cells (BMCs) into mouse hearts post-myocardial infarction (MI) limits cardiac functional decline. However, clinical trials of post-MI BMC therapy have yielded conflicting results. While most laboratory experiments use healthy BMC donor mice, clinical trials use post-MI autologous BMCs. Post-MI mouse BMCs are therapeutically impaired, due to inflammatory changes in BMC composition. Thus, therapeutic efficacy of the BMCs progressively worsens after MI but recovers as donor inflammatory response resolves. The availability of post-MI patient BM mononuclear cells (MNCs) from the TIME and LateTIME clinical trials enabled us to test if human post-MI MNCs undergo a similar period of impaired efficacy. We hypothesized that MNCs from TIME trial patients would be less therapeutic than healthy human donor MNCs when implanted into post-MI mouse hearts, and that therapeutic properties would be restored in MNCs from LateTIME trial patients. Post-MI SCID mice received MNCs from healthy donors, TIME patients, or LateTIME patients. Cardiac function improved considerably in the healthy donor group, but neither the TIME nor LateTIME group showed therapeutic effect. Conclusion: post-MI human MNCs lack therapeutic benefits possessed by healthy MNCs, which may partially explain why BMC clinical trials have been less successful than mouse studies.
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Affiliation(s)
- Xiaoyin Wang
- Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, United States of America
| | | | - Ronak Derakhshandeh
- Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, United States of America
| | - Hilda J. Rodriguez
- Division of Cardiology, University of California, San Francisco, San Francisco, CA, United States of America
- Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, United States of America
| | - Daniel D. Han
- Division of Cardiology, University of California, San Francisco, San Francisco, CA, United States of America
| | - Dmitry S. Kostyushev
- Division of Cardiology, University of California, San Francisco, San Francisco, CA, United States of America
| | - Timothy D. Henry
- The Carl and Edyth Lindner Center for Research and Education at The Christ Hospital, Cincinnati, OH, United States of America
| | - Jay H. Traverse
- Minneapolis Heart Institute Foundation, Minneapolis, MN, United States of America
| | - Lem Moyé
- University of Texas Health School of Public Health, Houston, TX, United States of America
| | - Robert D. Simari
- Kansas University Medical Center, Kansas City, KS, United States of America
| | - Doris A. Taylor
- Texas Heart Institute, Houston, TX, United States of America
| | - Matthew L. Springer
- Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, United States of America
- Division of Cardiology, University of California, San Francisco, San Francisco, CA, United States of America
- Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, United States of America
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8
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Konno A, Matsumoto N, Tomono Y, Okazaki S. Pathological application of carbocyanine dye-based multicolour imaging of vasculature and associated structures. Sci Rep 2020; 10:12613. [PMID: 32724051 PMCID: PMC7387484 DOI: 10.1038/s41598-020-69394-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Accepted: 07/09/2020] [Indexed: 12/28/2022] Open
Abstract
Simultaneous visualisation of vasculature and surrounding tissue structures is essential for a better understanding of vascular pathologies. In this work, we describe a histochemical strategy for three-dimensional, multicolour imaging of vasculature and associated structures, using a carbocyanine dye-based technique, vessel painting. We developed a series of applications to allow the combination of vessel painting with other histochemical methods, including immunostaining and tissue clearing for confocal and two-photon microscopies. We also introduced a two-photon microscopy setup that incorporates an aberration correction system to correct aberrations caused by the mismatch of refractive indices between samples and immersion mediums, for higher-quality images of intact tissue structures. Finally, we demonstrate the practical utility of our approach by visualising fine pathological alterations to the renal glomeruli of IgA nephropathy model mice in unprecedented detail. The technical advancements should enhance the versatility of vessel painting, offering rapid and cost-effective methods for vascular pathologies.
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Affiliation(s)
- Alu Konno
- Institute for Medical Photonics Research, Preeminent Medical Photonics Education and Research Center, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Naoya Matsumoto
- Central Research Laboratory, Hamamatsu Photonics K.K., Hamamatsu, Japan
| | - Yasuko Tomono
- Division of Molecular and Cell Biology, Shigei Medical Research Institute, Okayama, Japan
| | - Shigetoshi Okazaki
- Institute for Medical Photonics Research, Preeminent Medical Photonics Education and Research Center, Hamamatsu University School of Medicine, Hamamatsu, Japan.
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9
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Xu H, Pumiglia K, LaFlamme SE. Laminin-511 and α6 integrins regulate the expression of CXCR4 to promote endothelial morphogenesis. J Cell Sci 2020; 133:jcs246595. [PMID: 32409567 DOI: 10.1242/jcs.246595] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Accepted: 04/11/2020] [Indexed: 12/25/2022] Open
Abstract
During angiogenesis, endothelial cells engage components of the extracellular matrix through integrin-mediated adhesion. Endothelial expression of laminin-411 and laminin-511 is known to promote vessel stability. However, little is known about the contribution of these laminins to endothelial morphogenesis. We used two organotypic cell culture angiogenesis assays, in conjunction with RNAi approaches, to demonstrate that depletion of either the α4 chain of laminin-411 (LAMA4) or the α5 chain of laminin-511 (LAMA5) from endothelial cells inhibits sprouting and tube formation. Depletion of α6 (ITGA6) integrins resulted in similar phenotypes. Gene expression analysis indicated that loss of either laminin-511 or α6 integrins inhibited the expression of CXCR4, a gene previously associated with angiogenic endothelial cells. Pharmacological or RNAi-dependent inhibition of CXCR4 suppressed endothelial sprouting and morphogenesis. Importantly, expression of recombinant CXCR4 rescued endothelial morphogenesis when α6 integrin expression was inhibited. Additionally, the depletion of α6 integrins from established tubes resulted in the loss of tube integrity and laminin-511. Taken together, our results indicate that α6 integrins and laminin-511 can promote endothelial morphogenesis by regulating the expression of CXCR4 and suggest that the α6-dependent deposition of laminin-511 protects the integrity of established endothelial tubes.
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Affiliation(s)
- Hao Xu
- Department of Regenerative and Cancer Cell Biology, Albany Medical College, Albany NY 12208, USA
| | - Kevin Pumiglia
- Department of Regenerative and Cancer Cell Biology, Albany Medical College, Albany NY 12208, USA
| | - Susan E LaFlamme
- Department of Regenerative and Cancer Cell Biology, Albany Medical College, Albany NY 12208, USA
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10
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Xu J, Xiong Y, Li Q, Hu M, Huang P, Xu J, Tian X, Jin C, Liu J, Qian L, Yang Y. Optimization of Timing and Times for Administration of Atorvastatin-Pretreated Mesenchymal Stem Cells in a Preclinical Model of Acute Myocardial Infarction. Stem Cells Transl Med 2019; 8:1068-1083. [PMID: 31245934 PMCID: PMC6766601 DOI: 10.1002/sctm.19-0013] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2019] [Accepted: 05/25/2019] [Indexed: 12/14/2022] Open
Abstract
Our previous studies showed that the combination of atorvastatin (ATV) and single injection of ATV-pretreated mesenchymal stem cells (MSCs) (ATV -MSCs) at 1 week post-acute myocardial infarction (AMI) promoted MSC recruitment and survival. This study aimed to investigate whether the combinatorial therapy of intensive ATV with multiple injections of ATV -MSCs has greater efficacy at different stages to better define the optimal strategy for MSC therapy in AMI. In order to determine the optimal time window for MSC treatment, we first assessed stromal cell-derived factor-1 (SDF-1) dynamic expression and inflammation. Next, we compared MSC recruitment and differentiation, cardiac function, infarct size, and angiogenesis among animal groups with single, dual, and triple injections of ATV -MSCs at early (Early1, Early2, Early3), mid-term (Mid1, Mid2, Mid3), and late (Late1, Late2, Late3) stages. Compared with AMI control, intensive ATV significantly augmented SDF-1 expression 1.5∼2.6-fold in peri-infarcted region with inhibited inflammation. ATV -MSCs implantation with ATV administration further enhanced MSC recruitment rate by 3.9%∼24.0%, improved left ventricular ejection fraction (LVEF) by 2.0%∼16.2%, and reduced infarct size in all groups 6 weeks post-AMI with most prominent improvement in mid groups and still effective in late groups. Mechanistically, ATV -MSCs remarkably suppressed inflammation and apoptosis while increasing angiogenesis. Furthermore, triple injections of ATV -MSCs were much more effective than single administration during early and mid-term stages of AMI with the best effects in Mid3 group. We conclude that the optimal strategy is multiple injections of ATV -MSCs combined with intensive ATV administration at mid-term stage of AMI. The translational potential of this strategy is clinically promising. Stem Cells Translational Medicine 2019;8:1068-1083.
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Affiliation(s)
- Jun Xu
- State Key Laboratory of Cardiovascular DiseaseFuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingPeople's Republic of China
- McAllister Heart Institute, University of North Carolina at Chapel HillChapel HillNorth CarolinaUnited States
- Department of Pathology and Laboratory MedicineUniversity of North Carolina at Chapel HillChapel HillNorth CarolinaUnited States
| | - Yu‐Yan Xiong
- State Key Laboratory of Cardiovascular DiseaseFuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingPeople's Republic of China
| | - Qing Li
- State Key Laboratory of Cardiovascular DiseaseFuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingPeople's Republic of China
| | - Meng‐Jin Hu
- State Key Laboratory of Cardiovascular DiseaseFuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingPeople's Republic of China
| | - Pei‐Sen Huang
- State Key Laboratory of Cardiovascular DiseaseFuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingPeople's Republic of China
- McAllister Heart Institute, University of North Carolina at Chapel HillChapel HillNorth CarolinaUnited States
- Department of Pathology and Laboratory MedicineUniversity of North Carolina at Chapel HillChapel HillNorth CarolinaUnited States
| | - Jun‐Yan Xu
- State Key Laboratory of Cardiovascular DiseaseFuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingPeople's Republic of China
| | - Xia‐Qiu Tian
- State Key Laboratory of Cardiovascular DiseaseFuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingPeople's Republic of China
| | - Chen Jin
- State Key Laboratory of Cardiovascular DiseaseFuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingPeople's Republic of China
| | - Jian‐Dong Liu
- McAllister Heart Institute, University of North Carolina at Chapel HillChapel HillNorth CarolinaUnited States
- Department of Pathology and Laboratory MedicineUniversity of North Carolina at Chapel HillChapel HillNorth CarolinaUnited States
| | - Li Qian
- McAllister Heart Institute, University of North Carolina at Chapel HillChapel HillNorth CarolinaUnited States
- Department of Pathology and Laboratory MedicineUniversity of North Carolina at Chapel HillChapel HillNorth CarolinaUnited States
| | - Yue‐Jin Yang
- State Key Laboratory of Cardiovascular DiseaseFuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingPeople's Republic of China
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11
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Korf-Klingebiel M, Reboll MR, Grote K, Schleiner H, Wang Y, Wu X, Klede S, Mikhed Y, Bauersachs J, Klintschar M, Rudat C, Kispert A, Niessen HW, Lübke T, Dierks T, Wollert KC. Heparan Sulfate-Editing Extracellular Sulfatases Enhance VEGF Bioavailability for Ischemic Heart Repair. Circ Res 2019; 125:787-801. [PMID: 31434553 DOI: 10.1161/circresaha.119.315023] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
RATIONALE Mechanistic insight into the inflammatory response after acute myocardial infarction may inform new molecularly targeted treatment strategies to prevent chronic heart failure. OBJECTIVE We identified the sulfatase SULF2 in an in silico secretome analysis in bone marrow cells from patients with acute myocardial infarction and detected increased sulfatase activity in myocardial autopsy samples. SULF2 (Sulf2 in mice) and its isoform SULF1 (Sulf1) act as endosulfatases removing 6-O-sulfate groups from heparan sulfate (HS) in the extracellular space, thus eliminating docking sites for HS-binding proteins. We hypothesized that the Sulfs have a role in tissue repair after myocardial infarction. METHODS AND RESULTS Both Sulfs were dynamically upregulated after coronary artery ligation in mice, attaining peak expression and activity levels during the first week after injury. Sulf2 was expressed by monocytes and macrophages, Sulf1 by endothelial cells and fibroblasts. Infarct border zone capillarization was impaired, scar size increased, and cardiac dysfunction more pronounced in mice with a genetic deletion of either Sulf1 or Sulf2. Studies in bone marrow-chimeric Sulf-deficient mice and Sulf-deficient cardiac endothelial cells established that inflammatory cell-derived Sulf2 and endothelial cell-autonomous Sulf1 promote angiogenesis. Mechanistically, both Sulfs reduced HS sulfation in the infarcted myocardium, thereby diminishing Vegfa (vascular endothelial growth factor A) interaction with HS. Along this line, both Sulfs rendered infarcted mouse heart explants responsive to the angiogenic effects of HS-binding Vegfa164 but did not modulate the angiogenic effects of non-HS-binding Vegfa120. Treating wild-type mice systemically with the small molecule HS-antagonist surfen (bis-2-methyl-4-amino-quinolyl-6-carbamide, 1 mg/kg/day) for 7 days after myocardial infarction released Vegfa from HS, enhanced infarct border-zone capillarization, and exerted sustained beneficial effects on cardiac function and survival. CONCLUSIONS These findings establish HS-editing Sulfs as critical inducers of postinfarction angiogenesis and identify HS sulfation as a therapeutic target for ischemic tissue repair.
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Affiliation(s)
- Mortimer Korf-Klingebiel
- From the Division of Molecular and Translational Cardiology (M.K.-K., M.R.R., K.G., H.S., Y.W., X.W., S.K., Y.M., K.C.W.), Hannover Medical School, Germany.,Department of Cardiology and Angiology (M.K.-K., M.R.R., K.G., H.S., Y.W., X.W., S.K., Y.M., J.B., K.C.W.), Hannover Medical School, Germany
| | - Marc R Reboll
- From the Division of Molecular and Translational Cardiology (M.K.-K., M.R.R., K.G., H.S., Y.W., X.W., S.K., Y.M., K.C.W.), Hannover Medical School, Germany.,Department of Cardiology and Angiology (M.K.-K., M.R.R., K.G., H.S., Y.W., X.W., S.K., Y.M., J.B., K.C.W.), Hannover Medical School, Germany
| | - Karsten Grote
- From the Division of Molecular and Translational Cardiology (M.K.-K., M.R.R., K.G., H.S., Y.W., X.W., S.K., Y.M., K.C.W.), Hannover Medical School, Germany.,Department of Cardiology and Angiology (M.K.-K., M.R.R., K.G., H.S., Y.W., X.W., S.K., Y.M., J.B., K.C.W.), Hannover Medical School, Germany
| | - Hauke Schleiner
- From the Division of Molecular and Translational Cardiology (M.K.-K., M.R.R., K.G., H.S., Y.W., X.W., S.K., Y.M., K.C.W.), Hannover Medical School, Germany.,Department of Cardiology and Angiology (M.K.-K., M.R.R., K.G., H.S., Y.W., X.W., S.K., Y.M., J.B., K.C.W.), Hannover Medical School, Germany
| | - Yong Wang
- From the Division of Molecular and Translational Cardiology (M.K.-K., M.R.R., K.G., H.S., Y.W., X.W., S.K., Y.M., K.C.W.), Hannover Medical School, Germany.,Department of Cardiology and Angiology (M.K.-K., M.R.R., K.G., H.S., Y.W., X.W., S.K., Y.M., J.B., K.C.W.), Hannover Medical School, Germany
| | - Xuekun Wu
- From the Division of Molecular and Translational Cardiology (M.K.-K., M.R.R., K.G., H.S., Y.W., X.W., S.K., Y.M., K.C.W.), Hannover Medical School, Germany.,Department of Cardiology and Angiology (M.K.-K., M.R.R., K.G., H.S., Y.W., X.W., S.K., Y.M., J.B., K.C.W.), Hannover Medical School, Germany
| | - Stefanie Klede
- From the Division of Molecular and Translational Cardiology (M.K.-K., M.R.R., K.G., H.S., Y.W., X.W., S.K., Y.M., K.C.W.), Hannover Medical School, Germany.,Department of Cardiology and Angiology (M.K.-K., M.R.R., K.G., H.S., Y.W., X.W., S.K., Y.M., J.B., K.C.W.), Hannover Medical School, Germany
| | - Yuliya Mikhed
- From the Division of Molecular and Translational Cardiology (M.K.-K., M.R.R., K.G., H.S., Y.W., X.W., S.K., Y.M., K.C.W.), Hannover Medical School, Germany.,Department of Cardiology and Angiology (M.K.-K., M.R.R., K.G., H.S., Y.W., X.W., S.K., Y.M., J.B., K.C.W.), Hannover Medical School, Germany
| | - Johann Bauersachs
- Department of Cardiology and Angiology (M.K.-K., M.R.R., K.G., H.S., Y.W., X.W., S.K., Y.M., J.B., K.C.W.), Hannover Medical School, Germany
| | | | - Carsten Rudat
- Institute of Molecular Biology (C.R., A.K.), Hannover Medical School, Germany
| | - Andreas Kispert
- Institute of Molecular Biology (C.R., A.K.), Hannover Medical School, Germany
| | - Hans W Niessen
- Department of Pathology and Department of Cardiac Surgery, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands (H.W.N.)
| | - Torben Lübke
- Department of Chemistry, Biochemistry I, Bielefeld University, Germany (T.L., T.D.)
| | - Thomas Dierks
- Department of Chemistry, Biochemistry I, Bielefeld University, Germany (T.L., T.D.)
| | - Kai C Wollert
- From the Division of Molecular and Translational Cardiology (M.K.-K., M.R.R., K.G., H.S., Y.W., X.W., S.K., Y.M., K.C.W.), Hannover Medical School, Germany.,Department of Cardiology and Angiology (M.K.-K., M.R.R., K.G., H.S., Y.W., X.W., S.K., Y.M., J.B., K.C.W.), Hannover Medical School, Germany
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12
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Al-Rifai R, Nguyen P, Bouland N, Terryn C, Kanagaratnam L, Poitevin G, François C, Boisson-Vidal C, Sevestre MA, Tournois C. In vivo efficacy of endothelial growth medium stimulated mesenchymal stem cells derived from patients with critical limb ischemia. J Transl Med 2019; 17:261. [PMID: 31399109 PMCID: PMC6688282 DOI: 10.1186/s12967-019-2003-3] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2018] [Accepted: 07/27/2019] [Indexed: 12/24/2022] Open
Abstract
Background Cell therapy has been proposed for patients with critical limb ischemia (CLI). Autologous bone marrow derived cells (BMCs) have been mostly used, mesenchymal stem cells (MSCs) being an alternative. The aim of this study was to characterize two types of MSCs and evaluate their efficacy. Methods MSCs were obtained from CLI-patients BMCs. Stimulated- (S-) MSCs were cultured in endothelial growth medium. Cells were characterized by the expression of cell surface markers, the relative expression of 6 genes, the secretion of 10 cytokines and the ability to form vessel-like structures. The cell proangiogenic properties was analysed in vivo, in a hindlimb ischemia model. Perfusion of lower limbs and functional tests were assessed for 28 days after cell infusion. Muscle histological analysis (neoangiogenesis, arteriogenesis and muscle repair) was performed. Results S-MSCs can be obtained from CLI-patients BMCs. They do not express endothelial specific markers but can be distinguished from MSCs by their secretome. S-MSCs have the ability to form tube-like structures and, in vivo, to induce blood flow recovery. No amputation was observed in S-MSCs treated mice. Functional tests showed improvement in treated groups with a superiority of MSCs and S-MSCs. In muscles, CD31+ and αSMA+ labelling were the highest in S-MSCs treated mice. S-MSCs induced the highest muscle repair. Conclusions S-MSCs exert angiogenic potential probably mediated by a paracrine mechanism. Their administration is associated with flow recovery, limb salvage and muscle repair. The secretome from S-MSCs or secretome-derived products may have a strong potential in vessel regeneration and muscle repair. Trial registration NCT00533104 Electronic supplementary material The online version of this article (10.1186/s12967-019-2003-3) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Rida Al-Rifai
- EA-3801, SFR CAP-santé, Université de Reims Champagne-Ardenne, 51092, Reims Cedex, France
| | - Philippe Nguyen
- EA-3801, SFR CAP-santé, Université de Reims Champagne-Ardenne, 51092, Reims Cedex, France.,Laboratoire d'Hématologie, CHU Robert Debré, Reims, France
| | - Nicole Bouland
- Laboratoire d'Anatomie Pathologique, Université de Reims Champagne-Ardenne, Reims, France
| | - Christine Terryn
- Plateforme PICT, Université de Reims Champagne Ardenne, Reims, France
| | | | - Gaël Poitevin
- EA-3801, SFR CAP-santé, Université de Reims Champagne-Ardenne, 51092, Reims Cedex, France
| | - Caroline François
- EA-3801, SFR CAP-santé, Université de Reims Champagne-Ardenne, 51092, Reims Cedex, France
| | - Catherine Boisson-Vidal
- Inserm UMR S1140, Faculté de Pharmacie de Paris, Paris, France.,Université Paris Descartes, Sorbonne Paris Cité, Paris, France
| | | | - Claire Tournois
- EA-3801, SFR CAP-santé, Université de Reims Champagne-Ardenne, 51092, Reims Cedex, France. .,Laboratoire d'Hématologie, CHU Robert Debré, Reims, France.
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13
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Yagyu T, Yasuda S, Nagaya N, Doi K, Nakatani T, Satomi K, Shimizu W, Kusano K, Anzai T, Noguchi T, Ohgushi H, Kitamura S, Kangawa K, Ogawa H. Long-Term Results of Intracardiac Mesenchymal Stem Cell Transplantation in Patients With Cardiomyopathy. Circ J 2019; 83:1590-1599. [PMID: 31105128 DOI: 10.1253/circj.cj-18-1179] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
BACKGROUND Mesenchymal stem cells (MSCs), which have the potential to differentiate into cardiomyocytes or vascular endothelial cells, have been used clinically as therapy for cardiomyopathy. In this study, we aimed to evaluate the long-term follow-up results. METHODS AND RESULTS We studied 8 patients with symptomatic heart failure (HF) on guideline-directed therapy (ischemic cardiomyopathy, n=3; nonischemic cardiomyopathy, n=5) who underwent intracardiac MSC transplantation using a catheter-based injection method between May 2004 and April 2006. Major adverse events and hospitalizations were investigated up to 10 years afterward. Compared with baseline, there were no significant differences in B-type natriuretic peptide (BNP) (from 211 to 173 pg/mL), left ventricular ejection fraction (LVEF) (from 24% to 26%), and peak oxygen uptake (from 16.5 to 19.2 mL/min/kg) at 2 months. During the follow-up period, no patients experienced serious adverse events such as arrhythmias. Three patients died of pneumonia in the 1st year, liver cancer in the 6th year, and HF in the 7th year. Of the remaining 5 patients, 3 patients were hospitalized for exacerbated HF, 1 of whom required heart transplantation in the 2nd year; 2 patients survived for 10 years without worsening HF. CONCLUSIONS The results of this exploratory study of intracardiac MSCs administration suggest further research regarding the feasibility and efficacy is warranted.
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Affiliation(s)
- Takeshi Yagyu
- Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center
- Department of Cardiovascular Medicine, Kumamoto University Graduate School of Medical Sciences
| | - Satoshi Yasuda
- Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center
- Department of Cardiovascular Medicine, Kumamoto University Graduate School of Medical Sciences
| | | | - Kaori Doi
- Research Institute, National Cerebral and Cardiovascular Center
| | - Takeshi Nakatani
- Department of Transplantation, National Cerebral and Cardiovascular Center
| | - Kazuhiro Satomi
- Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center
- Department of Cardiology, Tokyo Medical University
| | - Wataru Shimizu
- Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center
- Department of Cardiovascular Medicine, Nippon Medical School
| | - Kengo Kusano
- Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center
| | - Toshihisa Anzai
- Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center
- Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine
| | - Teruo Noguchi
- Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center
| | - Hajime Ohgushi
- National Institute of Advanced Industrial Science and Technology
| | - Soichiro Kitamura
- Department of Transplantation, National Cerebral and Cardiovascular Center
| | - Kenji Kangawa
- Research Institute, National Cerebral and Cardiovascular Center
| | - Hisao Ogawa
- Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center
- Research Institute, National Cerebral and Cardiovascular Center
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14
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Inoue O, Takamura M. Insights From 10-Year Outcomes of Mesenchymal Stem Cell Transplantation in Heart Failure Patients. Circ J 2019; 83:1446-1448. [PMID: 31142705 DOI: 10.1253/circj.cj-19-0410] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Affiliation(s)
- Oto Inoue
- Department of Cardiology, Graduate School of Medical Science, Kanazawa University
| | - Masayuki Takamura
- Department of Cardiology, Graduate School of Medical Science, Kanazawa University
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15
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Genet G, Boyé K, Mathivet T, Ola R, Zhang F, Dubrac A, Li J, Genet N, Henrique Geraldo L, Benedetti L, Künzel S, Pibouin-Fragner L, Thomas JL, Eichmann A. Endophilin-A2 dependent VEGFR2 endocytosis promotes sprouting angiogenesis. Nat Commun 2019; 10:2350. [PMID: 31138815 PMCID: PMC6538628 DOI: 10.1038/s41467-019-10359-x] [Citation(s) in RCA: 58] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2018] [Accepted: 04/30/2019] [Indexed: 12/17/2022] Open
Abstract
Endothelial cell migration, proliferation and survival are triggered by VEGF-A activation of VEGFR2. However, how these cell behaviors are regulated individually is still unknown. Here we identify Endophilin-A2 (ENDOA2), a BAR-domain protein that orchestrates CLATHRIN-independent internalization, as a critical mediator of endothelial cell migration and sprouting angiogenesis. We show that EndoA2 knockout mice exhibit postnatal angiogenesis defects and impaired front-rear polarization of sprouting tip cells. ENDOA2 deficiency reduces VEGFR2 internalization and inhibits downstream activation of the signaling effector PAK but not ERK, thereby affecting front-rear polarity and migration but not proliferation or survival. Mechanistically, VEGFR2 is directed towards ENDOA2-mediated endocytosis by the SLIT2-ROBO pathway via SLIT-ROBO-GAP1 bridging of ENDOA2 and ROBO1. Blocking ENDOA2-mediated endothelial cell migration attenuates pathological angiogenesis in oxygen-induced retinopathy models. This work identifies a specific endocytic pathway controlling a subset of VEGFR2 mediated responses that could be targeted to prevent excessive sprouting angiogenesis in pathological conditions.
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Affiliation(s)
- Gael Genet
- Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, 06511, USA
| | - Kevin Boyé
- Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, 06511, USA
| | - Thomas Mathivet
- Inserm U970, Paris Cardiovascular Research Center, Paris, 75015, France
| | - Roxana Ola
- Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, 06511, USA
- Functional Genomics, Proteomics and Experimental Pathology Department, Prof. Dr. I. Chiricuta Oncology Institute, Cluj-Napoca, Romania, Department of Basic, Preventive and Clinical Science, University of Transylvania, Brasov, Romania
| | - Feng Zhang
- Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, 06511, USA
| | - Alexandre Dubrac
- Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, 06511, USA
| | - Jinyu Li
- Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, 06511, USA
| | - Nafiisha Genet
- Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, 06511, USA
| | | | - Lorena Benedetti
- Department of Neuroscience and Cell Biology, School of Medicine, Yale University School of Medicine, New Haven, CT, 06511, USA
| | - Steffen Künzel
- Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, 06511, USA
| | | | - Jean-Leon Thomas
- Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, 06511, USA
- Department of Neurology, Yale University School of Medicine, New Haven, CT, 06511, USA
- Sorbonne Universités, UPMC Université Paris 06, Institut National de la Santé et de la Recherche Médicale U1127, Centre National de la Recherche Scientifique, AP-HP, Institut du Cerveau et de la Moelle Epinière, Hôpital Pitié-Salpêtrière, Paris, France
| | - Anne Eichmann
- Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, 06511, USA.
- Inserm U970, Paris Cardiovascular Research Center, Paris, 75015, France.
- Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT, 06511, USA.
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16
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Corti F, Wang Y, Rhodes JM, Atri D, Archer-Hartmann S, Zhang J, Zhuang ZW, Chen D, Wang T, Wang Z, Azadi P, Simons M. N-terminal syndecan-2 domain selectively enhances 6-O heparan sulfate chains sulfation and promotes VEGFA 165-dependent neovascularization. Nat Commun 2019; 10:1562. [PMID: 30952866 PMCID: PMC6450910 DOI: 10.1038/s41467-019-09605-z] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2018] [Accepted: 03/19/2019] [Indexed: 01/26/2023] Open
Abstract
The proteoglycan Syndecan-2 (Sdc2) has been implicated in regulation of cytoskeleton organization, integrin signaling and developmental angiogenesis in zebrafish. Here we report that mice with global and inducible endothelial-specific deletion of Sdc2 display marked angiogenic and arteriogenic defects and impaired VEGFA165 signaling. No such abnormalities are observed in mice with deletion of the closely related Syndecan-4 (Sdc4) gene. These differences are due to a significantly higher 6-O sulfation level in Sdc2 versus Sdc4 heparan sulfate (HS) chains, leading to an increase in VEGFA165 binding sites and formation of a ternary Sdc2-VEGFA165-VEGFR2 complex which enhances VEGFR2 activation. The increased Sdc2 HS chains 6-O sulfation is driven by a specific N-terminal domain sequence; the insertion of this sequence in Sdc4 N-terminal domain increases 6-O sulfation of its HS chains and promotes Sdc2-VEGFA165-VEGFR2 complex formation. This demonstrates the existence of core protein-determined HS sulfation patterns that regulate specific biological activities.
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Affiliation(s)
- Federico Corti
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, 300 George Street, New Haven, CT, 06511, USA
| | - Yingdi Wang
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, 300 George Street, New Haven, CT, 06511, USA
| | - John M Rhodes
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, 300 George Street, New Haven, CT, 06511, USA
| | - Deepak Atri
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, 300 George Street, New Haven, CT, 06511, USA
| | - Stephanie Archer-Hartmann
- Complex Carbohydrate Research Center, The University of Georgia, 315 Riverbend Road, Athens, GA, 30602, USA
| | - Jiasheng Zhang
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, 300 George Street, New Haven, CT, 06511, USA
| | - Zhen W Zhuang
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, 300 George Street, New Haven, CT, 06511, USA
| | - Dongying Chen
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, 300 George Street, New Haven, CT, 06511, USA
| | - Tianyun Wang
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, 300 George Street, New Haven, CT, 06511, USA
| | - Zhirui Wang
- Complex Carbohydrate Research Center, The University of Georgia, 315 Riverbend Road, Athens, GA, 30602, USA
| | - Parastoo Azadi
- Complex Carbohydrate Research Center, The University of Georgia, 315 Riverbend Road, Athens, GA, 30602, USA
| | - Michael Simons
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, 300 George Street, New Haven, CT, 06511, USA.
- Department of Cell Biology, Yale University School of Medicine, New Haven, CT, 06520, USA.
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17
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Gremmels H, van Rhijn-Brouwer FCC, Papazova DA, Fledderus JO, Teraa M, Verhaar MC. Exhaustion of the bone marrow progenitor cell reserve is associated with major events in severe limb ischemia. Angiogenesis 2019; 22:411-420. [PMID: 30929097 PMCID: PMC6652783 DOI: 10.1007/s10456-019-09666-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2018] [Accepted: 02/25/2019] [Indexed: 12/25/2022]
Abstract
Lower numbers of progenitor cells (PCs) in peripheral blood (PB) have been associated with cardiovascular events in high-risk populations. Therapies aiming to increase the numbers of PCs in circulation have been developed, but clinical trials did not result in better outcomes. It is currently unknown what causes the reduction in PB PC numbers: whether it is primary depletion of the progenitor cell reserve, or a reduced mobilization of PCs from the bone marrow (BM). In this study, we examine if PB and BM PC numbers predict Amputation-Free Survival (AFS) in patients with Severe Limb Ischemia (SLI). We obtained PB and BM from 160 patients enrolled in a clinical trial investigating BM cell therapy for SLI. Samples were incubated with antibodies against CD34, KDR, CD133, CD184, CD14, CD105, CD140b, and CD31; PC populations were enumerated by flow cytometry. Higher PB CD34+ and CD133+ PC numbers were related to AFS (Both Hazard Ratio [HRevent] = 0.56, p = 0.003 and p = 0.0007, respectively). AFS was not associated with the other cell populations in PB. BM PC numbers correlated with PB PC numbers and showed similar HRs for AFS. A further subdivision based on relative BM and PB PC numbers showed that BM PC numbers, rather than mobilization, associated with AFS. Both PB and BM PC numbers are associated with AFS independently from traditional risk factor and show very similar risk profiles. Our data suggest that depletion of the progenitor cell reserve, rather than decreased PC mobilization, underlies the association between PB PC numbers and cardiovascular risk.
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Affiliation(s)
- Hendrik Gremmels
- Department of Nephrology and Hypertension, University Medical Center Utrecht, Postal Box 85500, 3508 GA, Utrecht, The Netherlands
| | - Femke C C van Rhijn-Brouwer
- Department of Nephrology and Hypertension, University Medical Center Utrecht, Postal Box 85500, 3508 GA, Utrecht, The Netherlands
| | - Diana A Papazova
- Department of Nephrology and Hypertension, University Medical Center Utrecht, Postal Box 85500, 3508 GA, Utrecht, The Netherlands
| | - Joost O Fledderus
- Department of Nephrology and Hypertension, University Medical Center Utrecht, Postal Box 85500, 3508 GA, Utrecht, The Netherlands
| | - Martin Teraa
- Department of Surgery, University Medical Center Utrecht, Utrecht, The Netherlands
- Department of Vascular Surgery, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Marianne C Verhaar
- Department of Nephrology and Hypertension, University Medical Center Utrecht, Postal Box 85500, 3508 GA, Utrecht, The Netherlands.
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18
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Functionally Improved Mesenchymal Stem Cells to Better Treat Myocardial Infarction. Stem Cells Int 2018; 2018:7045245. [PMID: 30622568 PMCID: PMC6286742 DOI: 10.1155/2018/7045245] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2018] [Revised: 09/10/2018] [Accepted: 09/30/2018] [Indexed: 12/14/2022] Open
Abstract
Myocardial infarction (MI) is one of the leading causes of death worldwide. Mesenchymal stem cell (MSC) transplantation is considered a promising approach and has made significant progress in preclinical studies and clinical trials for treating MI. However, hurdles including poor survival, retention, homing, and differentiation capacity largely limit the therapeutic effect of transplanted MSCs. Many strategies such as preconditioning, genetic modification, cotransplantation with bioactive factors, and tissue engineering were developed to improve the survival and function of MSCs. On the other hand, optimizing the hostile transplantation microenvironment of the host myocardium is also of importance. Here, we review the modifications of MSCs as well as the host myocardium to improve the efficacy of MSC-based therapy against MI.
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19
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Sundaram S, Sellamuthu K, Nagavelu K, Suma HR, Das A, Narayan R, Chakravortty D, Gopalan J, Eswarappa SM. Stimulation of angiogenesis using single-pulse low-pressure shock wave treatment. J Mol Med (Berl) 2018; 96:1177-1187. [PMID: 30155768 DOI: 10.1007/s00109-018-1690-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2018] [Revised: 08/08/2018] [Accepted: 08/22/2018] [Indexed: 01/19/2023]
Abstract
Endothelial cells respond to mechanical stimuli such as stretch. This property can be exploited with caution to induce angiogenesis which will have immense potential to treat pathological conditions associated with insufficient angiogenesis. The primary aim of this study is to test if low-pressure shock waves can be used to induce angiogenesis. Using a simple diaphragm-based shock tube, we demonstrate that a single pulse of low pressure (0.4 bar) shock wave is enough to induce proliferation in bovine aortic endothelial cells and human pulmonary microvascular endothelial cells. We show that this is associated with enhanced Ca++ influx and phosphorylation of phosphatidylinositol-3-kinase (PI3K) which is normally observed when endothelial cells are exposed to stretch. We also demonstrate the pro-angiogenic effect of shock waves of single pulse (per dose) using murine back punch wound model. Shock wave treated mice showed enhanced wound-induced angiogenesis as reflected by increased vascular area and vessel length. They also showed accelerated wound closure compared to control mice. Overall, our study shows that just a single pulse/shot (per dose) of shock waves can be used to induce angiogenesis. Importantly, we demonstrate this effect using a pulse of low-pressure shock waves (0.4 bar, in vitro and 0.15 bar, in vivo). KEY MESSAGES: Low-pressure single-pulse shock waves can induce endothelial cell migration and proliferation. This effect is endothelial cell specific. These shock waves enhance wound-induced angiogenesis in vivo. These shock waves can also accelerate wound healing in vivo.
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Affiliation(s)
- Susinder Sundaram
- Department of Biochemistry, Indian Institute of Science, Bengaluru, India
| | - Karthi Sellamuthu
- Department of Biochemistry, Indian Institute of Science, Bengaluru, India
| | | | - Harikumar R Suma
- Department of Biochemistry, Indian Institute of Science, Bengaluru, India
| | - Arpan Das
- Department of Biochemistry, Indian Institute of Science, Bengaluru, India
| | - Raghu Narayan
- Department of Aerospace Engineering, Indian Institute of Science, Bengaluru, India
| | - Dipshikha Chakravortty
- Department of Microbiology and Cell Biology, Indian Institute of Science, Bengaluru, India
| | - Jagadeesh Gopalan
- Department of Aerospace Engineering, Indian Institute of Science, Bengaluru, India.
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20
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Affiliation(s)
- Peter V. Johnston
- From the Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD (P.V.J.)
| | | | - Amish N. Raval
- Division of Cardiovascular Medicine, University of Wisconsin School of Medicine and Public Health, Madison (A.N.R.)
| | - Thomas D. Cook
- Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison (T.D.C.)
| | - Carl J. Pepine
- Division of Cardiovascular Medicine, University of Florida, Gainesville (C.J.P.)
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21
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Zwetsloot PP, Gremmels H, Assmus B, Koudstaal S, Sluijter JPG, Zeiher AM, Chamuleau SAJ. Responder Definition in Clinical Stem Cell Trials in Cardiology: Will the Real Responder Please Stand Up? Circ Res 2018; 119:514-8. [PMID: 27492842 DOI: 10.1161/circresaha.116.308733] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Affiliation(s)
- Peter Paul Zwetsloot
- From the Experimental Cardiology Laboratory, Department of Cardiology (P.P.Z., S.K., J.P.G.S., S.A.J.C.), Department of Nephrology and Hypertension (H.G., A.M.Z.), and UMC Utrecht Regenerative Medicine Center (J.P.G.S., S.A.J.C.), University Medical Center Utrecht, Utrecht, The Netherlands; Division of Cardiology, Department of Medicine III, Goethe University Frankfurt, Frankfurt, Germany (B.A.); and Netherlands Heart Institute (ICIN), Utrecht, The Netherlands (J.P.G.S., S.A.J.C.).
| | - Hendrik Gremmels
- From the Experimental Cardiology Laboratory, Department of Cardiology (P.P.Z., S.K., J.P.G.S., S.A.J.C.), Department of Nephrology and Hypertension (H.G., A.M.Z.), and UMC Utrecht Regenerative Medicine Center (J.P.G.S., S.A.J.C.), University Medical Center Utrecht, Utrecht, The Netherlands; Division of Cardiology, Department of Medicine III, Goethe University Frankfurt, Frankfurt, Germany (B.A.); and Netherlands Heart Institute (ICIN), Utrecht, The Netherlands (J.P.G.S., S.A.J.C.)
| | - Birgit Assmus
- From the Experimental Cardiology Laboratory, Department of Cardiology (P.P.Z., S.K., J.P.G.S., S.A.J.C.), Department of Nephrology and Hypertension (H.G., A.M.Z.), and UMC Utrecht Regenerative Medicine Center (J.P.G.S., S.A.J.C.), University Medical Center Utrecht, Utrecht, The Netherlands; Division of Cardiology, Department of Medicine III, Goethe University Frankfurt, Frankfurt, Germany (B.A.); and Netherlands Heart Institute (ICIN), Utrecht, The Netherlands (J.P.G.S., S.A.J.C.)
| | - Stefan Koudstaal
- From the Experimental Cardiology Laboratory, Department of Cardiology (P.P.Z., S.K., J.P.G.S., S.A.J.C.), Department of Nephrology and Hypertension (H.G., A.M.Z.), and UMC Utrecht Regenerative Medicine Center (J.P.G.S., S.A.J.C.), University Medical Center Utrecht, Utrecht, The Netherlands; Division of Cardiology, Department of Medicine III, Goethe University Frankfurt, Frankfurt, Germany (B.A.); and Netherlands Heart Institute (ICIN), Utrecht, The Netherlands (J.P.G.S., S.A.J.C.)
| | - Joost P G Sluijter
- From the Experimental Cardiology Laboratory, Department of Cardiology (P.P.Z., S.K., J.P.G.S., S.A.J.C.), Department of Nephrology and Hypertension (H.G., A.M.Z.), and UMC Utrecht Regenerative Medicine Center (J.P.G.S., S.A.J.C.), University Medical Center Utrecht, Utrecht, The Netherlands; Division of Cardiology, Department of Medicine III, Goethe University Frankfurt, Frankfurt, Germany (B.A.); and Netherlands Heart Institute (ICIN), Utrecht, The Netherlands (J.P.G.S., S.A.J.C.)
| | - Andreas M Zeiher
- From the Experimental Cardiology Laboratory, Department of Cardiology (P.P.Z., S.K., J.P.G.S., S.A.J.C.), Department of Nephrology and Hypertension (H.G., A.M.Z.), and UMC Utrecht Regenerative Medicine Center (J.P.G.S., S.A.J.C.), University Medical Center Utrecht, Utrecht, The Netherlands; Division of Cardiology, Department of Medicine III, Goethe University Frankfurt, Frankfurt, Germany (B.A.); and Netherlands Heart Institute (ICIN), Utrecht, The Netherlands (J.P.G.S., S.A.J.C.)
| | - Steven A J Chamuleau
- From the Experimental Cardiology Laboratory, Department of Cardiology (P.P.Z., S.K., J.P.G.S., S.A.J.C.), Department of Nephrology and Hypertension (H.G., A.M.Z.), and UMC Utrecht Regenerative Medicine Center (J.P.G.S., S.A.J.C.), University Medical Center Utrecht, Utrecht, The Netherlands; Division of Cardiology, Department of Medicine III, Goethe University Frankfurt, Frankfurt, Germany (B.A.); and Netherlands Heart Institute (ICIN), Utrecht, The Netherlands (J.P.G.S., S.A.J.C.)
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22
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Bassetti B, Capogrossi MC, Pompilio G. Power Is Nothing Without Control: The Enduring Search for the Best Cell in Cardiac Cell Therapy at a Crossroads. Circ Res 2018; 119:988-991. [PMID: 27737943 DOI: 10.1161/circresaha.116.309619] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
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23
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An S, Wang X, Ruck MA, Rodriguez HJ, Kostyushev DS, Varga M, Luu E, Derakhshandeh R, Suchkov SV, Kogan SC, Hermiston ML, Springer ML. Age-Related Impaired Efficacy of Bone Marrow Cell Therapy for Myocardial Infarction Reflects a Decrease in B Lymphocytes. Mol Ther 2018; 26:1685-1693. [PMID: 29914756 DOI: 10.1016/j.ymthe.2018.05.015] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2018] [Revised: 05/17/2018] [Accepted: 05/18/2018] [Indexed: 12/19/2022] Open
Abstract
Treatment of myocardial infarction (MI) with bone marrow cells (BMCs) improves post-MI cardiac function in rodents. However, clinical trials of BMC therapy have been less effective. While most rodent experiments use young healthy donors, patients undergoing autologous cell therapy are older and post-MI. We previously demonstrated that BMCs from aged and post-MI donor mice are therapeutically impaired, and that donor MI induces inflammatory changes in BMC composition including reduced levels of B lymphocytes. Here, we hypothesized that B cell alterations in bone marrow account for the reduced therapeutic potential of post-MI and aged donor BMCs. Injection of BMCs from increasingly aged donor mice resulted in progressively poorer cardiac function and larger infarct size. Flow cytometry revealed fewer B cells in aged donor bone marrow. Therapeutic efficacy of young healthy donor BMCs was reduced by depletion of B cells. Implantation of intact or lysed B cells improved cardiac function, whereas intact or lysed T cells provided only minor benefit. We conclude that B cells play an important paracrine role in effective BMC therapy for MI. Reduction of bone marrow B cells because of age or MI may partially explain why clinical autologous cell therapy has not matched the success of rodent experiments.
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Affiliation(s)
- Songtao An
- Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143, USA; Division of Cardiology, Henan Provincial People's Hospital, Zhengzhou University, Zhengzhou, Henan 450003, China
| | - Xiaoyin Wang
- Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Melissa A Ruck
- Department of Pediatrics, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Hilda J Rodriguez
- Division of Cardiology, University of California, San Francisco, San Francisco, CA 94143, USA; Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Dmitry S Kostyushev
- Division of Cardiology, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Monika Varga
- Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Emmy Luu
- Division of Cardiology, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Ronak Derakhshandeh
- Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Sergey V Suchkov
- Center for Personalized Medicine, Sechenov University, Moscow, Russia; Department for Translational Medicine, Moscow Engineering Physical Institute, Moscow, Russia
| | - Scott C Kogan
- Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Michelle L Hermiston
- Department of Pediatrics, University of California, San Francisco, San Francisco, CA 94143, USA; Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Matthew L Springer
- Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143, USA; Division of Cardiology, University of California, San Francisco, San Francisco, CA 94143, USA; Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA.
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24
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Grimaldi V, Zullo A, Donatelli F, Mancini FP, Cacciatore F, Napoli C. Potential clinical benefits of cell therapy in coronary heart disease: an update. J Thorac Dis 2018; 10:S2412-S2422. [PMID: 30123579 DOI: 10.21037/jtd.2018.04.149] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Cell therapy is a central issue of regenerative medicine and is raising a growing interest in the scientific community, but its full therapeutic potential in coronary heart disease (CHD) has not been reached yet. Several different methods, cell types, delivery routes, and supporting techniques have been attempted and improved to elicit cardiac regeneration in CHD, but only some of them showed a really convincing potential for the use in clinical practice. Here we provide an update on approaches and clinical trials of cell therapy applied to CHD, which are ongoing or that have been realized in the last 5 years. Moreover, we discuss the evidence collected so far in favor or against the validity of stem cell therapy for CHD. In particular, we review and comment the recent advances in cell therapy applied to CHD, the most promising cell types, delivery strategies, biochemical and engineering techniques that have been adopted in this context.
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Affiliation(s)
- Vincenzo Grimaldi
- U.O.C. Division of Immunohematology, Transfusion Medicine and Transplant Immunology, Department of Internal Medicine and Specialistics, Azienda Ospedaliera Universitaria, University of Campania "Luigi Vanvitelli", Naples, Italy.,Department of Sciences and Technologies, University of Sannio, Benevento, Italy
| | - Alberto Zullo
- Department of Sciences and Technologies, University of Sannio, Benevento, Italy.,CEINGE-Advanced Biotechnologies, Naples, Italy
| | - Francesco Donatelli
- Department of Clinical and Community Sciences University of Milan, Milan, Italy.,Department of Cardiac Surgery, Ospedale Monaldi, Azienda dei Colli, 80131 Naples, Italy
| | | | - Francesco Cacciatore
- Department of Clinical and Community Sciences University of Milan, Milan, Italy.,Department of Cardiac Surgery, Ospedale Monaldi, Azienda dei Colli, 80131 Naples, Italy.,Department of Translational Medical Sciences, "Federico II" University of Naples, 80131 Naples, Italy.,Fondazione Salvatore Maugeri, IRCCS, Telese Terme, Benevento, Italy
| | - Claudio Napoli
- U.O.C. Division of Immunohematology, Transfusion Medicine and Transplant Immunology, Department of Internal Medicine and Specialistics, Azienda Ospedaliera Universitaria, University of Campania "Luigi Vanvitelli", Naples, Italy.,Institute of Diagnostic and Nuclear Development (SDN), IRCCS, Naples, Italy
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25
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Wu R, Hu X, Wang J. Concise Review: Optimized Strategies for Stem Cell-Based Therapy in Myocardial Repair: Clinical Translatability and Potential Limitation. Stem Cells 2018; 36:482-500. [PMID: 29330880 DOI: 10.1002/stem.2778] [Citation(s) in RCA: 58] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2017] [Revised: 12/28/2017] [Accepted: 12/31/2017] [Indexed: 12/15/2022]
Abstract
Ischemic heart diseases (IHDs) remain major public health problems with high rates of morbidity and mortality worldwide. Despite significant advances, current therapeutic approaches are unable to rescue the extensive and irreversible loss of cardiomyocytes caused by severe ischemia. Over the past 16 years, stem cell-based therapy has been recognized as an innovative strategy for cardiac repair/regeneration and functional recovery after IHDs. Although substantial preclinical animal studies using a variety of stem/progenitor cells have shown promising results, there is a tremendous degree of skepticism in the clinical community as many stem cell trials do not confer any beneficial effects. How to accelerate stem cell-based therapy toward successful clinical application attracts considerate attention. However, many important issues need to be fully addressed. In this Review, we have described and compared the effects of different types of stem cells with their dose, delivery routes, and timing that have been routinely tested in recent preclinical and clinical findings. We have also discussed the potential mechanisms of action of stem cells, and explored the role and underlying regulatory components of stem cell-derived secretomes/exosomes in myocardial repair. Furthermore, we have critically reviewed the different strategies for optimizing both donor stem cells and the target cardiac microenvironments to enhance the engraftment and efficacy of stem cells, highlighting their clinical translatability and potential limitation. Stem Cells 2018;36:482-500.
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Affiliation(s)
- Rongrong Wu
- Department of Cardiology, Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People's Republic of China.,Cardiovascular Key Laboratory of Zhejiang Province, Hangzhou, People's Republic of China
| | - Xinyang Hu
- Department of Cardiology, Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People's Republic of China.,Cardiovascular Key Laboratory of Zhejiang Province, Hangzhou, People's Republic of China
| | - Jian'an Wang
- Department of Cardiology, Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People's Republic of China.,Cardiovascular Key Laboratory of Zhejiang Province, Hangzhou, People's Republic of China
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26
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Dorobantu M, Popa-Fotea NM, Popa M, Rusu I, Micheu MM. Pursuing meaningful end-points for stem cell therapy assessment in ischemic cardiac disease. World J Stem Cells 2017; 9:203-218. [PMID: 29321822 PMCID: PMC5746641 DOI: 10.4252/wjsc.v9.i12.203] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2017] [Revised: 11/08/2017] [Accepted: 11/27/2017] [Indexed: 02/06/2023] Open
Abstract
Despite optimal interventional and medical therapy, ischemic heart disease is still an important cause of morbidity and mortality worldwide. Although not included in standard of care rehabilitation, stem cell therapy (SCT) could be a solution for prompting cardiac regeneration. Multiple studies have been published from the beginning of SCT until now, but overall no unanimous conclusion could be drawn in part due to the lack of appropriate end-points. In order to appreciate the impact of SCT, multiple markers from different categories should be considered: Structural, biological, functional, physiological, but also major adverse cardiac events or quality of life. Imaging end-points are among the most used - especially left ventricle ejection fraction (LVEF) measured through different methods. Other imaging parameters are infarct size, myocardial viability and perfusion. The impact of SCT on all of the aforementioned end-points is controversial and debatable. 2D-echocardiography is widely exploited, but new approaches such as tissue Doppler, strain/strain rate or 3D-echocardiography are more accurate, especially since the latter one is comparable with the MRI gold standard estimation of LVEF. Apart from the objective parameters, there are also patient-centered evaluations to reveal the benefits of SCT, such as quality of life and performance status, the most valuable from the patient point of view. Emerging parameters investigating molecular pathways such as non-coding RNAs or inflammation cytokines have a high potential as prognostic factors. Due to the disadvantages of current techniques, new imaging methods with labelled cells tracked along their lifetime seem promising, but until now only pre-clinical trials have been conducted in humans. Overall, SCT is characterized by high heterogeneity not only in preparation, administration and type of cells, but also in quantification of therapy effects.
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Affiliation(s)
- Maria Dorobantu
- Department of Cardiology, Clinical Emergency Hospital of Bucharest, Bucharest 014461, Romania
| | | | - Mihaela Popa
- Carol Davila, University of Medicine, "Carol Davila" University of Medicine and Pharmacy Bucharest, Bucharest 020022, Romania
| | - Iulia Rusu
- Carol Davila, University of Medicine, "Carol Davila" University of Medicine and Pharmacy Bucharest, Bucharest 020022, Romania
| | - Miruna Mihaela Micheu
- Department of Cardiology, Clinical Emergency Hospital of Bucharest, Bucharest 014461, Romania.
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27
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A Novel Technique for Accelerated Culture of Murine Mesenchymal Stem Cells that Allows for Sustained Multipotency. Sci Rep 2017; 7:13334. [PMID: 29042571 PMCID: PMC5645326 DOI: 10.1038/s41598-017-13477-y] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2017] [Accepted: 09/25/2017] [Indexed: 12/15/2022] Open
Abstract
Bone marrow derived mesenchymal stem cells (MSCs) are regularly utilized for translational therapeutic strategies including cell therapy, tissue engineering, and regenerative medicine and are frequently used in preclinical mouse models for both mechanistic studies and screening of new cell based therapies. Current methods to culture murine MSCs (mMSCs) select for rapidly dividing colonies and require long-term expansion. These methods thus require months of culture to generate sufficient cell numbers for feasibility studies in a lab setting and the cell populations often have reduced proliferation and differentiation potential, or have become immortalized cells. Here we describe a simple and reproducible method to generate mMSCs by utilizing hypoxia and basic fibroblast growth factor supplementation. Cells produced using these conditions were generated 2.8 times faster than under traditional methods and the mMSCs showed decreased senescence and maintained their multipotency and differentiation potential until passage 11 and beyond. Our method for mMSC isolation and expansion will significantly improve the utility of this critical cell source in pre-clinical studies for the investigation of MSC mechanisms, therapies, and cell manufacturing strategies.
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28
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Reboll MR, Korf-Klingebiel M, Klede S, Polten F, Brinkmann E, Reimann I, Schönfeld HJ, Bobadilla M, Faix J, Kensah G, Gruh I, Klintschar M, Gaestel M, Niessen HW, Pich A, Bauersachs J, Gogos JA, Wang Y, Wollert KC. EMC10 (Endoplasmic Reticulum Membrane Protein Complex Subunit 10) Is a Bone Marrow-Derived Angiogenic Growth Factor Promoting Tissue Repair After Myocardial Infarction. Circulation 2017; 136:1809-1823. [PMID: 28931551 DOI: 10.1161/circulationaha.117.029980] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2017] [Accepted: 08/31/2017] [Indexed: 01/05/2023]
Abstract
BACKGROUND Clinical trials of bone marrow cell-based therapies after acute myocardial infarction (MI) have produced mostly neutral results. Treatment with specific bone marrow cell-derived secreted proteins may provide an alternative biological approach to improving tissue repair and heart function after MI. We recently performed a bioinformatic secretome analysis in bone marrow cells from patients with acute MI and discovered a poorly characterized secreted protein, EMC10 (endoplasmic reticulum membrane protein complex subunit 10), showing activity in an angiogenic screen. METHODS We investigated the angiogenic potential of EMC10 and its mouse homolog (Emc10) in cultured endothelial cells and infarcted heart explants. We defined the cellular sources and function of Emc10 after MI using wild-type, Emc10-deficient, and Emc10 bone marrow-chimeric mice subjected to transient coronary artery ligation. Furthermore, we explored the therapeutic potential of recombinant Emc10 delivered by osmotic minipumps after MI in heart failure-prone FVB/N mice. RESULTS Emc10 signaled through small GTPases, p21-activated kinase, and the p38 mitogen-activated protein kinase (MAPK)-MAPK-activated protein kinase 2 (MK2) pathway to promote actin polymerization and endothelial cell migration. Confirming the importance of these signaling events in the context of acute MI, Emc10 stimulated endothelial cell outgrowth from infarcted mouse heart explants via p38 MAPK-MK2. Emc10 protein abundance was increased in the infarcted region of the left ventricle and in the circulation of wild-type mice after MI. Emc10 expression was also increased in left ventricular tissue samples from patients with acute MI. Bone marrow-derived monocytes and macrophages were the predominant sources of Emc10 in the infarcted murine heart. Emc10 KO mice showed no cardiovascular phenotype at baseline. After MI, however, capillarization of the infarct border zone was impaired in KO mice, and the animals developed larger infarct scars and more pronounced left ventricular remodeling compared with wild-type mice. Transplanting KO mice with wild-type bone marrow cells rescued the angiogenic defect and ameliorated left ventricular remodeling. Treating FVB/N mice with recombinant Emc10 enhanced infarct border-zone capillarization and exerted a sustained beneficial effect on left ventricular remodeling. CONCLUSIONS We have identified Emc10 as a previously unknown angiogenic growth factor that is produced by bone marrow-derived monocytes and macrophages as part of an endogenous adaptive response that can be enhanced therapeutically to repair the heart after MI.
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Affiliation(s)
- Marc R Reboll
- From Division of Molecular and Translational Cardiology, Department of Cardiology and Angiology (M.R.R., M.K.-K., S.K., E.B., I.R., Y.W., K.C.W.), Core Unit Proteomics, Institute of Toxicology (F.P., A.P.), Department of Biophysical Chemistry (J.F.), Leibniz Research Laboratories for Biotechnology and Artificial Organs, Department of Cardiothoracic, Transplantation, and Vascular Surgery (G.K., I.G.), Institute of Legal Medicine (M.K.), Institute of Physiological Chemistry (M.G.), and Department of Cardiology and Angiology (J.B.), Hannover Medical School, Germany; F. Hoffmann-La Roche, Pharma Research and Early Development, Basel, Switzerland (H.-J.S., M.B.); Department of Pathology and Department of Cardiac Surgery, Institute for Cardiovascular Research, Vrije Universiteit University Medical Center, Amsterdam, The Netherlands (H.W.N.); and Department of Physiology and Cellular Biophysics and Department of Neuroscience, College of Physicians and Surgeons, Columbia University, New York, NY (J.A.G.)
| | - Mortimer Korf-Klingebiel
- From Division of Molecular and Translational Cardiology, Department of Cardiology and Angiology (M.R.R., M.K.-K., S.K., E.B., I.R., Y.W., K.C.W.), Core Unit Proteomics, Institute of Toxicology (F.P., A.P.), Department of Biophysical Chemistry (J.F.), Leibniz Research Laboratories for Biotechnology and Artificial Organs, Department of Cardiothoracic, Transplantation, and Vascular Surgery (G.K., I.G.), Institute of Legal Medicine (M.K.), Institute of Physiological Chemistry (M.G.), and Department of Cardiology and Angiology (J.B.), Hannover Medical School, Germany; F. Hoffmann-La Roche, Pharma Research and Early Development, Basel, Switzerland (H.-J.S., M.B.); Department of Pathology and Department of Cardiac Surgery, Institute for Cardiovascular Research, Vrije Universiteit University Medical Center, Amsterdam, The Netherlands (H.W.N.); and Department of Physiology and Cellular Biophysics and Department of Neuroscience, College of Physicians and Surgeons, Columbia University, New York, NY (J.A.G.)
| | - Stefanie Klede
- From Division of Molecular and Translational Cardiology, Department of Cardiology and Angiology (M.R.R., M.K.-K., S.K., E.B., I.R., Y.W., K.C.W.), Core Unit Proteomics, Institute of Toxicology (F.P., A.P.), Department of Biophysical Chemistry (J.F.), Leibniz Research Laboratories for Biotechnology and Artificial Organs, Department of Cardiothoracic, Transplantation, and Vascular Surgery (G.K., I.G.), Institute of Legal Medicine (M.K.), Institute of Physiological Chemistry (M.G.), and Department of Cardiology and Angiology (J.B.), Hannover Medical School, Germany; F. Hoffmann-La Roche, Pharma Research and Early Development, Basel, Switzerland (H.-J.S., M.B.); Department of Pathology and Department of Cardiac Surgery, Institute for Cardiovascular Research, Vrije Universiteit University Medical Center, Amsterdam, The Netherlands (H.W.N.); and Department of Physiology and Cellular Biophysics and Department of Neuroscience, College of Physicians and Surgeons, Columbia University, New York, NY (J.A.G.)
| | - Felix Polten
- From Division of Molecular and Translational Cardiology, Department of Cardiology and Angiology (M.R.R., M.K.-K., S.K., E.B., I.R., Y.W., K.C.W.), Core Unit Proteomics, Institute of Toxicology (F.P., A.P.), Department of Biophysical Chemistry (J.F.), Leibniz Research Laboratories for Biotechnology and Artificial Organs, Department of Cardiothoracic, Transplantation, and Vascular Surgery (G.K., I.G.), Institute of Legal Medicine (M.K.), Institute of Physiological Chemistry (M.G.), and Department of Cardiology and Angiology (J.B.), Hannover Medical School, Germany; F. Hoffmann-La Roche, Pharma Research and Early Development, Basel, Switzerland (H.-J.S., M.B.); Department of Pathology and Department of Cardiac Surgery, Institute for Cardiovascular Research, Vrije Universiteit University Medical Center, Amsterdam, The Netherlands (H.W.N.); and Department of Physiology and Cellular Biophysics and Department of Neuroscience, College of Physicians and Surgeons, Columbia University, New York, NY (J.A.G.)
| | - Eva Brinkmann
- From Division of Molecular and Translational Cardiology, Department of Cardiology and Angiology (M.R.R., M.K.-K., S.K., E.B., I.R., Y.W., K.C.W.), Core Unit Proteomics, Institute of Toxicology (F.P., A.P.), Department of Biophysical Chemistry (J.F.), Leibniz Research Laboratories for Biotechnology and Artificial Organs, Department of Cardiothoracic, Transplantation, and Vascular Surgery (G.K., I.G.), Institute of Legal Medicine (M.K.), Institute of Physiological Chemistry (M.G.), and Department of Cardiology and Angiology (J.B.), Hannover Medical School, Germany; F. Hoffmann-La Roche, Pharma Research and Early Development, Basel, Switzerland (H.-J.S., M.B.); Department of Pathology and Department of Cardiac Surgery, Institute for Cardiovascular Research, Vrije Universiteit University Medical Center, Amsterdam, The Netherlands (H.W.N.); and Department of Physiology and Cellular Biophysics and Department of Neuroscience, College of Physicians and Surgeons, Columbia University, New York, NY (J.A.G.)
| | - Ines Reimann
- From Division of Molecular and Translational Cardiology, Department of Cardiology and Angiology (M.R.R., M.K.-K., S.K., E.B., I.R., Y.W., K.C.W.), Core Unit Proteomics, Institute of Toxicology (F.P., A.P.), Department of Biophysical Chemistry (J.F.), Leibniz Research Laboratories for Biotechnology and Artificial Organs, Department of Cardiothoracic, Transplantation, and Vascular Surgery (G.K., I.G.), Institute of Legal Medicine (M.K.), Institute of Physiological Chemistry (M.G.), and Department of Cardiology and Angiology (J.B.), Hannover Medical School, Germany; F. Hoffmann-La Roche, Pharma Research and Early Development, Basel, Switzerland (H.-J.S., M.B.); Department of Pathology and Department of Cardiac Surgery, Institute for Cardiovascular Research, Vrije Universiteit University Medical Center, Amsterdam, The Netherlands (H.W.N.); and Department of Physiology and Cellular Biophysics and Department of Neuroscience, College of Physicians and Surgeons, Columbia University, New York, NY (J.A.G.)
| | - Hans-Joachim Schönfeld
- From Division of Molecular and Translational Cardiology, Department of Cardiology and Angiology (M.R.R., M.K.-K., S.K., E.B., I.R., Y.W., K.C.W.), Core Unit Proteomics, Institute of Toxicology (F.P., A.P.), Department of Biophysical Chemistry (J.F.), Leibniz Research Laboratories for Biotechnology and Artificial Organs, Department of Cardiothoracic, Transplantation, and Vascular Surgery (G.K., I.G.), Institute of Legal Medicine (M.K.), Institute of Physiological Chemistry (M.G.), and Department of Cardiology and Angiology (J.B.), Hannover Medical School, Germany; F. Hoffmann-La Roche, Pharma Research and Early Development, Basel, Switzerland (H.-J.S., M.B.); Department of Pathology and Department of Cardiac Surgery, Institute for Cardiovascular Research, Vrije Universiteit University Medical Center, Amsterdam, The Netherlands (H.W.N.); and Department of Physiology and Cellular Biophysics and Department of Neuroscience, College of Physicians and Surgeons, Columbia University, New York, NY (J.A.G.)
| | - Maria Bobadilla
- From Division of Molecular and Translational Cardiology, Department of Cardiology and Angiology (M.R.R., M.K.-K., S.K., E.B., I.R., Y.W., K.C.W.), Core Unit Proteomics, Institute of Toxicology (F.P., A.P.), Department of Biophysical Chemistry (J.F.), Leibniz Research Laboratories for Biotechnology and Artificial Organs, Department of Cardiothoracic, Transplantation, and Vascular Surgery (G.K., I.G.), Institute of Legal Medicine (M.K.), Institute of Physiological Chemistry (M.G.), and Department of Cardiology and Angiology (J.B.), Hannover Medical School, Germany; F. Hoffmann-La Roche, Pharma Research and Early Development, Basel, Switzerland (H.-J.S., M.B.); Department of Pathology and Department of Cardiac Surgery, Institute for Cardiovascular Research, Vrije Universiteit University Medical Center, Amsterdam, The Netherlands (H.W.N.); and Department of Physiology and Cellular Biophysics and Department of Neuroscience, College of Physicians and Surgeons, Columbia University, New York, NY (J.A.G.)
| | - Jan Faix
- From Division of Molecular and Translational Cardiology, Department of Cardiology and Angiology (M.R.R., M.K.-K., S.K., E.B., I.R., Y.W., K.C.W.), Core Unit Proteomics, Institute of Toxicology (F.P., A.P.), Department of Biophysical Chemistry (J.F.), Leibniz Research Laboratories for Biotechnology and Artificial Organs, Department of Cardiothoracic, Transplantation, and Vascular Surgery (G.K., I.G.), Institute of Legal Medicine (M.K.), Institute of Physiological Chemistry (M.G.), and Department of Cardiology and Angiology (J.B.), Hannover Medical School, Germany; F. Hoffmann-La Roche, Pharma Research and Early Development, Basel, Switzerland (H.-J.S., M.B.); Department of Pathology and Department of Cardiac Surgery, Institute for Cardiovascular Research, Vrije Universiteit University Medical Center, Amsterdam, The Netherlands (H.W.N.); and Department of Physiology and Cellular Biophysics and Department of Neuroscience, College of Physicians and Surgeons, Columbia University, New York, NY (J.A.G.)
| | - George Kensah
- From Division of Molecular and Translational Cardiology, Department of Cardiology and Angiology (M.R.R., M.K.-K., S.K., E.B., I.R., Y.W., K.C.W.), Core Unit Proteomics, Institute of Toxicology (F.P., A.P.), Department of Biophysical Chemistry (J.F.), Leibniz Research Laboratories for Biotechnology and Artificial Organs, Department of Cardiothoracic, Transplantation, and Vascular Surgery (G.K., I.G.), Institute of Legal Medicine (M.K.), Institute of Physiological Chemistry (M.G.), and Department of Cardiology and Angiology (J.B.), Hannover Medical School, Germany; F. Hoffmann-La Roche, Pharma Research and Early Development, Basel, Switzerland (H.-J.S., M.B.); Department of Pathology and Department of Cardiac Surgery, Institute for Cardiovascular Research, Vrije Universiteit University Medical Center, Amsterdam, The Netherlands (H.W.N.); and Department of Physiology and Cellular Biophysics and Department of Neuroscience, College of Physicians and Surgeons, Columbia University, New York, NY (J.A.G.)
| | - Ina Gruh
- From Division of Molecular and Translational Cardiology, Department of Cardiology and Angiology (M.R.R., M.K.-K., S.K., E.B., I.R., Y.W., K.C.W.), Core Unit Proteomics, Institute of Toxicology (F.P., A.P.), Department of Biophysical Chemistry (J.F.), Leibniz Research Laboratories for Biotechnology and Artificial Organs, Department of Cardiothoracic, Transplantation, and Vascular Surgery (G.K., I.G.), Institute of Legal Medicine (M.K.), Institute of Physiological Chemistry (M.G.), and Department of Cardiology and Angiology (J.B.), Hannover Medical School, Germany; F. Hoffmann-La Roche, Pharma Research and Early Development, Basel, Switzerland (H.-J.S., M.B.); Department of Pathology and Department of Cardiac Surgery, Institute for Cardiovascular Research, Vrije Universiteit University Medical Center, Amsterdam, The Netherlands (H.W.N.); and Department of Physiology and Cellular Biophysics and Department of Neuroscience, College of Physicians and Surgeons, Columbia University, New York, NY (J.A.G.)
| | - Michael Klintschar
- From Division of Molecular and Translational Cardiology, Department of Cardiology and Angiology (M.R.R., M.K.-K., S.K., E.B., I.R., Y.W., K.C.W.), Core Unit Proteomics, Institute of Toxicology (F.P., A.P.), Department of Biophysical Chemistry (J.F.), Leibniz Research Laboratories for Biotechnology and Artificial Organs, Department of Cardiothoracic, Transplantation, and Vascular Surgery (G.K., I.G.), Institute of Legal Medicine (M.K.), Institute of Physiological Chemistry (M.G.), and Department of Cardiology and Angiology (J.B.), Hannover Medical School, Germany; F. Hoffmann-La Roche, Pharma Research and Early Development, Basel, Switzerland (H.-J.S., M.B.); Department of Pathology and Department of Cardiac Surgery, Institute for Cardiovascular Research, Vrije Universiteit University Medical Center, Amsterdam, The Netherlands (H.W.N.); and Department of Physiology and Cellular Biophysics and Department of Neuroscience, College of Physicians and Surgeons, Columbia University, New York, NY (J.A.G.)
| | - Matthias Gaestel
- From Division of Molecular and Translational Cardiology, Department of Cardiology and Angiology (M.R.R., M.K.-K., S.K., E.B., I.R., Y.W., K.C.W.), Core Unit Proteomics, Institute of Toxicology (F.P., A.P.), Department of Biophysical Chemistry (J.F.), Leibniz Research Laboratories for Biotechnology and Artificial Organs, Department of Cardiothoracic, Transplantation, and Vascular Surgery (G.K., I.G.), Institute of Legal Medicine (M.K.), Institute of Physiological Chemistry (M.G.), and Department of Cardiology and Angiology (J.B.), Hannover Medical School, Germany; F. Hoffmann-La Roche, Pharma Research and Early Development, Basel, Switzerland (H.-J.S., M.B.); Department of Pathology and Department of Cardiac Surgery, Institute for Cardiovascular Research, Vrije Universiteit University Medical Center, Amsterdam, The Netherlands (H.W.N.); and Department of Physiology and Cellular Biophysics and Department of Neuroscience, College of Physicians and Surgeons, Columbia University, New York, NY (J.A.G.)
| | - Hans W Niessen
- From Division of Molecular and Translational Cardiology, Department of Cardiology and Angiology (M.R.R., M.K.-K., S.K., E.B., I.R., Y.W., K.C.W.), Core Unit Proteomics, Institute of Toxicology (F.P., A.P.), Department of Biophysical Chemistry (J.F.), Leibniz Research Laboratories for Biotechnology and Artificial Organs, Department of Cardiothoracic, Transplantation, and Vascular Surgery (G.K., I.G.), Institute of Legal Medicine (M.K.), Institute of Physiological Chemistry (M.G.), and Department of Cardiology and Angiology (J.B.), Hannover Medical School, Germany; F. Hoffmann-La Roche, Pharma Research and Early Development, Basel, Switzerland (H.-J.S., M.B.); Department of Pathology and Department of Cardiac Surgery, Institute for Cardiovascular Research, Vrije Universiteit University Medical Center, Amsterdam, The Netherlands (H.W.N.); and Department of Physiology and Cellular Biophysics and Department of Neuroscience, College of Physicians and Surgeons, Columbia University, New York, NY (J.A.G.)
| | - Andreas Pich
- From Division of Molecular and Translational Cardiology, Department of Cardiology and Angiology (M.R.R., M.K.-K., S.K., E.B., I.R., Y.W., K.C.W.), Core Unit Proteomics, Institute of Toxicology (F.P., A.P.), Department of Biophysical Chemistry (J.F.), Leibniz Research Laboratories for Biotechnology and Artificial Organs, Department of Cardiothoracic, Transplantation, and Vascular Surgery (G.K., I.G.), Institute of Legal Medicine (M.K.), Institute of Physiological Chemistry (M.G.), and Department of Cardiology and Angiology (J.B.), Hannover Medical School, Germany; F. Hoffmann-La Roche, Pharma Research and Early Development, Basel, Switzerland (H.-J.S., M.B.); Department of Pathology and Department of Cardiac Surgery, Institute for Cardiovascular Research, Vrije Universiteit University Medical Center, Amsterdam, The Netherlands (H.W.N.); and Department of Physiology and Cellular Biophysics and Department of Neuroscience, College of Physicians and Surgeons, Columbia University, New York, NY (J.A.G.)
| | - Johann Bauersachs
- From Division of Molecular and Translational Cardiology, Department of Cardiology and Angiology (M.R.R., M.K.-K., S.K., E.B., I.R., Y.W., K.C.W.), Core Unit Proteomics, Institute of Toxicology (F.P., A.P.), Department of Biophysical Chemistry (J.F.), Leibniz Research Laboratories for Biotechnology and Artificial Organs, Department of Cardiothoracic, Transplantation, and Vascular Surgery (G.K., I.G.), Institute of Legal Medicine (M.K.), Institute of Physiological Chemistry (M.G.), and Department of Cardiology and Angiology (J.B.), Hannover Medical School, Germany; F. Hoffmann-La Roche, Pharma Research and Early Development, Basel, Switzerland (H.-J.S., M.B.); Department of Pathology and Department of Cardiac Surgery, Institute for Cardiovascular Research, Vrije Universiteit University Medical Center, Amsterdam, The Netherlands (H.W.N.); and Department of Physiology and Cellular Biophysics and Department of Neuroscience, College of Physicians and Surgeons, Columbia University, New York, NY (J.A.G.)
| | - Joseph A Gogos
- From Division of Molecular and Translational Cardiology, Department of Cardiology and Angiology (M.R.R., M.K.-K., S.K., E.B., I.R., Y.W., K.C.W.), Core Unit Proteomics, Institute of Toxicology (F.P., A.P.), Department of Biophysical Chemistry (J.F.), Leibniz Research Laboratories for Biotechnology and Artificial Organs, Department of Cardiothoracic, Transplantation, and Vascular Surgery (G.K., I.G.), Institute of Legal Medicine (M.K.), Institute of Physiological Chemistry (M.G.), and Department of Cardiology and Angiology (J.B.), Hannover Medical School, Germany; F. Hoffmann-La Roche, Pharma Research and Early Development, Basel, Switzerland (H.-J.S., M.B.); Department of Pathology and Department of Cardiac Surgery, Institute for Cardiovascular Research, Vrije Universiteit University Medical Center, Amsterdam, The Netherlands (H.W.N.); and Department of Physiology and Cellular Biophysics and Department of Neuroscience, College of Physicians and Surgeons, Columbia University, New York, NY (J.A.G.)
| | - Yong Wang
- From Division of Molecular and Translational Cardiology, Department of Cardiology and Angiology (M.R.R., M.K.-K., S.K., E.B., I.R., Y.W., K.C.W.), Core Unit Proteomics, Institute of Toxicology (F.P., A.P.), Department of Biophysical Chemistry (J.F.), Leibniz Research Laboratories for Biotechnology and Artificial Organs, Department of Cardiothoracic, Transplantation, and Vascular Surgery (G.K., I.G.), Institute of Legal Medicine (M.K.), Institute of Physiological Chemistry (M.G.), and Department of Cardiology and Angiology (J.B.), Hannover Medical School, Germany; F. Hoffmann-La Roche, Pharma Research and Early Development, Basel, Switzerland (H.-J.S., M.B.); Department of Pathology and Department of Cardiac Surgery, Institute for Cardiovascular Research, Vrije Universiteit University Medical Center, Amsterdam, The Netherlands (H.W.N.); and Department of Physiology and Cellular Biophysics and Department of Neuroscience, College of Physicians and Surgeons, Columbia University, New York, NY (J.A.G.)
| | - Kai C Wollert
- From Division of Molecular and Translational Cardiology, Department of Cardiology and Angiology (M.R.R., M.K.-K., S.K., E.B., I.R., Y.W., K.C.W.), Core Unit Proteomics, Institute of Toxicology (F.P., A.P.), Department of Biophysical Chemistry (J.F.), Leibniz Research Laboratories for Biotechnology and Artificial Organs, Department of Cardiothoracic, Transplantation, and Vascular Surgery (G.K., I.G.), Institute of Legal Medicine (M.K.), Institute of Physiological Chemistry (M.G.), and Department of Cardiology and Angiology (J.B.), Hannover Medical School, Germany; F. Hoffmann-La Roche, Pharma Research and Early Development, Basel, Switzerland (H.-J.S., M.B.); Department of Pathology and Department of Cardiac Surgery, Institute for Cardiovascular Research, Vrije Universiteit University Medical Center, Amsterdam, The Netherlands (H.W.N.); and Department of Physiology and Cellular Biophysics and Department of Neuroscience, College of Physicians and Surgeons, Columbia University, New York, NY (J.A.G.).
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Inhibition of Histone Methyltransferase, Histone Deacetylase, and β-Catenin Synergistically Enhance the Cardiac Potential of Bone Marrow Cells. Stem Cells Int 2017; 2017:3464953. [PMID: 28791052 PMCID: PMC5534312 DOI: 10.1155/2017/3464953] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2017] [Revised: 05/02/2017] [Accepted: 05/17/2017] [Indexed: 11/17/2022] Open
Abstract
Previously, we reported that treatment with the G9a histone methyltransferase inhibitor BIX01294 causes bone marrow mesenchymal stem cells (MSCs) to exhibit a cardiocompetent phenotype, as indicated by the induction of the precardiac markers Mesp1 and brachyury. Here, we report that combining the histone deacetylase inhibitor trichostatin A (TSA) with BIX01294 synergistically enhances MSC cardiogenesis. Although TSA by itself had no effect on cardiac gene expression, coaddition of TSA to MSC cultures enhanced BIX01294-induced levels of Mesp1 and brachyury expression 5.6- and 7.2-fold. Moreover, MSCs exposed to the cardiogenic stimulus Wnt11 generated 2.6- to 5.6-fold higher levels of the cardiomyocyte markers GATA4, Nkx2.5, and myocardin when pretreated with TSA in addition to BIX01294. MSC cultures also showed a corresponding increase in the prevalence of sarcomeric protein-positive cells when treated with these small molecule inhibitors. These results correlated with data showing synergism between (1) TSA and BIX01294 in promoting acetylation of lysine 27 on histone H3 and (2) BIX01294 and Wnt11 in decreasing β-catenin accumulation in MSCs. The implications of these findings are discussed in light of observations in the early embryo on the importance of β-catenin signaling and histone modifications for cardiomyocyte differentiation and heart development.
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Shahrivari M, Wise E, Resende M, Shuster JJ, Zhang J, Bolli R, Cooke JP, Hare JM, Henry TD, Khan A, Taylor DA, Traverse JH, Yang PC, Pepine CJ, Cogle CR. Peripheral Blood Cytokine Levels After Acute Myocardial Infarction: IL-1β- and IL-6-Related Impairment of Bone Marrow Function. Circ Res 2017; 120:1947-1957. [PMID: 28490433 DOI: 10.1161/circresaha.116.309947] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2016] [Revised: 04/24/2017] [Accepted: 05/09/2017] [Indexed: 12/15/2022]
Abstract
RATIONALE Intracoronary infusion of bone marrow (BM) mononuclear cells after acute myocardial infarction (AMI) has led to limited improvement in left ventricular function. Although experimental AMI models have implicated cytokine-related impairment of progenitor cell function, this response has not been investigated in humans. OBJECTIVE To test the hypothesis that peripheral blood (PB) cytokines predict BM endothelial progenitor cell colony outgrowth and cardiac function after AMI. METHODS AND RESULTS BM and PB samples were collected from 87 participants 14 to 21 days after AMI and BM from healthy donors was used as a reference. Correlations between cytokine concentrations and cell phenotypes, cell functions, and post-AMI cardiac function were determined. PB interleukin-6 (IL-6) negatively correlated with endothelial colony-forming cell colony maximum in the BM of patients with AMI (estimate±SE, -0.13±0.05; P=0.007). BM from healthy individuals showed a dose-dependent decrease in endothelial colony-forming cell colony outgrowth in the presence of exogenous IL-1β or IL-6 (P<0.05). Blocking the IL-1R or IL-6R reversed cytokine impairment. In AMI study participants, the angiogenic cytokine platelet-derived growth factor BB glycoprotein correlated positively with BM-derived colony-forming unit-endothelial colony maximum (estimate±SE, 0.01±0.002; P<0.001), multipotent mesenchymal stromal cell colony maximum (estimate±SE, 0.01±0.002; P=0.002) in BM, and mesenchymal stromal cell colony maximum in PB (estimate±SE, 0.02±0.005; P<0.001). CONCLUSIONS Two weeks after AMI, increased PB platelet-derived growth factor BB glycoprotein was associated with increased BM function, whereas increased IL-6 was associated with BM impairment. Validation studies confirmed inflammatory cytokine impairment of BM that could be reversed by blocking IL-1R or IL-6R. Together, these studies suggest that blocking IL-1 or IL-6 receptors may improve the regenerative capacity of BM cells after AMI. CLINICAL TRIAL REGISTRATIONS URL: http://www.clinicaltrials.gov. Unique identifier: NCT00684060.
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Affiliation(s)
- Mahan Shahrivari
- From the Department of Medicine, College of Medicine, University of Florida, Gainesville (M.S., E.W., J.J.S., J.Z., C.J.P., C.R.C.); Regenerative Medicine Research, Texas Heart Institute, CHI St. Luke's Health Baylor College of Medicine Medical Center, Houston (M.R., D.A.T.); Department of Medicine, University of Louisville, KY (R.B.); Department of Cardiovascular Sciences, Methodist DeBakey Heart and Vascular Center, the Houston Methodist Research Institute, TX (J.P.C.); Interdisciplinary Stem Cell Institute, University of Miami School of Medicine, FL (J.M.H., A.K.); Department of Medicine, Cedars-Sinai Heart Institute, Los Angeles, CA (T.D.H.); Department of Cardiology, Minneapolis Heart Institute Foundation at Abbott Northwestern Hospital, MN (J.H.T.); and Department of Cardiovascular Medicine, Stanford University, School of Medicine, CA (P.C.Y.)
| | - Elizabeth Wise
- From the Department of Medicine, College of Medicine, University of Florida, Gainesville (M.S., E.W., J.J.S., J.Z., C.J.P., C.R.C.); Regenerative Medicine Research, Texas Heart Institute, CHI St. Luke's Health Baylor College of Medicine Medical Center, Houston (M.R., D.A.T.); Department of Medicine, University of Louisville, KY (R.B.); Department of Cardiovascular Sciences, Methodist DeBakey Heart and Vascular Center, the Houston Methodist Research Institute, TX (J.P.C.); Interdisciplinary Stem Cell Institute, University of Miami School of Medicine, FL (J.M.H., A.K.); Department of Medicine, Cedars-Sinai Heart Institute, Los Angeles, CA (T.D.H.); Department of Cardiology, Minneapolis Heart Institute Foundation at Abbott Northwestern Hospital, MN (J.H.T.); and Department of Cardiovascular Medicine, Stanford University, School of Medicine, CA (P.C.Y.)
| | - Micheline Resende
- From the Department of Medicine, College of Medicine, University of Florida, Gainesville (M.S., E.W., J.J.S., J.Z., C.J.P., C.R.C.); Regenerative Medicine Research, Texas Heart Institute, CHI St. Luke's Health Baylor College of Medicine Medical Center, Houston (M.R., D.A.T.); Department of Medicine, University of Louisville, KY (R.B.); Department of Cardiovascular Sciences, Methodist DeBakey Heart and Vascular Center, the Houston Methodist Research Institute, TX (J.P.C.); Interdisciplinary Stem Cell Institute, University of Miami School of Medicine, FL (J.M.H., A.K.); Department of Medicine, Cedars-Sinai Heart Institute, Los Angeles, CA (T.D.H.); Department of Cardiology, Minneapolis Heart Institute Foundation at Abbott Northwestern Hospital, MN (J.H.T.); and Department of Cardiovascular Medicine, Stanford University, School of Medicine, CA (P.C.Y.)
| | - Jonathan J Shuster
- From the Department of Medicine, College of Medicine, University of Florida, Gainesville (M.S., E.W., J.J.S., J.Z., C.J.P., C.R.C.); Regenerative Medicine Research, Texas Heart Institute, CHI St. Luke's Health Baylor College of Medicine Medical Center, Houston (M.R., D.A.T.); Department of Medicine, University of Louisville, KY (R.B.); Department of Cardiovascular Sciences, Methodist DeBakey Heart and Vascular Center, the Houston Methodist Research Institute, TX (J.P.C.); Interdisciplinary Stem Cell Institute, University of Miami School of Medicine, FL (J.M.H., A.K.); Department of Medicine, Cedars-Sinai Heart Institute, Los Angeles, CA (T.D.H.); Department of Cardiology, Minneapolis Heart Institute Foundation at Abbott Northwestern Hospital, MN (J.H.T.); and Department of Cardiovascular Medicine, Stanford University, School of Medicine, CA (P.C.Y.)
| | - Jingnan Zhang
- From the Department of Medicine, College of Medicine, University of Florida, Gainesville (M.S., E.W., J.J.S., J.Z., C.J.P., C.R.C.); Regenerative Medicine Research, Texas Heart Institute, CHI St. Luke's Health Baylor College of Medicine Medical Center, Houston (M.R., D.A.T.); Department of Medicine, University of Louisville, KY (R.B.); Department of Cardiovascular Sciences, Methodist DeBakey Heart and Vascular Center, the Houston Methodist Research Institute, TX (J.P.C.); Interdisciplinary Stem Cell Institute, University of Miami School of Medicine, FL (J.M.H., A.K.); Department of Medicine, Cedars-Sinai Heart Institute, Los Angeles, CA (T.D.H.); Department of Cardiology, Minneapolis Heart Institute Foundation at Abbott Northwestern Hospital, MN (J.H.T.); and Department of Cardiovascular Medicine, Stanford University, School of Medicine, CA (P.C.Y.)
| | - Roberto Bolli
- From the Department of Medicine, College of Medicine, University of Florida, Gainesville (M.S., E.W., J.J.S., J.Z., C.J.P., C.R.C.); Regenerative Medicine Research, Texas Heart Institute, CHI St. Luke's Health Baylor College of Medicine Medical Center, Houston (M.R., D.A.T.); Department of Medicine, University of Louisville, KY (R.B.); Department of Cardiovascular Sciences, Methodist DeBakey Heart and Vascular Center, the Houston Methodist Research Institute, TX (J.P.C.); Interdisciplinary Stem Cell Institute, University of Miami School of Medicine, FL (J.M.H., A.K.); Department of Medicine, Cedars-Sinai Heart Institute, Los Angeles, CA (T.D.H.); Department of Cardiology, Minneapolis Heart Institute Foundation at Abbott Northwestern Hospital, MN (J.H.T.); and Department of Cardiovascular Medicine, Stanford University, School of Medicine, CA (P.C.Y.)
| | - John P Cooke
- From the Department of Medicine, College of Medicine, University of Florida, Gainesville (M.S., E.W., J.J.S., J.Z., C.J.P., C.R.C.); Regenerative Medicine Research, Texas Heart Institute, CHI St. Luke's Health Baylor College of Medicine Medical Center, Houston (M.R., D.A.T.); Department of Medicine, University of Louisville, KY (R.B.); Department of Cardiovascular Sciences, Methodist DeBakey Heart and Vascular Center, the Houston Methodist Research Institute, TX (J.P.C.); Interdisciplinary Stem Cell Institute, University of Miami School of Medicine, FL (J.M.H., A.K.); Department of Medicine, Cedars-Sinai Heart Institute, Los Angeles, CA (T.D.H.); Department of Cardiology, Minneapolis Heart Institute Foundation at Abbott Northwestern Hospital, MN (J.H.T.); and Department of Cardiovascular Medicine, Stanford University, School of Medicine, CA (P.C.Y.)
| | - Joshua M Hare
- From the Department of Medicine, College of Medicine, University of Florida, Gainesville (M.S., E.W., J.J.S., J.Z., C.J.P., C.R.C.); Regenerative Medicine Research, Texas Heart Institute, CHI St. Luke's Health Baylor College of Medicine Medical Center, Houston (M.R., D.A.T.); Department of Medicine, University of Louisville, KY (R.B.); Department of Cardiovascular Sciences, Methodist DeBakey Heart and Vascular Center, the Houston Methodist Research Institute, TX (J.P.C.); Interdisciplinary Stem Cell Institute, University of Miami School of Medicine, FL (J.M.H., A.K.); Department of Medicine, Cedars-Sinai Heart Institute, Los Angeles, CA (T.D.H.); Department of Cardiology, Minneapolis Heart Institute Foundation at Abbott Northwestern Hospital, MN (J.H.T.); and Department of Cardiovascular Medicine, Stanford University, School of Medicine, CA (P.C.Y.)
| | - Timothy D Henry
- From the Department of Medicine, College of Medicine, University of Florida, Gainesville (M.S., E.W., J.J.S., J.Z., C.J.P., C.R.C.); Regenerative Medicine Research, Texas Heart Institute, CHI St. Luke's Health Baylor College of Medicine Medical Center, Houston (M.R., D.A.T.); Department of Medicine, University of Louisville, KY (R.B.); Department of Cardiovascular Sciences, Methodist DeBakey Heart and Vascular Center, the Houston Methodist Research Institute, TX (J.P.C.); Interdisciplinary Stem Cell Institute, University of Miami School of Medicine, FL (J.M.H., A.K.); Department of Medicine, Cedars-Sinai Heart Institute, Los Angeles, CA (T.D.H.); Department of Cardiology, Minneapolis Heart Institute Foundation at Abbott Northwestern Hospital, MN (J.H.T.); and Department of Cardiovascular Medicine, Stanford University, School of Medicine, CA (P.C.Y.)
| | - Aisha Khan
- From the Department of Medicine, College of Medicine, University of Florida, Gainesville (M.S., E.W., J.J.S., J.Z., C.J.P., C.R.C.); Regenerative Medicine Research, Texas Heart Institute, CHI St. Luke's Health Baylor College of Medicine Medical Center, Houston (M.R., D.A.T.); Department of Medicine, University of Louisville, KY (R.B.); Department of Cardiovascular Sciences, Methodist DeBakey Heart and Vascular Center, the Houston Methodist Research Institute, TX (J.P.C.); Interdisciplinary Stem Cell Institute, University of Miami School of Medicine, FL (J.M.H., A.K.); Department of Medicine, Cedars-Sinai Heart Institute, Los Angeles, CA (T.D.H.); Department of Cardiology, Minneapolis Heart Institute Foundation at Abbott Northwestern Hospital, MN (J.H.T.); and Department of Cardiovascular Medicine, Stanford University, School of Medicine, CA (P.C.Y.)
| | - Doris A Taylor
- From the Department of Medicine, College of Medicine, University of Florida, Gainesville (M.S., E.W., J.J.S., J.Z., C.J.P., C.R.C.); Regenerative Medicine Research, Texas Heart Institute, CHI St. Luke's Health Baylor College of Medicine Medical Center, Houston (M.R., D.A.T.); Department of Medicine, University of Louisville, KY (R.B.); Department of Cardiovascular Sciences, Methodist DeBakey Heart and Vascular Center, the Houston Methodist Research Institute, TX (J.P.C.); Interdisciplinary Stem Cell Institute, University of Miami School of Medicine, FL (J.M.H., A.K.); Department of Medicine, Cedars-Sinai Heart Institute, Los Angeles, CA (T.D.H.); Department of Cardiology, Minneapolis Heart Institute Foundation at Abbott Northwestern Hospital, MN (J.H.T.); and Department of Cardiovascular Medicine, Stanford University, School of Medicine, CA (P.C.Y.)
| | - Jay H Traverse
- From the Department of Medicine, College of Medicine, University of Florida, Gainesville (M.S., E.W., J.J.S., J.Z., C.J.P., C.R.C.); Regenerative Medicine Research, Texas Heart Institute, CHI St. Luke's Health Baylor College of Medicine Medical Center, Houston (M.R., D.A.T.); Department of Medicine, University of Louisville, KY (R.B.); Department of Cardiovascular Sciences, Methodist DeBakey Heart and Vascular Center, the Houston Methodist Research Institute, TX (J.P.C.); Interdisciplinary Stem Cell Institute, University of Miami School of Medicine, FL (J.M.H., A.K.); Department of Medicine, Cedars-Sinai Heart Institute, Los Angeles, CA (T.D.H.); Department of Cardiology, Minneapolis Heart Institute Foundation at Abbott Northwestern Hospital, MN (J.H.T.); and Department of Cardiovascular Medicine, Stanford University, School of Medicine, CA (P.C.Y.)
| | - Phillip C Yang
- From the Department of Medicine, College of Medicine, University of Florida, Gainesville (M.S., E.W., J.J.S., J.Z., C.J.P., C.R.C.); Regenerative Medicine Research, Texas Heart Institute, CHI St. Luke's Health Baylor College of Medicine Medical Center, Houston (M.R., D.A.T.); Department of Medicine, University of Louisville, KY (R.B.); Department of Cardiovascular Sciences, Methodist DeBakey Heart and Vascular Center, the Houston Methodist Research Institute, TX (J.P.C.); Interdisciplinary Stem Cell Institute, University of Miami School of Medicine, FL (J.M.H., A.K.); Department of Medicine, Cedars-Sinai Heart Institute, Los Angeles, CA (T.D.H.); Department of Cardiology, Minneapolis Heart Institute Foundation at Abbott Northwestern Hospital, MN (J.H.T.); and Department of Cardiovascular Medicine, Stanford University, School of Medicine, CA (P.C.Y.)
| | - Carl J Pepine
- From the Department of Medicine, College of Medicine, University of Florida, Gainesville (M.S., E.W., J.J.S., J.Z., C.J.P., C.R.C.); Regenerative Medicine Research, Texas Heart Institute, CHI St. Luke's Health Baylor College of Medicine Medical Center, Houston (M.R., D.A.T.); Department of Medicine, University of Louisville, KY (R.B.); Department of Cardiovascular Sciences, Methodist DeBakey Heart and Vascular Center, the Houston Methodist Research Institute, TX (J.P.C.); Interdisciplinary Stem Cell Institute, University of Miami School of Medicine, FL (J.M.H., A.K.); Department of Medicine, Cedars-Sinai Heart Institute, Los Angeles, CA (T.D.H.); Department of Cardiology, Minneapolis Heart Institute Foundation at Abbott Northwestern Hospital, MN (J.H.T.); and Department of Cardiovascular Medicine, Stanford University, School of Medicine, CA (P.C.Y.)
| | - Christopher R Cogle
- From the Department of Medicine, College of Medicine, University of Florida, Gainesville (M.S., E.W., J.J.S., J.Z., C.J.P., C.R.C.); Regenerative Medicine Research, Texas Heart Institute, CHI St. Luke's Health Baylor College of Medicine Medical Center, Houston (M.R., D.A.T.); Department of Medicine, University of Louisville, KY (R.B.); Department of Cardiovascular Sciences, Methodist DeBakey Heart and Vascular Center, the Houston Methodist Research Institute, TX (J.P.C.); Interdisciplinary Stem Cell Institute, University of Miami School of Medicine, FL (J.M.H., A.K.); Department of Medicine, Cedars-Sinai Heart Institute, Los Angeles, CA (T.D.H.); Department of Cardiology, Minneapolis Heart Institute Foundation at Abbott Northwestern Hospital, MN (J.H.T.); and Department of Cardiovascular Medicine, Stanford University, School of Medicine, CA (P.C.Y.).
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Redox regulation of ischemic limb neovascularization - What we have learned from animal studies. Redox Biol 2017; 12:1011-1019. [PMID: 28505880 PMCID: PMC5430575 DOI: 10.1016/j.redox.2017.04.040] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2017] [Revised: 04/08/2017] [Accepted: 04/24/2017] [Indexed: 12/31/2022] Open
Abstract
Mouse hindlimb ischemia has been widely used as a model to study peripheral artery disease. Genetic modulation of the enzymatic source of oxidants or components of the antioxidant system reveal that physiological levels of oxidants are essential to promote the process of arteriogenesis and angiogenesis after femoral artery occlusion, although mice with diabetes or atherosclerosis may have higher deleterious levels of oxidants. Therefore, fine control of oxidants is required to stimulate vascularization in the limb muscle. Oxidants transduce cellular signaling through oxidative modifications of redox sensitive cysteine thiols. Of particular importance, the reversible modification with abundant glutathione, called S-glutathionylation (or GSH adducts), is relatively stable and alters protein function including signaling, transcription, and cytoskeletal arrangement. Glutaredoxin-1 (Glrx) is an enzyme which catalyzes reversal of GSH adducts, and does not scavenge oxidants itself. Glrx may control redox signaling under fluctuation of oxidants levels. In ischemic muscle increased GSH adducts through Glrx deletion improves in vivo limb revascularization, indicating endogenous Glrx has anti-angiogenic roles. In accordance, Glrx overexpression attenuates VEGF signaling in vitro and ischemic vascularization in vivo. There are several Glrx targets including HIF-1α which may contribute to inhibition of vascularization by reducing GSH adducts. These animal studies provide a caution that excess antioxidants may be counter-productive for treatment of ischemic limbs, and highlights Glrx as a potential therapeutic target to improve ischemic limb vascularization.
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Contreras A, Orozco AF, Resende M, Schutt RC, Traverse JH, Henry TD, Lai D, Cooke JP, Bolli R, Cohen ML, Moyé L, Pepine CJ, Yang PC, Perin EC, Willerson JT, Taylor DA. Identification of cardiovascular risk factors associated with bone marrow cell subsets in patients with STEMI: a biorepository evaluation from the CCTRN TIME and LateTIME clinical trials. Basic Res Cardiol 2017; 112:3. [PMID: 27882430 PMCID: PMC5760218 DOI: 10.1007/s00395-016-0592-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2016] [Accepted: 11/14/2016] [Indexed: 12/13/2022]
Abstract
Autologous bone marrow mononuclear cell (BM-MNC) therapy for patients with ST-segment elevation myocardial infarction (STEMI) has produced inconsistent results, possibly due to BM-MNC product heterogeneity. Patient-specific cardiovascular risk factors (CRFs) may contribute to variations in BM-MNC composition. We sought to identify associations between BM-MNC subset frequencies and specific CRFs in STEMI patients. Bone marrow was collected from 191 STEMI patients enrolled in the CCTRN TIME and LateTIME trials. Relationships between BM-MNC subsets and CRFs were determined with multivariate analyses. An assessment of CRFs showed that hyperlipidemia and hypertension were associated with a higher frequency of CD11b+ cells (P = 0.045 and P = 0.016, respectively). In addition, we found that females had lower frequencies of CD11b+ (P = 0.018) and CD45+CD14+ (P = 0.028) cells than males, age was inversely associated with the frequency of CD45+CD31+ cells (P = 0.001), smoking was associated with a decreased frequency of CD45+CD31+ cells (P = 0.013), glucose level was positively associated with the frequency of CD45+CD3+ cells, and creatinine level (an indicator of renal function) was inversely associated with the frequency of CD45+CD3+ cells (P = 0.015). In conclusion, the frequencies of monocytic, lymphocytic, and angiogenic BM-MNCs varied in relation to patients' CRFs. These phenotypic variations may affect cell therapy outcomes and might be an important consideration when selecting patients for and reviewing results from autologous cell therapy trials.
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Affiliation(s)
| | | | | | - Robert C Schutt
- Houston Methodist DeBakey Heart and Vascular Center, Houston Methodist Research Institute, Houston, TX, USA
| | - Jay H Traverse
- Minneapolis Heart Institute Foundation, Abbott Northwestern Hospital, Minneapolis, MN, USA
| | | | - Dejian Lai
- UT Health School of Public Health, Houston, TX, USA
| | - John P Cooke
- Houston Methodist DeBakey Heart and Vascular Center, Houston Methodist Research Institute, Houston, TX, USA
| | | | | | - Lem Moyé
- UT Health School of Public Health, Houston, TX, USA.
| | - Carl J Pepine
- College of Medicine, University of Florida, Gainesville, FL, USA
| | - Phillip C Yang
- Stanford University School of Medicine, Stanford, CA, USA
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Ola R, Dubrac A, Han J, Zhang F, Fang JS, Larrivée B, Lee M, Urarte AA, Kraehling JR, Genet G, Hirschi KK, Sessa WC, Canals FV, Graupera M, Yan M, Young LH, Oh PS, Eichmann A. PI3 kinase inhibition improves vascular malformations in mouse models of hereditary haemorrhagic telangiectasia. Nat Commun 2016; 7:13650. [PMID: 27897192 PMCID: PMC5141347 DOI: 10.1038/ncomms13650] [Citation(s) in RCA: 127] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2016] [Accepted: 10/20/2016] [Indexed: 12/26/2022] Open
Abstract
Activin receptor-like kinase 1 (ALK1) is an endothelial serine-threonine kinase receptor for bone morphogenetic proteins (BMPs) 9 and 10. Inactivating mutations in the ALK1 gene cause hereditary haemorrhagic telangiectasia type 2 (HHT2), a disabling disease characterized by excessive angiogenesis with arteriovenous malformations (AVMs). Here we show that inducible, endothelial-specific homozygous Alk1 inactivation and BMP9/10 ligand blockade both lead to AVM formation in postnatal retinal vessels and internal organs including the gastrointestinal (GI) tract in mice. VEGF and PI3K/AKT signalling are increased on Alk1 deletion and BMP9/10 ligand blockade. Genetic deletion of the signal-transducing Vegfr2 receptor prevents excessive angiogenesis but does not fully revert AVM formation. In contrast, pharmacological PI3K inhibition efficiently prevents AVM formation and reverts established AVMs. Thus, Alk1 deletion leads to increased endothelial PI3K pathway activation that may be a novel target for the treatment of vascular lesions in HHT2.
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Affiliation(s)
- Roxana Ola
- Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06511, USA
| | - Alexandre Dubrac
- Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06511, USA
| | - Jinah Han
- Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06511, USA
| | - Feng Zhang
- Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06511, USA
| | - Jennifer S. Fang
- Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06511, USA
| | - Bruno Larrivée
- Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06511, USA
| | - Monica Lee
- Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520, USA
| | - Ana A. Urarte
- Vascular Signalling Laboratory, Institut d'Investigació Biomèdica de Bellvitge, L'Hospitalet de Llobregat, Barcelona 08908, Spain
| | - Jan R. Kraehling
- Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520, USA
| | - Gael Genet
- Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06511, USA
| | - Karen K. Hirschi
- Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06511, USA
| | - William C. Sessa
- Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520, USA
| | - Francesc V. Canals
- Translation Research Laboratory, Catalan Institute of Oncology, Idibell, Barcelona 08908, Spain
| | - Mariona Graupera
- Vascular Signalling Laboratory, Institut d'Investigació Biomèdica de Bellvitge, L'Hospitalet de Llobregat, Barcelona 08908, Spain
| | - Minhong Yan
- Molecular Oncology, Genentech, Inc., South San Francisco, California 94080-4990, USA
| | - Lawrence H. Young
- Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06511, USA
| | - Paul S. Oh
- Department of Physiology and Functional Genomics, University of Florida College of Medicine, PO Box 100274, Gainesville, Florida 32610, USA
| | - Anne Eichmann
- Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06511, USA
- Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA
- Inserm U970, Paris Cardiovascular Research Center, Paris 75015, France
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Endothelial Antioxidant-1: a Key Mediator of Copper-dependent Wound Healing in vivo. Sci Rep 2016; 6:33783. [PMID: 27666810 PMCID: PMC5036036 DOI: 10.1038/srep33783] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2016] [Accepted: 09/01/2016] [Indexed: 12/21/2022] Open
Abstract
Copper (Cu), an essential nutrient, promotes wound healing, however, target of Cu action and underlying mechanisms remain elusive. Cu chaperone Antioxidant-1 (Atox1) in the cytosol supplies Cu to the secretory enzymes such as lysyl oxidase (LOX), while Atox1 in the nucleus functions as a Cu-dependent transcription factor. Using mouse cutaneous wound healing model, here we show that Cu content (by X-ray Fluorescence Microscopy) and nuclear Atox1 are increased after wounding, and that wound healing with and without Cu treatment is impaired in Atox1-/- mice. Endothelial cell (EC)-specific Atox1-/- mice and gene transfer of nuclear-target Atox1 in Atox1-/- mice reveal that Atox1 in ECs as well as transcription factor function of Atox1 are required for wound healing. Mechanistically, Atox1-/- mice show reduced Atox1 target proteins such as p47phox NADPH oxidase and cyclin D1 as well as extracellular matrix Cu enzyme LOX activity in wound tissues. This in turn results in reducing O2- production in ECs, NFkB activity, cell proliferation and collagen formation, thereby inhibiting angiogenesis, macrophage recruitment and extracellular matrix maturation. Our findings suggest that Cu-dependent transcription factor/Cu chaperone Atox1 in ECs plays an important role to sense Cu to accelerate wound angiogenesis and healing.
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Bhatnagar A, Bolli R, Johnstone BH, Traverse JH, Henry TD, Pepine CJ, Willerson JT, Perin EC, Ellis SG, Zhao DXM, Yang PC, Cooke JP, Schutt RC, Trachtenberg BH, Orozco A, Resende M, Ebert RF, Sayre SL, Simari RD, Moyé L, Cogle CR, Taylor DA. Bone marrow cell characteristics associated with patient profile and cardiac performance outcomes in the LateTIME-Cardiovascular Cell Therapy Research Network (CCTRN) trial. Am Heart J 2016; 179:142-50. [PMID: 27595689 PMCID: PMC5014395 DOI: 10.1016/j.ahj.2016.06.018] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2015] [Accepted: 06/25/2016] [Indexed: 12/16/2022]
Abstract
BACKGROUND Although several preclinical studies have shown that bone marrow cell (BMC) transplantation promotes cardiac recovery after myocardial infarction, clinical trials with unfractionated bone marrow have shown variable improvements in cardiac function. METHODS To determine whether in a population of post-myocardial infarction patients, functional recovery after BM transplant is associated with specific BMC subpopulation, we examined the association between BMCs with left ventricular (LV) function in the LateTIME-CCTRN trial. RESULTS In this population, we found that older individuals had higher numbers of BM CD133(+) and CD3(+) cells. Bone marrow from individuals with high body mass index had lower CD45(dim)/CD11b(dim) levels, whereas those with hypertension and higher C-reactive protein levels had higher numbers of CD133(+) cells. Smoking was associated with higher levels of CD133(+)/CD34(+)/VEGFR2(+) cells and lower levels of CD3(+) cells. Adjusted multivariate analysis indicated that CD11b(dim) cells were negatively associated with changes in LV ejection fraction and wall motion in both the infarct and border zones. Change in LV ejection fraction was positively associated with CD133(+), CD34(+), and CD45(+)/CXCR4(dim) cells as well as faster BMC growth rates in endothelial colony forming assays. CONCLUSIONS In the LateTIME population, BM composition varied with patient characteristics and treatment. Irrespective of cell therapy, recovery of LV function was greater in patients with greater BM abundance of CD133(+) and CD34(+) cells and worse in those with higher levels of CD11b(dim) cells. Bone marrow phenotype might predict clinical response before BMC therapy and administration of selected BM constituents could potentially improve outcomes of other future clinical trials.
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Affiliation(s)
| | | | | | - Jay H Traverse
- Minneapolis Heart Institute Foundation at Abbott Northwestern Hospital, Minneapolis, MN
| | | | - Carl J Pepine
- University of Florida College of Medicine, Gainesville, FL
| | - James T Willerson
- Texas Heart Institute, CHI St. Luke's Health Baylor College of Medicine Medical Center, Houston, TX
| | - Emerson C Perin
- Texas Heart Institute, CHI St. Luke's Health Baylor College of Medicine Medical Center, Houston, TX
| | | | | | | | - John P Cooke
- Houston Methodist DeBakey Heart & Vascular Center, Houston, TX
| | - Robert C Schutt
- Houston Methodist DeBakey Heart & Vascular Center, Houston, TX
| | | | - Aaron Orozco
- Texas Heart Institute, CHI St. Luke's Health Baylor College of Medicine Medical Center, Houston, TX
| | - Micheline Resende
- Texas Heart Institute, CHI St. Luke's Health Baylor College of Medicine Medical Center, Houston, TX
| | - Ray F Ebert
- National Heart, Lung, and Blood Institute, Bethesda, MD
| | - Shelly L Sayre
- University of Texas School of Public Health, Houston, TX
| | | | - Lem Moyé
- University of Texas School of Public Health, Houston, TX.
| | | | - Doris A Taylor
- Texas Heart Institute, CHI St. Luke's Health Baylor College of Medicine Medical Center, Houston, TX
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Bernier-Latmani J, Petrova TV. High-resolution 3D analysis of mouse small-intestinal stroma. Nat Protoc 2016; 11:1617-29. [PMID: 27560169 DOI: 10.1038/nprot.2016.092] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Here we detail a protocol for whole-mount immunostaining of mouse small-intestinal villi that can be used to generate high-resolution 3D images of all gut cell types, including blood and lymphatic vessel cells, neurons, smooth muscle cells, fibroblasts and immune cells. The procedure describes perfusion, fixation, dissection, immunostaining, mounting, clearing, confocal imaging and quantification, using intestinal vasculature as an example. As intestinal epithelial cells prevent visualization with some antibodies, we also provide an optional protocol to remove these cells before fixation. In contrast to alternative current techniques, our protocol enables the entire villus to be visualized with increased spatial resolution of cell location, morphology and cell-cell interactions, thus allowing for easy quantification of phenotypes. The technique, which takes 7 d from mouse dissection to microscopic examination, will be useful for researchers who are interested in most aspects of intestinal biology, including mucosal immunology, infection, nutrition, cancer biology and intestinal microbiota.
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Affiliation(s)
- Jeremiah Bernier-Latmani
- Department of Fundamental Oncology, Ludwig Institute for Cancer Research and Institute of Pathology, Centre Hospitalier Universitaire Vaudois (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland
| | - Tatiana V Petrova
- Department of Fundamental Oncology, Ludwig Institute for Cancer Research and Institute of Pathology, Centre Hospitalier Universitaire Vaudois (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland.,Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences. Swiss Federal Institute of Technology Lausanne (EPFL), Lausanne, Switzerland
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Kako F, Gabunia K, Ray M, Kelemen SE, England RN, Kako B, Scalia RG, Autieri MV. Interleukin-19 induces angiogenesis in the absence of hypoxia by direct and indirect immune mechanisms. Am J Physiol Cell Physiol 2016; 310:C931-41. [PMID: 27053520 DOI: 10.1152/ajpcell.00006.2016] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2016] [Accepted: 04/04/2016] [Indexed: 12/25/2022]
Abstract
Neovascularization and inflammation are independent biological processes but are linked in response to injury. The role of inflammation-dampening cytokines in the regulation of angiogenesis remains to be clarified. The purpose of this work was to test the hypothesis that IL-19 can induce angiogenesis in the absence of tissue hypoxia and to identify potential mechanisms. Using the aortic ring model of angiogenesis, we found significantly reduced sprouting capacity in aortic rings from IL-19(-/-) compared with wild-type mice. Using an in vivo assay, we found that IL-19(-/-) mice respond to vascular endothelial growth factor (VEGF) significantly less than wild-type mice and demonstrate decreased capillary formation in Matrigel plugs. IL-19 signals through the IL-20 receptor complex, and IL-19 induces IL-20 receptor subunit expression in aortic rings and cultured human vascular smooth muscle cells, but not endothelial cells, in a peroxisome proliferator-activated receptor-γ-dependent mechanism. IL-19 activates STAT3, and IL-19 angiogenic activity in aortic rings is STAT3-dependent. Using a quantitative RT-PCR screening assay, we determined that IL-19 has direct proangiogenic effects on aortic rings by inducing angiogenic gene expression. M2 macrophages participate in angiogenesis, and IL-19 has indirect angiogenic effects, as IL-19-stimulated bone marrow-derived macrophages secrete proangiogenic factors that induce greater sprouting of aortic rings than unstimulated controls. Using a quantitative RT-PCR screen, we determined that IL-19 induces expression of angiogenic cytokines in bone marrow-derived macrophages. Together, these data suggest that IL-19 can promote angiogenesis in the absence of hypoxia by at least two distinct mechanisms: 1) direct effects on vascular cells and 2) indirect effects by stimulation of macrophages.
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Affiliation(s)
- Farah Kako
- Department of Physiology, Independence Blue Cross Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania
| | - Khatuna Gabunia
- Department of Physiology, Independence Blue Cross Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania
| | - Mitali Ray
- Department of Physiology, Independence Blue Cross Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania
| | - Sheri E Kelemen
- Department of Physiology, Independence Blue Cross Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania
| | - Ross N England
- Department of Physiology, Independence Blue Cross Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania
| | - Bashar Kako
- Department of Physiology, Independence Blue Cross Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania
| | - Rosario G Scalia
- Department of Physiology, Independence Blue Cross Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania
| | - Michael V Autieri
- Department of Physiology, Independence Blue Cross Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania
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Yu B, Yang Y, Liu H, Gong M, Millard RW, Wang YG, Ashraf M, Xu M. Clusterin/Akt Up-Regulation Is Critical for GATA-4 Mediated Cytoprotection of Mesenchymal Stem Cells against Ischemia Injury. PLoS One 2016; 11:e0151542. [PMID: 26962868 PMCID: PMC4786134 DOI: 10.1371/journal.pone.0151542] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2015] [Accepted: 02/29/2016] [Indexed: 01/12/2023] Open
Abstract
Background Clusterin (Clu) is a stress-responding protein with multiple biological functions. Our preliminary microarray studies show that clusterin was prominently upregulated in mesenchymal stem cells (MSCs) overexpressing GATA-4 (MSCGATA-4). We hypothesized that the upregulation of clusterin is involved in overexpression of GATA-4 mediated cytoprotection. Methods MSCs harvested from bone marrow of rats were transduced with GATA-4. The expression of clusterin in MSCs was further confirmed by real-time PCR and western blotting. Simulation of ischemia was achieved by exposure of MSCs to a hypoxic environment. Lactate dehydrogenase (LDH) released from MSCs was served as a biomarker of cell injury and MTs uptake was used to estimate cell viability. Mitochondrial function was evaluated by measuring mitochondrial membrane potential (ΔΨm) and caspase 3/7 activity. Results (1) Clusterin expression was up-regulated in MSCGATA-4 compared to control MSCs transfected with empty-vector (MSCNull). MSCGATA-4 were tolerant to 72 h hypoxia exposure as shown by reduced LDH release and higher MTs uptake. This protection was abrogated by transfecting Clu-siRNA into MSCGATA-4. (2) Exogenous clusterin significantly decreased LDH release and increased MSC survival in hypoxic environment. Moreover, ΔΨm was maintained and caspase 3/7 activity was reduced by clusterin in a concentration-dependent manner. (3) p-Akt expression in MSCs was upregulated following pre-treatment with clusterin, with no change in total Akt. Moreover, cytoprotection mediated by clusterin was partially abrogated by Akt inhibitor LY294002. Conclusions Clusterin/Akt signaling pathway is involved in GATA-4 mediated cytoprotection against hypoxia stress. It is suggested that clusterin may be therapeutically exploited in MSC based therapy for cardiovascular diseases.
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Affiliation(s)
- Bin Yu
- Department of Pathology and Laboratory Medicine, University of Cincinnati Medical Center, Cincinnati, Ohio, United States of America
| | - Yueting Yang
- Department of Pathology and Laboratory Medicine, University of Cincinnati Medical Center, Cincinnati, Ohio, United States of America
| | - Huan Liu
- Department of Pathology and Laboratory Medicine, University of Cincinnati Medical Center, Cincinnati, Ohio, United States of America
| | - Min Gong
- Department of Pathology and Laboratory Medicine, University of Cincinnati Medical Center, Cincinnati, Ohio, United States of America
| | - Ronald W. Millard
- Department of Pharmacology & Cell Biophysics, University of Cincinnati Medical Center, Cincinnati, Ohio, United States of America
| | - Yi-Gang Wang
- Department of Pathology and Laboratory Medicine, University of Cincinnati Medical Center, Cincinnati, Ohio, United States of America
| | - Muhammad Ashraf
- Department of Pathology and Laboratory Medicine, University of Cincinnati Medical Center, Cincinnati, Ohio, United States of America
| | - Meifeng Xu
- Department of Pathology and Laboratory Medicine, University of Cincinnati Medical Center, Cincinnati, Ohio, United States of America
- * E-mail:
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Chen Q, Varga M, Wang X, Haddad DJ, An S, Medzikovic L, Derakhshandeh R, Kostyushev DS, Zhang Y, Clifford BT, Luu E, Danforth OM, Rafikov R, Gong W, Black SM, Suchkov SV, Fineman JR, Heiss C, Aschbacher K, Yeghiazarians Y, Springer ML. Overexpression of Nitric Oxide Synthase Restores Circulating Angiogenic Cell Function in Patients With Coronary Artery Disease: Implications for Autologous Cell Therapy for Myocardial Infarction. J Am Heart Assoc 2016; 5:e002257. [PMID: 26738788 PMCID: PMC4859354 DOI: 10.1161/jaha.115.002257] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2015] [Accepted: 11/25/2015] [Indexed: 12/24/2022]
Abstract
BACKGROUND Circulating angiogenic cells (CACs) are peripheral blood cells whose functional capacity inversely correlates with cardiovascular risk and that have therapeutic benefits in animal models of cardiovascular disease. However, donor age and disease state influence the efficacy of autologous cell therapy. We sought to determine whether age or coronary artery disease (CAD) impairs the therapeutic potential of CACs for myocardial infarction (MI) and whether the use of ex vivo gene therapy to overexpress endothelial nitric oxide (NO) synthase (eNOS) overcomes these defects. METHODS AND RESULTS We recruited 40 volunteers varying by sex, age (< or ≥45 years), and CAD and subjected their CACs to well-established functional tests. Age and CAD were associated with reduced CAC intrinsic migration (but not specific response to vascular endothelial growth factor, adherence of CACs to endothelial tubes, eNOS mRNA and protein levels, and NO production. To determine how CAC function influences therapeutic potential, we injected the 2 most functional and the 2 least functional CAC isolates into mouse hearts post MI. The high-function isolates substantially improved cardiac function, whereas the low-function isolates led to cardiac function only slightly better than vehicle control. Transduction of the worst isolate with eNOS cDNA adenovirus increased NO production, migration, and cardiac function of post-MI mice implanted with the CACs. Transduction of the best isolate with eNOS small interfering RNA adenovirus reduced all of these capabilities. CONCLUSIONS Age and CAD impair multiple functions of CACs and limit therapeutic potential for the treatment of MI. eNOS gene therapy in CACs from older donors or those with CAD has the potential to improve autologous cell therapy outcomes.
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Affiliation(s)
- Qiumei Chen
- Cardiovascular Research InstituteUniversity of California, San FranciscoSan FranciscoCA
| | - Monika Varga
- Cardiovascular Research InstituteUniversity of California, San FranciscoSan FranciscoCA
| | - Xiaoyin Wang
- Cardiovascular Research InstituteUniversity of California, San FranciscoSan FranciscoCA
| | - Daniel J. Haddad
- Cardiovascular Research InstituteUniversity of California, San FranciscoSan FranciscoCA
| | - Songtao An
- Cardiovascular Research InstituteUniversity of California, San FranciscoSan FranciscoCA
| | - Lejla Medzikovic
- Division of CardiologyUniversity of California, San FranciscoSan FranciscoCA
| | - Ronak Derakhshandeh
- Division of CardiologyUniversity of California, San FranciscoSan FranciscoCA
| | | | - Yan Zhang
- Division of CardiologyUniversity of California, San FranciscoSan FranciscoCA
| | - Brian T. Clifford
- Cardiovascular Research InstituteUniversity of California, San FranciscoSan FranciscoCA
| | - Emmy Luu
- Division of CardiologyUniversity of California, San FranciscoSan FranciscoCA
| | - Olivia M. Danforth
- Cardiovascular Research InstituteUniversity of California, San FranciscoSan FranciscoCA
| | | | - Wenhui Gong
- Department of PediatricsUniversity of California, San FranciscoSan FranciscoCA
| | | | | | - Jeffrey R. Fineman
- Cardiovascular Research InstituteUniversity of California, San FranciscoSan FranciscoCA
- Department of PediatricsUniversity of California, San FranciscoSan FranciscoCA
| | - Christian Heiss
- Division of CardiologyUniversity of California, San FranciscoSan FranciscoCA
| | - Kirstin Aschbacher
- Department of PsychiatryUniversity of California, San FranciscoSan FranciscoCA
| | - Yerem Yeghiazarians
- Cardiovascular Research InstituteUniversity of California, San FranciscoSan FranciscoCA
- Division of CardiologyUniversity of California, San FranciscoSan FranciscoCA
- Eli & Edythe Broad Institute of Regeneration Medicine and Stem Cell ResearchUniversity of California, San FranciscoSan FranciscoCA
| | - Matthew L. Springer
- Cardiovascular Research InstituteUniversity of California, San FranciscoSan FranciscoCA
- Division of CardiologyUniversity of California, San FranciscoSan FranciscoCA
- Eli & Edythe Broad Institute of Regeneration Medicine and Stem Cell ResearchUniversity of California, San FranciscoSan FranciscoCA
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Pharmacological Therapy in the Heart as an Alternative to Cellular Therapy: A Place for the Brain Natriuretic Peptide? Stem Cells Int 2016; 2016:5961342. [PMID: 26880973 PMCID: PMC4735943 DOI: 10.1155/2016/5961342] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2015] [Revised: 09/08/2015] [Accepted: 10/08/2015] [Indexed: 02/08/2023] Open
Abstract
The discovery that stem cells isolated from different organs have the ability to differentiate into mature beating cardiomyocytes has fostered considerable interest in developing cellular regenerative therapies to treat cardiac diseases associated with the loss of viable myocardium. Clinical studies evaluating the potential of stem cells (from heart, blood, bone marrow, skeletal muscle, and fat) to regenerate the myocardium and improve its functional status indicated that although the method appeared generally safe, its overall efficacy has remained modest. Several issues raised by these studies were notably related to the nature and number of injected cells, as well as the route and timing of their administration, to cite only a few. Besides the direct administration of cardiac precursor cells, a distinct approach to cardiac regeneration could be based upon the stimulation of the heart's natural ability to regenerate, using pharmacological approaches. Indeed, differentiation and/or proliferation of cardiac precursor cells is controlled by various endogenous mediators, such as growth factors and cytokines, which could thus be used as pharmacological agents to promote regeneration. To illustrate such approach, we present recent results showing that the exogenous administration of the natriuretic peptide BNP triggers “endogenous” cardiac regeneration, following experimental myocardial infarction.
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Taylor DA, Perin EC, Willerson JT, Zierold C, Resende M, Carlson M, Nestor B, Wise E, Orozco A, Pepine CJ, Henry TD, Ellis SG, Zhao DXM, Traverse JH, Cooke JP, Schutt RC, Bhatnagar A, Grant MB, Lai D, Johnstone BH, Sayre SL, Moyé L, Ebert RF, Bolli R, Simari RD, Cogle CR. Identification of Bone Marrow Cell Subpopulations Associated With Improved Functional Outcomes in Patients With Chronic Left Ventricular Dysfunction: An Embedded Cohort Evaluation of the FOCUS-CCTRN Trial. Cell Transplant 2015; 25:1675-1687. [PMID: 26590374 PMCID: PMC5088500 DOI: 10.3727/096368915x689901] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
In the current study, we sought to identify bone marrow-derived mononuclear cell (BM-MNC) subpopulations associated with a combined improvement in left ventricular ejection fraction (LVEF), left ventricular end-systolic volume (LVESV), and maximal oxygen consumption (VO2 max) in patients with chronic ischemic cardiomyopathy 6 months after receiving transendocardial injections of autologous BM-MNCs or placebo. For this prospectively planned analysis, we conducted an embedded cohort study comprising 78 patients from the FOCUS-Cardiovascular Cell Therapy Research Network (CCTRN) trial. Baseline BM-MNC immunophenotypes and progenitor cell activity were determined by flow cytometry and colony-forming assays, respectively. Previously stable patients who demonstrated improvement in LVEF, LVESV, and VO2 max during the 6-month course of the FOCUS-CCTRN study (group 1, n = 17) were compared to those who showed no change or worsened in one to three of these endpoints (group 2, n = 61) and to a subset of patients from group 2 who declined in all three functional endpoints (group 2A, n = 11). Group 1 had higher frequencies of B-cell and CXCR4+ BM-MNC subpopulations at study baseline than group 2 or 2A. Furthermore, patients in group 1 had fewer endothelial colony-forming cells and monocytes/macrophages in their bone marrow than those in group 2A. To our knowledge, this is the first study to show that in patients with ischemic cardiomyopathy, certain bone marrow-derived cell subsets are associated with improvement in LVEF, LVESV, and VO2 max at 6 months. These results suggest that the presence of both progenitor and immune cell populations in the bone marrow may influence the natural history of chronic ischemic cardiomyopathy-even in stable patients. Thus, it may be important to consider the bone marrow composition and associated regenerative capacity of patients when assigning them to treatment groups and evaluating the results of cell therapy trials.
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Affiliation(s)
- Doris A. Taylor
- Texas Heart Institute, CHI St. Luke’s Health, Houston, TX, USA
| | | | | | - Claudia Zierold
- University of Minnesota School of Medicine, Minneapolis, MN, USA
| | | | - Marjorie Carlson
- University of Minnesota School of Medicine, Minneapolis, MN, USA
| | - Belinda Nestor
- Texas Heart Institute, CHI St. Luke’s Health, Houston, TX, USA
| | - Elizabeth Wise
- University of Florida College of Medicine, Gainesville, FL, USA
| | - Aaron Orozco
- Texas Heart Institute, CHI St. Luke’s Health, Houston, TX, USA
| | - Carl J. Pepine
- University of Florida College of Medicine, Gainesville, FL, USA
| | - Timothy D. Henry
- Cedars-Sinai Heart Institute, Los Angeles, CA, USA
- Minneapolis Heart Institute Foundation at Abbott, Minneapolis, MN, USA
| | | | | | - Jay H. Traverse
- Minneapolis Heart Institute Foundation at Abbott, Minneapolis, MN, USA
| | - John P. Cooke
- Houston Methodist DeBakey Heart & Vascular Center, Houston, TX, USA
- Houston Methodist Research Institute, Houston, TX, USA
| | - Robert C. Schutt
- Houston Methodist DeBakey Heart & Vascular Center, Houston, TX, USA
- Houston Methodist Research Institute, Houston, TX, USA
| | | | - Maria B. Grant
- University of Florida College of Medicine, Gainesville, FL, USA
| | - Dejian Lai
- University of Texas School of Public Health, Houston, TX, USA
| | | | - Shelly L. Sayre
- University of Texas School of Public Health, Houston, TX, USA
| | - Lem Moyé
- University of Texas School of Public Health, Houston, TX, USA
| | - Ray F. Ebert
- National Heart, Lung, and Blood Institute, Bethesda, MD, USA
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Hou J, Yan P, Guo T, Xing Y, Zheng S, Zhou C, Huang H, Long H, Zhong T, Wu Q, Wang J, Wang T. Cardiac stem cells transplantation enhances the expression of connexin 43 via the ANG II/AT1R/TGF-beta1 signaling pathway in a rat model of myocardial infarction. Exp Mol Pathol 2015; 99:693-701. [PMID: 26554848 DOI: 10.1016/j.yexmp.2015.11.013] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2015] [Accepted: 11/06/2015] [Indexed: 10/22/2022]
Abstract
BACKGROUND In this study, we hypothesized that CSCs mediated the expression of Cx43 after transplantation post MI via the ANG II/AT1R/TGF-beta1 signaling pathway. METHODS Myocardial infarction (MI) was induced in twenty male Sprague-Dawley rats. The rats were randomized into two groups and were then received the injection of 5 × 10(6) CSCs labeled with PKH26 in phosphate buffer solution (PBS) or equal PBS alone into the infarct anterior ventricular free wall two weeks after MI. Six weeks later, relevant signaling molecules involved were all examined. RESULTS In the CSCs group, an increased expression of Cx43 could be observed in different zones of the left ventricle (P<0.01). There was a significant reduction of the angiotensin II (ANG II) level in plasma and different regions of the left ventricular cardiac tissues (P<0.05; P<0.01). The angiotensin II type I receptor (AT1R) was decreased accompanied with an enhanced expression of angiotensin II type II receptor (AT2R) (P<0.01). Transforming growth factor beta-1(TGF-beta1) was downregulated (P<0.01). The expression of mothers against decapentaplegic homolog (SMAD) proteins including SMAD2 and SMAD3 was attenuated whereas SMAD7 was elevated (P<0.01, P<0.01, P<0.05). In addition, the expression of mitogen-activated protein kinases (MAPKs) including extracellular kinases 1/2 (ERK1/2) and p38 was also found to be reduced (P<0.01). CONCLUSION CSCs transplantation could enhance the level of Cx43 after MI. They might function through intervening the ANGII/AT1R/TGF-beta1 signaling pathway to regulate the expression of Cx43.
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Affiliation(s)
- Jingying Hou
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, the Sun Yat-sen Memorial Hospital of Sun Yat-sen University, 107 Yanjiang Xi Road, Guangzhou, Guangdong 510120, China; Department of Emergency, the Sun Yat-sen Memorial Hospital of Sun Yat-sen University, 107 Yanjiang Xi Road, Guangzhou, Guangdong, China
| | - Ping Yan
- The First Affiliated Hospital of Guangzhou Medical University, 151 Yanjiang Xi Road, Guangzhou, Guangdong, China
| | - Tianzhu Guo
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, the Sun Yat-sen Memorial Hospital of Sun Yat-sen University, 107 Yanjiang Xi Road, Guangzhou, Guangdong 510120, China; Department of Emergency, the Sun Yat-sen Memorial Hospital of Sun Yat-sen University, 107 Yanjiang Xi Road, Guangzhou, Guangdong, China
| | - Yue Xing
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, the Sun Yat-sen Memorial Hospital of Sun Yat-sen University, 107 Yanjiang Xi Road, Guangzhou, Guangdong 510120, China
| | - Shaoxin Zheng
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, the Sun Yat-sen Memorial Hospital of Sun Yat-sen University, 107 Yanjiang Xi Road, Guangzhou, Guangdong 510120, China; Guangdong Province Key Laboratory of Arrhythmia and Electrophysiology, 107 Yanjiang Xi Road, Guangzhou, Guangdong, China
| | - Changqing Zhou
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, the Sun Yat-sen Memorial Hospital of Sun Yat-sen University, 107 Yanjiang Xi Road, Guangzhou, Guangdong 510120, China; Department of Emergency, the Sun Yat-sen Memorial Hospital of Sun Yat-sen University, 107 Yanjiang Xi Road, Guangzhou, Guangdong, China
| | - Hui Huang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, the Sun Yat-sen Memorial Hospital of Sun Yat-sen University, 107 Yanjiang Xi Road, Guangzhou, Guangdong 510120, China; Guangdong Province Key Laboratory of Arrhythmia and Electrophysiology, 107 Yanjiang Xi Road, Guangzhou, Guangdong, China
| | - Huibao Long
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, the Sun Yat-sen Memorial Hospital of Sun Yat-sen University, 107 Yanjiang Xi Road, Guangzhou, Guangdong 510120, China; Department of Emergency, the Sun Yat-sen Memorial Hospital of Sun Yat-sen University, 107 Yanjiang Xi Road, Guangzhou, Guangdong, China
| | - Tingting Zhong
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, the Sun Yat-sen Memorial Hospital of Sun Yat-sen University, 107 Yanjiang Xi Road, Guangzhou, Guangdong 510120, China; The First Affiliated Hospital of Guangzhou Medical University, 151 Yanjiang Xi Road, Guangzhou, Guangdong, China
| | - Quanhua Wu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, the Sun Yat-sen Memorial Hospital of Sun Yat-sen University, 107 Yanjiang Xi Road, Guangzhou, Guangdong 510120, China; Department of Emergency, the Sun Yat-sen Memorial Hospital of Sun Yat-sen University, 107 Yanjiang Xi Road, Guangzhou, Guangdong, China
| | - Jingfeng Wang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, the Sun Yat-sen Memorial Hospital of Sun Yat-sen University, 107 Yanjiang Xi Road, Guangzhou, Guangdong 510120, China; Guangdong Province Key Laboratory of Arrhythmia and Electrophysiology, 107 Yanjiang Xi Road, Guangzhou, Guangdong, China
| | - Tong Wang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, the Sun Yat-sen Memorial Hospital of Sun Yat-sen University, 107 Yanjiang Xi Road, Guangzhou, Guangdong 510120, China; Guangdong Province Key Laboratory of Arrhythmia and Electrophysiology, 107 Yanjiang Xi Road, Guangzhou, Guangdong, China; Department of Emergency, the Sun Yat-sen Memorial Hospital of Sun Yat-sen University, 107 Yanjiang Xi Road, Guangzhou, Guangdong, China.
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Fisher SA, Zhang H, Doree C, Mathur A, Martin‐Rendon E. Stem cell treatment for acute myocardial infarction. Cochrane Database Syst Rev 2015; 2015:CD006536. [PMID: 26419913 PMCID: PMC8572033 DOI: 10.1002/14651858.cd006536.pub4] [Citation(s) in RCA: 81] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND Cell transplantation offers a potential therapeutic approach to the repair and regeneration of damaged vascular and cardiac tissue after acute myocardial infarction (AMI). This has resulted in multiple randomised controlled trials (RCTs) across the world. OBJECTIVES To determine the safety and efficacy of autologous adult bone marrow stem cells as a treatment for acute myocardial infarction (AMI), focusing on clinical outcomes. SEARCH METHODS This Cochrane review is an update of a previous version (published in 2012). We searched the Cochrane Central Register of Controlled Trials (CENTRAL 2015, Issue 2), MEDLINE (1950 to March 2015), EMBASE (1974 to March 2015), CINAHL (1982 to March 2015) and the Transfusion Evidence Library (1980 to March 2015). In addition, we searched several international and ongoing trial databases in March 2015 and handsearched relevant conference proceedings to January 2011. SELECTION CRITERIA RCTs comparing autologous bone marrow-derived cells with no cells in patients diagnosed with AMI were eligible. DATA COLLECTION AND ANALYSIS Two review authors independently screened all references, assessed the risk of bias of the included trials and extracted data. We conducted meta-analyses using random-effects models throughout. We analysed outcomes at short-term (less than 12 months) and long-term (12 months or more) follow-up. Dichotomous outcomes are reported as risk ratio (RR) and continuous outcomes are reported as mean difference (MD) or standardised MD (SMD). We performed sensitivity analyses to evaluate the results in the context of the risk of selection, performance and attrition bias. Exploratory subgroup analysis investigated the effects of baseline cardiac function (left ventricular ejection fraction, LVEF) and cell dose, type and timing of administration, as well as the use of heparin in the final cell solution. MAIN RESULTS Forty-one RCTs with a total of 2732 participants (1564 cell therapy, 1168 controls) were eligible for inclusion. Cell treatment was not associated with any changes in the risk of all-cause mortality (34/538 versus 32/458; RR 0.93, 95% CI 0.58 to 1.50; 996 participants; 14 studies; moderate quality evidence), cardiovascular mortality (23/277 versus 18/250; RR 1.04, 95% CI 0.54 to 1.99; 527 participants; nine studies; moderate quality evidence) or a composite measure of mortality, reinfarction and re-hospitalisation for heart failure (24/262 versus 33/235; RR 0.63, 95% CI 0.36 to 1.10; 497 participants; six studies; moderate quality evidence) at long-term follow-up. Statistical heterogeneity was low (I(2) = 0% to 12%). Serious periprocedural adverse events were rare and were generally unlikely to be related to cell therapy. Additionally, cell therapy had no effect on morbidity, quality of life/performance or LVEF measured by magnetic resonance imaging. Meta-analyses of LVEF measured by echocardiography, single photon emission computed tomography and left ventricular angiography showed evidence of differences in mean LVEF between treatment groups although the mean differences ranged between 2% and 5%, which are accepted not to be clinically relevant. Results were robust to the risk of selection, performance and attrition bias from individual studies. AUTHORS' CONCLUSIONS The results of this review suggest that there is insufficient evidence for a beneficial effect of cell therapy for AMI patients. However, most of the evidence comes from small trials that showed no difference in clinically relevant outcomes. Further adequately powered trials are needed and until then the efficacy of this intervention remains unproven.
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Affiliation(s)
- Sheila A Fisher
- NHS Blood and TransplantSystematic Review InitiativeLevel 2, John Radcliffe HospitalHeadingtonOxfordOxonUKOX3 9BQ
| | - Huajun Zhang
- PLA General Hospital, Institute of Cardiac SurgeryDepartment of Cardiovascular Surgery28 Fuxing RoadBeijingChina100853
| | - Carolyn Doree
- NHS Blood and TransplantSystematic Review InitiativeLevel 2, John Radcliffe HospitalHeadingtonOxfordOxonUKOX3 9BQ
| | - Anthony Mathur
- William Harvey Research InstituteDepartment of Clinical PharmacologyCharterhouse SquareLondonUKEC1M 6BQ
| | - Enca Martin‐Rendon
- NHS Blood and TransplantStem Cell Research DepartmentJohn Radcliffe HospitalHeadingtonOxfordUKOX3 9BQ
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Huang R, Yao K, Sun A, Qian J, Ge L, Zhang Y, Niu Y, Wang K, Zou Y, Ge J. Timing for intracoronary administration of bone marrow mononuclear cells after acute ST-elevation myocardial infarction: a pilot study. Stem Cell Res Ther 2015; 6:112. [PMID: 26021558 PMCID: PMC4509778 DOI: 10.1186/s13287-015-0102-5] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2014] [Revised: 07/16/2014] [Accepted: 05/20/2015] [Indexed: 12/21/2022] Open
Abstract
INTRODUCTION Most studies on intracoronary bone marrow mononuclear cell transplantation for acute myocardial infarction involve treatment 3-7 days after primary percutaneous coronary intervention (PCI); however, the optimal timing is unknown. The present study assessed the therapeutic effect at different times after ST-elevation myocardial infarction. METHODS The present trial was not blinded. A total of 104 patients with a first ST-elevation myocardial infarction and a left ventricular ejection fraction below 50 %, who had PCI of the infarct-related artery, were randomly assigned to receive intracoronary infusion of bone marrow mononuclear cells within 24 hours (group A, n = 27), 3 to 7 days after PCI (group B, n = 26), or 7 to 30 days after PCI (group C, n = 26), or to the control group (n = 25), which received saline infusion performed immediately after emergency PCI. All patients in groups A, B and C received an injection of 15 ml cell suspension containing approximately 4.9 × 10(8) bone marrow mononuclear cells into the infarct-related artery after successful PCI. RESULTS Compared to control and group C patients, group A and B patients had a significantly higher absolute increase in left ventricular ejection fraction from baseline to 12 months (change: 3.4 ± 5.7 % in control, 7.9 ± 4.9 % in group A, 6.9 ± 3.9 % in group B, 4.7 ± 3.7 % in group C), a greater decrease in left ventricular end-systolic volumes (change: -6.4 ± 15.9 ml in control, -20.5 ± 13.3 ml in group A, -19.6 ± 11.1 ml in group B, -9.4 ± 16.3 ml in group C), and significantly greater myocardial perfusion (change from baseline: -4.7 ± 5.7 % in control, -7.8 ± 4.5 % in group A, -7.5 ± 2.9 % in group B, -5.0 ± 4.0 % in group C). Group A and B patients had similar beneficial effects on cardiac function (p = 0.163) and left ventricular geometry (left ventricular end-distolic volume: p = 0.685; left ventricular end-systolic volume: p = 0.622) assessed by echocardiography, whereas group C showed similar results to those of the control group. Group B showed more expensive care (p < 0.001) and longer hospital stays during the first month after emergency PCI (p < 0.001) than group A, with a similar improvement after repeat cardiac catheterization following emergency PCI. CONCLUSION Cell therapy in acute myocardial infarction patients that is given within 24 hours is similar to 3-7 days after the primary PCI. TRIAL REGISTRATION NCT02425358 , registered 30 April 2015.
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Affiliation(s)
- Rongchong Huang
- The First Affiliated Hospital of Dalian Medical University, 222 Zhongshan Road, Dalian, 116011, China
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai, 200032, China
| | - Kang Yao
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai, 200032, China
| | - Aijun Sun
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai, 200032, China
- Institutes of Biomedical Science, Fudan University, 138 Dong'an Road, Shanghai, 200032, China
| | - Juying Qian
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai, 200032, China
| | - Lei Ge
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai, 200032, China
| | - Yiqi Zhang
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai, 200032, China
| | - Yuhong Niu
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai, 200032, China
| | - Keqiang Wang
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai, 200032, China
| | - Yunzeng Zou
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai, 200032, China
- Institutes of Biomedical Science, Fudan University, 138 Dong'an Road, Shanghai, 200032, China
| | - Junbo Ge
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai, 200032, China.
- Institutes of Biomedical Science, Fudan University, 138 Dong'an Road, Shanghai, 200032, China.
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Crespo-Diaz R, Yamada S, Bartunek J, Perez-Terzic C, de Waele P, Mauën S, Terzic A, Behfar A. Cardiopoietic index predicts heart repair fitness of patient-derived stem cells. Biomark Med 2015; 9:639-49. [PMID: 26014833 DOI: 10.2217/bmm.15.31] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Stem cell therapy shows promise for regeneration in heart disease, yet interpatient variability challenges implementation into practice. AIM To establish a biomarker profile, predictive of reparative potential in patient-derived progenitors, human mesenchymal stem cells were isolated from patients undergoing coronary artery bypass grafting. MATERIALS & METHODS Stem cell delivery postinfarction translated into divergent benefit, distinguishing reparative from nonreparative populations. RESULTS While the nonreparative subtype was characterized by low expression of cardiac transcription factors, reparative human mesenchymal stem cells demonstrated high expression of cardiac transcription factors. CONCLUSION This index of factors (cardiopoietic index) was found sensitive and specific in predicting impact of stem cell benefit on left ventricular function. The cardiopoietic index thus offers a tool to screen stem cell fitness for heart repair prior to intervention.
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Affiliation(s)
- Ruben Crespo-Diaz
- Center for Regenerative Medicine, Marriott Heart Disease Research Program, Division of Cardiovascular Diseases, Department of Medicine, Molecular Pharmacology & Experimental Therapeutics, Rochester, MN 55905, USA
| | - Satsuki Yamada
- Center for Regenerative Medicine, Marriott Heart Disease Research Program, Division of Cardiovascular Diseases, Department of Medicine, Molecular Pharmacology & Experimental Therapeutics, Rochester, MN 55905, USA
| | | | - Carmen Perez-Terzic
- Center for Regenerative Medicine, Marriott Heart Disease Research Program, Division of Cardiovascular Diseases, Department of Medicine, Molecular Pharmacology & Experimental Therapeutics, Rochester, MN 55905, USA.,Department of Physical Medicine & Rehabilitation, Mayo Clinic, Rochester, MN 55905, USA
| | | | | | - Andre Terzic
- Center for Regenerative Medicine, Marriott Heart Disease Research Program, Division of Cardiovascular Diseases, Department of Medicine, Molecular Pharmacology & Experimental Therapeutics, Rochester, MN 55905, USA
| | - Atta Behfar
- Center for Regenerative Medicine, Marriott Heart Disease Research Program, Division of Cardiovascular Diseases, Department of Medicine, Molecular Pharmacology & Experimental Therapeutics, Rochester, MN 55905, USA
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Logan SJ, Yin L, Geldenhuys WJ, Enrick MK, Stevanov KM, Carroll RT, Ohanyan VA, Kolz CL, Chilian WM. Novel thiazolidinedione mitoNEET ligand-1 acutely improves cardiac stem cell survival under oxidative stress. Basic Res Cardiol 2015; 110:19. [PMID: 25725808 DOI: 10.1007/s00395-015-0471-z] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2014] [Revised: 02/10/2015] [Accepted: 02/17/2015] [Indexed: 11/29/2022]
Abstract
Ischemic heart disease (IHD) is a leading cause of death worldwide, and regenerative therapies through exogenous stem cell delivery hold promising potential. One limitation of such therapies is the vulnerability of stem cells to the oxidative environment associated with IHD. Accordingly, manipulation of stem cell mitochondrial metabolism may be an effective strategy to improve survival of stem cells under oxidative stress. MitoNEET is a redox-sensitive, mitochondrial target of thiazolidinediones (TZDs), and influences cellular oxidative capacity. Pharmacological targeting of mitoNEET with the novel TZD, mitoNEET Ligand-1 (NL-1), improved cardiac stem cell (CSC) survival compared to vehicle (0.1% DMSO) during in vitro oxidative stress (H2O2). 10 μM NL-1 also reduced CSC maximal oxygen consumption rate (OCR) compared to vehicle. Following treatment with dexamethasone, CSC maximal OCR increased compared to baseline, but NL-1 prevented this effect. Smooth muscle α-actin expression increased significantly in CSC following differentiation compared to baseline, irrespective of NL-1 treatment. When CSCs were treated with glucose oxidase for 7 days, NL-1 significantly improved cell survival compared to vehicle (trypan blue exclusion). NL-1 treatment of cells isolated from mitoNEET knockout mice did not increase CSC survival with H2O2 treatment. Following intramyocardial injection of CSCs into Zucker obese fatty rats, NL-1 significantly improved CSC survival after 24 h, but not after 10 days. These data suggest that pharmacological targeting of mitoNEET with TZDs may acutely protect stem cells following transplantation into an oxidative environment. Continued treatment or manipulation of mitochondrial metabolism may be necessary to produce long-term benefits related to stem cell therapies.
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Affiliation(s)
- Suzanna J Logan
- Department of Integrative Medical Sciences, Northeast Ohio Medical University, 4209 State Rt. 44, Rootstown, OH, 44272, USA
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Picozza M, Pompilio G, Capogrossi MC. Bone good to the heart: bone marrow cell characteristics and cardiac repair after STEMI in the CCTRN TIME cohort. Circ Res 2015; 116:16-8. [PMID: 25552689 DOI: 10.1161/circresaha.114.305502] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Affiliation(s)
- Mario Picozza
- From the Laboratory of Vascular Pathology, Istituto Dermopatico dell'Immacolata-IRCCS, Rome, Italy (M.P., M.C.C.); Laboratory of Vascular Biology and Regenerative Medicine, Centro Cardiologico Monzino-IRCCS, Milan, Italy (G.P.); and Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy (G.P.)
| | - Giulio Pompilio
- From the Laboratory of Vascular Pathology, Istituto Dermopatico dell'Immacolata-IRCCS, Rome, Italy (M.P., M.C.C.); Laboratory of Vascular Biology and Regenerative Medicine, Centro Cardiologico Monzino-IRCCS, Milan, Italy (G.P.); and Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy (G.P.)
| | - Maurizio C Capogrossi
- From the Laboratory of Vascular Pathology, Istituto Dermopatico dell'Immacolata-IRCCS, Rome, Italy (M.P., M.C.C.); Laboratory of Vascular Biology and Regenerative Medicine, Centro Cardiologico Monzino-IRCCS, Milan, Italy (G.P.); and Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy (G.P.).
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