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Yang J. Partial Cell Fate Transitions to Promote Cardiac Regeneration. Cells 2024; 13:2002. [PMID: 39682750 PMCID: PMC11640292 DOI: 10.3390/cells13232002] [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: 10/23/2024] [Revised: 11/24/2024] [Accepted: 12/02/2024] [Indexed: 12/18/2024] Open
Abstract
Heart disease, including myocardial infarction (MI), remains a leading cause of morbidity and mortality worldwide, necessitating the development of more effective regenerative therapies. Direct reprogramming of cardiomyocyte-like cells from resident fibroblasts offers a promising avenue for myocardial regeneration, but its efficiency and consistency in generating functional cardiomyocytes remain limited. Alternatively, reprogramming induced cardiac progenitor cells (iCPCs) could generate essential cardiac lineages, but existing methods often involve complex procedures. These limitations underscore the need for advanced mechanistic insights and refined reprogramming strategies to improve reparative outcomes in the heart. Partial cellular fate transitions, while still a relatively less well-defined area and primarily explored in longevity and neurobiology, hold remarkable promise for cardiac repair. It enables the reprogramming or rejuvenation of resident cardiac cells into a stem or progenitor-like state with enhanced cardiogenic potential, generating the reparative lineages necessary for comprehensive myocardial recovery while reducing safety risks. As an emerging strategy, partial cellular fate transitions play a pivotal role in reversing myocardial infarction damage and offer substantial potential for therapeutic innovation. This review will summarize current advances in these areas, including recent findings involving two transcription factors that critically regulate stemness and cardiogenesis. It will also explore considerations for further refining these approaches to enhance their therapeutic potential and safety.
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Affiliation(s)
- Jianchang Yang
- Michael E. DeBakey Department of Surgery, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
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2
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Alizadeh R, Asghari A, Taghizadeh-Hesary F, Moradi S, Farhadi M, Mehdizadeh M, Simorgh S, Nourazarian A, Shademan B, Susanabadi A, Kamrava K. Intranasal delivery of stem cells labeled by nanoparticles in neurodegenerative disorders: Challenges and opportunities. WILEY INTERDISCIPLINARY REVIEWS. NANOMEDICINE AND NANOBIOTECHNOLOGY 2023; 15:e1915. [PMID: 37414546 DOI: 10.1002/wnan.1915] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/08/2022] [Revised: 05/05/2023] [Accepted: 06/11/2023] [Indexed: 07/08/2023]
Abstract
Neurodegenerative disorders occur through progressive loss of function or structure of neurons, with loss of sensation and cognition values. The lack of successful therapeutic approaches to solve neurologic disorders causes physical disability and paralysis and has a significant socioeconomic impact on patients. In recent years, nanocarriers and stem cells have attracted tremendous attention as a reliable approach to treating neurodegenerative disorders. In this regard, nanoparticle-based labeling combined with imaging technologies has enabled researchers to survey transplanted stem cells and fully understand their fate by monitoring their survival, migration, and differentiation. For the practical implementation of stem cell therapies in the clinical setting, it is necessary to accurately label and follow stem cells after administration. Several approaches to labeling and tracking stem cells using nanotechnology have been proposed as potential treatment strategies for neurological diseases. Considering the limitations of intravenous or direct stem cell administration, intranasal delivery of nanoparticle-labeled stem cells in neurological disorders is a new method of delivering stem cells to the central nervous system (CNS). This review describes the challenges and limitations of stem cell-based nanotechnology methods for labeling/tracking, intranasal delivery of cells, and cell fate regulation as theragnostic labeling. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Neurological Disease.
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Affiliation(s)
- Rafieh Alizadeh
- ENT and Head and Neck Research Center and Department, The Five Senses Health Institute, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Alimohamad Asghari
- Skull Base Research Center, The Five Senses Health Institute, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Farzad Taghizadeh-Hesary
- ENT and Head and Neck Research Center and Department, The Five Senses Health Institute, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Salah Moradi
- Department of Life Science Engineering, Faculty of New Science and Technology, University of Tehran, Tehran, Iran
| | - Mohammad Farhadi
- ENT and Head and Neck Research Center and Department, The Five Senses Health Institute, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mehdi Mehdizadeh
- Department of Anatomical Sciences, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Sara Simorgh
- Department of Tissue Engineering and Regenerative Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Alireza Nourazarian
- Department of Basic Medical Sciences, Khoy University of Medical Sciences, Khoy, Iran
| | - Behrouz Shademan
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Alireza Susanabadi
- Department of Anesthesia and Pain Medicine, Arak University of Medical Sciences, Arak, Iran
| | - Kamran Kamrava
- ENT and Head and Neck Research Center and Department, The Five Senses Health Institute, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
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Xie J, Jiang L, Wang J, Yin Y, Wang R, Du L, Chen T, Ni Z, Qiao S, Gong H, Xu B, Xu Q. Multilineage contribution of CD34 + cells in cardiac remodeling after ischemia/reperfusion injury. Basic Res Cardiol 2023; 118:17. [PMID: 37147443 PMCID: PMC10163140 DOI: 10.1007/s00395-023-00981-8] [Citation(s) in RCA: 3] [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: 01/29/2022] [Revised: 02/25/2023] [Accepted: 02/26/2023] [Indexed: 05/07/2023]
Abstract
The ambiguous results of multiple CD34+ cell-based therapeutic trials for patients with heart disease have halted the large-scale application of stem/progenitor cell treatment. This study aimed to delineate the biological functions of heterogenous CD34+ cell populations and investigate the net effect of CD34+ cell intervention on cardiac remodeling. We confirmed, by combining single-cell RNA sequencing on human and mouse ischemic hearts and an inducible Cd34 lineage-tracing mouse model, that Cd34+ cells mainly contributed to the commitment of mesenchymal cells, endothelial cells (ECs), and monocytes/macrophages during heart remodeling with distinct pathological functions. The Cd34+-lineage-activated mesenchymal cells were responsible for cardiac fibrosis, while CD34+Sca-1high was an active precursor and intercellular player that facilitated Cd34+-lineage angiogenic EC-induced postinjury vessel development. We found through bone marrow transplantation that bone marrow-derived CD34+ cells only accounted for inflammatory response. We confirmed using a Cd34-CreERT2; R26-DTA mouse model that the depletion of Cd34+ cells could alleviate the severity of ventricular fibrosis after ischemia/reperfusion (I/R) injury with improved cardiac function. This study provided a transcriptional and cellular landscape of CD34+ cells in normal and ischemic hearts and illustrated that the heterogeneous population of Cd34+ cell-derived cells served as crucial contributors to cardiac remodeling and function after the I/R injury, with their capacity to generate diverse cellular lineages.
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Affiliation(s)
- Jun Xie
- Department of Cardiology, Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing Universityrsity, State Key Laboratory of Pharmaceutical Biotechnology, No. 321 Zhongshan Road, Nanjing, 210008, Jiangsu, People's Republic of China
| | - Liujun Jiang
- Department of Cardiology, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, Zhejiang Province, People's Republic of China
| | - Junzhuo Wang
- Department of Cardiology, Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing Universityrsity, State Key Laboratory of Pharmaceutical Biotechnology, No. 321 Zhongshan Road, Nanjing, 210008, Jiangsu, People's Republic of China
| | - Yong Yin
- Department of Cardiology, Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing Universityrsity, State Key Laboratory of Pharmaceutical Biotechnology, No. 321 Zhongshan Road, Nanjing, 210008, Jiangsu, People's Republic of China
| | - Ruilin Wang
- Department of Cardiology, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, Zhejiang Province, People's Republic of China
| | - Luping Du
- Department of Cardiology, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, Zhejiang Province, People's Republic of China
| | - Ting Chen
- Department of Cardiology, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, Zhejiang Province, People's Republic of China
- Alibaba-Zhejiang University Joint Research Center of Future Digital Healthcare, Hangzhou, People's Republic of China
| | - Zhichao Ni
- Department of Cardiology, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, Zhejiang Province, People's Republic of China
| | - Shuaihua Qiao
- Department of Cardiology, Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing Universityrsity, State Key Laboratory of Pharmaceutical Biotechnology, No. 321 Zhongshan Road, Nanjing, 210008, Jiangsu, People's Republic of China
| | - Hui Gong
- Department of Cardiology, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, Zhejiang Province, People's Republic of China
| | - Biao Xu
- Department of Cardiology, Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing Universityrsity, State Key Laboratory of Pharmaceutical Biotechnology, No. 321 Zhongshan Road, Nanjing, 210008, Jiangsu, People's Republic of China.
| | - Qingbo Xu
- Department of Cardiology, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, Zhejiang Province, People's Republic of China.
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Shin IS, Park CH, Moon JH, Lee JK, Lee DH, Yang MJ. Human Bone Marrow-derived Clonal Mesenchymal Stem Cells Decrease the Initial C-Reactive Protein Level in Patients With Moderately Severe to Severe Acute Pancreatitis. Gastroenterology 2023; 164:1317-1320.e2. [PMID: 36801388 DOI: 10.1053/j.gastro.2023.02.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Revised: 02/04/2023] [Accepted: 02/12/2023] [Indexed: 02/23/2023]
Affiliation(s)
- Il Sang Shin
- Department of Internal Medicine, SoonChunHyang University School of Medicine, Bucheon, Korea
| | - Chang-Hwan Park
- Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea
| | - Jong Ho Moon
- Department of Internal Medicine, SoonChunHyang University School of Medicine, Bucheon, Korea.
| | - Jun Kyu Lee
- Department of Internal Medicine, Dongguk University School of Medicine, Ilsan, Korea
| | - Don Haeng Lee
- Department of Internal Medicine, Inha University School of Medicine, Incheon, Korea
| | - Min Jae Yang
- Department of Internal Medicine, Ajou University School of Medicine, Suwon, Korea
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Kanda M, Nagai T, Kondo N, Matsuura K, Akazawa H, Komuro I, Kobayashi Y. Pericardial Grafting of Cardiac Progenitor Cells in Self-Assembling Peptide Scaffold Improves Cardiac Function After Myocardial Infarction. Cell Transplant 2023; 32:9636897231174078. [PMID: 37191272 PMCID: PMC10192947 DOI: 10.1177/09636897231174078] [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: 03/17/2022] [Revised: 04/03/2023] [Accepted: 04/19/2023] [Indexed: 05/17/2023] Open
Abstract
Many studies have explored cardiac progenitor cell (CPC) therapy for heart disease. However, optimal scaffolds are needed to ensure the engraftment of transplanted cells. We produced a three-dimensional hydrogel scaffold (CPC-PRGmx) in which high-viability CPCs were cultured for up to 8 weeks. CPC-PRGmx contained an RGD peptide-conjugated self-assembling peptide with insulin-like growth factor-1 (IGF-1). Immediately after creating myocardial infarction (MI), we transplanted CPC-PRGmx into the pericardial space on to the surface of the MI area. Four weeks after transplantation, red fluorescent protein-expressing CPCs and in situ hybridization analysis in sex-mismatched transplantations revealed the engraftment of CPCs in the transplanted scaffold (which was cellularized with host cells). The average scar area of the CPC-PRGmx-treated group was significantly smaller than that of the non-treated group (CPC-PRGmx-treated group = 46 ± 5.1%, non-treated MI group = 59 ± 4.5%; p < 0.05). Echocardiography showed that the transplantation of CPC-PRGmx improved cardiac function and attenuated cardiac remodeling after MI. The transplantation of CPCs-PRGmx promoted angiogenesis and inhibited apoptosis, compared to the untreated MI group. CPCs-PRGmx secreted more vascular endothelial growth factor than CPCs cultured on two-dimensional dishes. Genetic fate mapping revealed that CPC-PRGmx-treated mice had more regenerated cardiomyocytes than non-treated mice in the MI area (CPC-PRGmx-treated group = 0.98 ± 0.25%, non-treated MI group = 0.25 ± 0.04%; p < 0.05). Our findings reveal the therapeutic potential of epicardial-transplanted CPC-PRGmx. Its beneficial effects may be mediated by sustainable cell viability, paracrine function, and the enhancement of de novo cardiomyogenesis.
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Affiliation(s)
- Masato Kanda
- Department of Cardiovascular Medicine,
Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Toshio Nagai
- Department of Cardiology, Chemotherapy
Research Institute, KAKEN Hospital, International University of Health and Welfare,
Ichikawa-shi, Japan
| | - Naomichi Kondo
- Department of Cardiovascular Medicine,
Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Katsuhisa Matsuura
- Institute of Advanced Biomedical
Engineering and Science, Tokyo Women’s Medical University, Tokyo, Japan
- Department of Cardiology, Tokyo Women’s
Medical University, Tokyo, Japan
| | - Hiroshi Akazawa
- Department of Cardiovascular Medicine,
Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Issei Komuro
- Department of Cardiovascular Medicine,
Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Yoshio Kobayashi
- Department of Cardiovascular Medicine,
Graduate School of Medicine, Chiba University, Chiba, Japan
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Cardiac regeneration following myocardial infarction: the need for regeneration and a review of cardiac stromal cell populations used for transplantation. Biochem Soc Trans 2022; 50:269-281. [PMID: 35129611 PMCID: PMC9042388 DOI: 10.1042/bst20210231] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 01/02/2022] [Accepted: 01/06/2022] [Indexed: 02/07/2023]
Abstract
Myocardial infarction is a leading cause of death globally due to the inability of the adult human heart to regenerate after injury. Cell therapy using cardiac-derived progenitor populations emerged about two decades ago with the aim of replacing cells lost after ischaemic injury. Despite early promise from rodent studies, administration of these populations has not translated to the clinic. We will discuss the need for cardiac regeneration and review the debate surrounding how cardiac progenitor populations exert a therapeutic effect following transplantation into the heart, including their ability to form de novo cardiomyocytes and the release of paracrine factors. We will also discuss limitations hindering the cell therapy field, which include the challenges of performing cell-based clinical trials and the low retention of administered cells, and how future research may overcome them.
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Yamada S, Bartunek J, Behfar A, Terzic A. Mass Customized Outlook for Regenerative Heart Failure Care. Int J Mol Sci 2021; 22:11394. [PMID: 34768825 PMCID: PMC8583673 DOI: 10.3390/ijms222111394] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 10/01/2021] [Accepted: 10/18/2021] [Indexed: 11/16/2022] Open
Abstract
Heart failure pathobiology is permissive to reparative intent. Regenerative therapies exemplify an emerging disruptive innovation aimed at achieving structural and functional organ restitution. However, mixed outcomes, complexity in use, and unsustainable cost have curtailed broader adoption, mandating the development of novel cardio-regenerative approaches. Lineage guidance offers a standardized path to customize stem cell fitness for therapy. A case in point is the molecular induction of the cardiopoiesis program in adult stem cells to yield cardiopoietic cell derivatives designed for heart failure treatment. Tested in early and advanced clinical trials in patients with ischemic heart failure, clinical grade cardiopoietic cells were safe and revealed therapeutic improvement within a window of treatment intensity and pre-treatment disease severity. With the prospect of mass customization, cardiopoietic guidance has been streamlined from the demanding, recombinant protein cocktail-based to a protein-free, messenger RNA-based single gene protocol to engineer affordable cardiac repair competent cells. Clinical trial biobanked stem cells enabled a systems biology deconvolution of the cardiopoietic cell secretome linked to therapeutic benefit, exposing a paracrine mode of action. Collectively, this new knowledge informs next generation regenerative therapeutics manufactured as engineered cellular or secretome mimicking cell-free platforms. Launching biotherapeutics tailored for optimal outcome and offered at mass production cost would contribute to advancing equitable regenerative care that addresses population health needs.
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Affiliation(s)
- Satsuki Yamada
- Center for Regenerative Medicine, Marriott Family Comprehensive Cardiac Regenerative Medicine, Marriott Heart Disease Research Program, Van Cleve Cardiac Regenerative Medicine Program, Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN 55905, USA; (S.Y.); (A.B.)
- Division of Geriatric Medicine and Gerontology, Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA
| | - Jozef Bartunek
- Cardiovascular Center, OLV Hospital, 9300 Aalst, Belgium
| | - Atta Behfar
- Center for Regenerative Medicine, Marriott Family Comprehensive Cardiac Regenerative Medicine, Marriott Heart Disease Research Program, Van Cleve Cardiac Regenerative Medicine Program, Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN 55905, USA; (S.Y.); (A.B.)
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA
| | - Andre Terzic
- Center for Regenerative Medicine, Marriott Family Comprehensive Cardiac Regenerative Medicine, Marriott Heart Disease Research Program, Van Cleve Cardiac Regenerative Medicine Program, Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN 55905, USA; (S.Y.); (A.B.)
- Department of Molecular Pharmacology and Experimental Therapeutics, Department of Clinical Genomics, Mayo Clinic, Rochester, MN 55905, USA
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Moonshi SS, Wu Y, Ta HT. Visualizing stem cells in vivo using magnetic resonance imaging. WILEY INTERDISCIPLINARY REVIEWS-NANOMEDICINE AND NANOBIOTECHNOLOGY 2021; 14:e1760. [PMID: 34651465 DOI: 10.1002/wnan.1760] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Revised: 08/18/2021] [Accepted: 08/31/2021] [Indexed: 12/16/2022]
Abstract
Stem cell (SC) therapies displayed encouraging efficacy and clinical outcome in various disorders. Despite this huge hype, clinical translation of SC therapy has been disheartening due to contradictory results from clinical trials. The ability to monitor migration and engraftment of cells in vivo represents an ideal strategy in cell therapy. Therefore, suitable imaging approach to track MSCs would allow understanding of migratory and homing efficiency, optimal route of delivery and engraftment of cells at targeted location. Hence, longitudinal tracking of SCs is crucial for the optimization of treatment parameters, leading to improved clinical outcome and translation. Magnetic resonance imaging (MRI) represents a suitable imaging modality to observe cells non-invasively and repeatedly. Tracking is achieved when cells are incubated prior to implantation with appropriate contrast agents (CA) or tracers which can then be detected in an MRI scan. This review explores and emphasizes the importance of monitoring the distribution and fate of SCs post-implantation using current contrast agents, such as positive CAs including paramagnetic metals (gadolinium), negative contrast agents such as superparamagnetic iron oxides and 19 F containing tracers, specifically for the in vivo tracking of MSCs using MRI. This article is categorized under: Diagnostic Tools > In Vivo Nanodiagnostics and Imaging Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Therapeutic Approaches and Drug Discovery > Emerging Technologies.
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Affiliation(s)
- Shehzahdi Shebbrin Moonshi
- Queensland Microtechnology and Nanotechnology Centre, Griffith University, Nathan, Queensland, Australia
| | - Yuao Wu
- Queensland Microtechnology and Nanotechnology Centre, Griffith University, Nathan, Queensland, Australia
| | - Hang Thu Ta
- Queensland Microtechnology and Nanotechnology Centre, Griffith University, Nathan, Queensland, Australia.,Australian Institute for Bioengineering and Nanotechnology, University of Queensland, St Lucia, Queensland, Australia.,School of Environment and Science, Griffith University, Nathan, Queensland, Australia
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Elde S, Wang H, Woo YJ. Navigating the Crossroads of Cell Therapy and Natural Heart Regeneration. Front Cell Dev Biol 2021; 9:674180. [PMID: 34046410 PMCID: PMC8148343 DOI: 10.3389/fcell.2021.674180] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Accepted: 04/15/2021] [Indexed: 01/14/2023] Open
Abstract
Cardiovascular disease remains the leading cause of death worldwide despite significant advances in our understanding of the disease and its treatment. Consequently, the therapeutic potential of cell therapy and induction of natural myocardial regeneration have stimulated a recent surge of research and clinical trials aimed at addressing this challenge. Recent developments in the field have shed new light on the intricate relationship between inflammation and natural regeneration, an intersection that warrants further investigation.
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Affiliation(s)
- Stefan Elde
- Department of Cardiothoracic Surgery, Stanford University, Stanford, CA, United States
| | - Hanjay Wang
- Department of Cardiothoracic Surgery, Stanford University, Stanford, CA, United States.,Stanford Cardiovascular Institute, Stanford University, Stanford, CA, United States
| | - Y Joseph Woo
- Department of Cardiothoracic Surgery, Stanford University, Stanford, CA, United States.,Stanford Cardiovascular Institute, Stanford University, Stanford, CA, United States.,Department of Bioengineering, Stanford University, Stanford, CA, United States
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Song BW, Lee CY, Kim R, Kim WJ, Lee HW, Lee MY, Kim J, Jeong JY, Chang W. Multiplexed targeting of miRNA-210 in stem cell-derived extracellular vesicles promotes selective regeneration in ischemic hearts. Exp Mol Med 2021; 53:695-708. [PMID: 33879860 PMCID: PMC8102609 DOI: 10.1038/s12276-021-00584-0] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Revised: 01/31/2021] [Accepted: 02/02/2021] [Indexed: 02/02/2023] Open
Abstract
Extracellular vesicles (EVs) are cell derivatives containing diverse cellular molecules, have various physiological properties and are also present in stem cells used for regenerative therapy. We selected a "multiplexed target" that demonstrates multiple effects on various cardiovascular cells, while functioning as a cargo of EVs. We screened various microRNAs (miRs) and identified miR-210 as a candidate target for survival and angiogenic function. We confirmed the cellular and biological functions of EV-210 (EVs derived from ASCmiR-210) secreted from adipose-derived stem cells (ASCs) transfected with miR-210 (ASCmiR-210). Under hypoxic conditions, we observed that ASCmiR-210 inhibits apoptosis by modulating protein tyrosine phosphatase 1B (PTP1B) and death-associated protein kinase 1 (DAPK1). In hypoxic endothelial cells, EV-210 exerted its angiogenic capacity by inhibiting Ephrin A (EFNA3). Furthermore, EV-210 enhanced cell survival under the control of PTP1B and induced antiapoptotic effects in hypoxic H9c2 cells. In cardiac fibroblasts, the fibrotic ratio was reduced after exposure to EV-210, but EVs derived from ASCmiR-210 did not communicate with fibroblasts. Finally, we observed the functional restoration of the ischemia/reperfusion-injured heart by maintaining the intercommunication of EVs and cardiovascular cells derived from ASCmiR-210. These results suggest that the multiplexed target with ASCmiR-210 is a useful tool for cardiovascular regeneration.
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Affiliation(s)
- Byeong-Wook Song
- Institute for Bio-Medical Convergence, Catholic Kwandong University International St. Mary's Hospital, Incheon, Republic of Korea
| | - Chang Youn Lee
- Department of Integrated Omics for Biomedical Sciences, Graduate School, Yonsei University, Seoul, Republic of Korea
| | - Ran Kim
- Department of Biology Education, College of Education, Pusan National University, Busan, Republic of Korea
| | - Won Jung Kim
- Department of Biology Education, College of Education, Pusan National University, Busan, Republic of Korea
| | - Hee Won Lee
- Department of Biology Education, College of Education, Pusan National University, Busan, Republic of Korea
| | - Min Young Lee
- Department of Molecular Physiology, College of Pharmacy, Kyungpook National University, Daegu, Republic of Korea
| | - Jongmin Kim
- Department of Life Systems, Sookmyung Women's University, Seoul, Republic of Korea
| | - Jee-Yeong Jeong
- Department of Biochemistry, Kosin University College of Medicine, Busan, Republic of Korea
| | - Woochul Chang
- Department of Biology Education, College of Education, Pusan National University, Busan, Republic of Korea.
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Yang Y, Schena GJ, Wang T, Houser SR. Postsurgery echocardiography can predict the amount of ischemia-reperfusion injury and the resultant scar size. Am J Physiol Heart Circ Physiol 2021; 320:H690-H698. [PMID: 33356964 DOI: 10.1152/ajpheart.00672.2020] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Revised: 12/15/2020] [Accepted: 12/15/2020] [Indexed: 11/22/2022]
Abstract
Despite advances in the diagnosis and treatment of ischemic heart disease (IHD), it remains the leading cause of death globally. Thus, there is a need to investigate the underlying pathophysiology and develop new therapies for the prevention and treatment of IHD. Murine models are widely used in IHD research because they are readily available, relatively inexpensive, and can be genetically modified to explore mechanistic questions. Ischemia-reperfusion (I/R)-induced myocardial infarction in mice is produced by the blockage followed by reperfusion of the left anterior descending branch (LAD) to imitate human IHD disease and its treatment. This I/R model can be widely used to investigate the potential reparative effect of putative treatments in the setting of reperfusion. However, the surgical technique is demanding and can produce an inconsistent amount of damage, which can make identification of treatment effects challenging. Therefore, determining which hearts have been significantly damaged by I/R is an important consideration in studies designed to either explore the mechanisms of disrupted function or test possible therapies. Noninvasive echocardiography (ECHO) is often used to determine structural and functional changes in the mouse heart following injury. In the present study, we determined that ECHO performed 3 days post I/R surgery could predict the permanent injury produced by the ischemic insult.NEW & NOTEWORTHY We believe our work is noteworthy due to its creation of standards for early evaluation of the level of myocardial injury in mouse models of ischemia-reperfusion. This improvement to study design could reduce the sample sizes used in evaluating therapeutics and lead to increased confidence in conclusions drawn regarding the therapeutic efficacy of treatments tested in these translational mouse models.
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Affiliation(s)
- Yijun Yang
- Independence Blue Cross Cardiovascular Research Center, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania
- Department of Pharmacology, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania
| | - Giana J Schena
- Independence Blue Cross Cardiovascular Research Center, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania
- Department of Pharmacology, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania
| | - Tao Wang
- Independence Blue Cross Cardiovascular Research Center, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania
- Department of Pharmacology, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania
| | - Steven R Houser
- Independence Blue Cross Cardiovascular Research Center, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania
- Department of Pharmacology, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania
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12
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Congestive Heart Failure. Mol Imaging 2021. [DOI: 10.1016/b978-0-12-816386-3.00050-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
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13
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Berezin AE, Berezin AA. Stem-Cell-Based Cardiac Regeneration: Is There a Place For Optimism in the Future? Stem Cells 2021. [DOI: 10.1007/978-3-030-77052-5_8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Abstract
Stem cell therapy offers a breakthrough opportunity for the improvement of ischemic heart diseases. Numerous clinical trials and meta-analyses appear to confirm its positive but variable effects on heart function. Whereas these trials widely differed in design, cell type, source, and doses reinjected, cell injection route and timing, and type of cardiac disease, crucial key factors that may favour the success of cell therapy emerge from the review of their data. Various types of cell have been delivered. Injection of myoblasts does not improve heart function and is often responsible for severe ventricular arrythmia occurrence. Using bone marrow mononuclear cells is a misconception, as they are not stem cells but mainly a mix of various cells of hematopoietic lineages and stromal cells, only containing very low numbers of cells that have stem cell-like features; this likely explain the neutral results or at best the modest improvement in heart function reported after their injection. The true existence of cardiac stem cells now appears to be highly discredited, at least in adults. Mesenchymal stem cells do not repair the damaged myocardial tissue but attenuate post-infarction remodelling and contribute to revascularization of the hibernated zone surrounding the scar. CD34+ stem cells - likely issued from pluripotent very small embryonic-like (VSEL) stem cells - emerge as the most convincing cell type, inducing structural and functional repair of the ischemic myocardial area, providing they can be delivered in large amounts via intra-myocardial rather than intra-coronary injection, and preferentially after myocardial infarct rather than chronic heart failure.
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Affiliation(s)
- Philippe Hénon
- CellProthera SAS and Institut de Recherche en Hématologie et Transplantation, CellProthera SAS 12 rue du Parc, 68100, Mulhouse, France.
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15
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Moon SH, Cho YW, Shim HE, Choi JH, Jung CH, Hwang IT, Kang SW. Electrically stimulable indium tin oxide plate for long-term in vitro cardiomyocyte culture. Biomater Res 2020; 24:10. [PMID: 32514370 PMCID: PMC7251917 DOI: 10.1186/s40824-020-00189-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Accepted: 05/10/2020] [Indexed: 12/16/2022] Open
Abstract
Background We investigated whether electrical stimulation via indium tin oxide (ITO) could enhance the in vitro culture of neonatal rat ventricular myocytes (NRVMs), which are important in vitro models for studying the mechanisms underlying many aspects of cardiology. Methods Cardiomyocytes were obtained from 1-day-old neonatal rat heart ventricles. To evaluate function of NRVMs cultured on ITO with electrical stimulation, the cell viability, change of cell morphology, immunochemistry using cardiac-specific antibodies, and gene expression were tested. Results Defined sarcomeric structure, cell enlargement, and increased distribution of NRVMs appeared in the presence of electrical stimulation. These characteristics were absent in NRVMs cultured under standard culture conditions. In addition, the expression levels of cardiomyocyte-specific and ion channel markers were higher in NRVMs seeded on ITO-coated dishes than in the control group at 14 days after seeding. ITO-coated dishes could effectively provide electrical cues to support the in vitro culture of NRVMs. Conclusions These results provide supporting evidence that electrical stimulation via ITO can be effectively used to maintain culture and enhance function of cardiomyocytes in vitro.
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Affiliation(s)
- Sung-Hwan Moon
- Department of Medical Science, School of Medicine, Konkuk University, Seoul, South Korea
| | - Young-Woo Cho
- Drug Safety and Toxicity Evaluation Team, New Drug Development Center, Osong Medical Innovation Foundation, Cheongju-Si, Chungbuk South Korea
| | - Hye-Eun Shim
- Research Group for Biomimetic Advanced Technology, Korea Institute of Toxicology, Daejeon, South Korea
| | - Jae-Hak Choi
- Department of Polymer Science and Engineering, Chungnam National University, Daejeon, South Korea
| | - Chan-Hee Jung
- Research Division for Industry and Environment, Advanced Radiation Technology Institute, Korea Atomic Energy Research Institute, Jeonbuk, South Korea
| | - In-Tae Hwang
- Research Division for Industry and Environment, Advanced Radiation Technology Institute, Korea Atomic Energy Research Institute, Jeonbuk, South Korea
| | - Sun-Woong Kang
- Research Group for Biomimetic Advanced Technology, Korea Institute of Toxicology, Daejeon, South Korea.,Department of Human and Environmental Toxicology, University of Science and Technology, Daejeon, South Korea
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Wang T, Nanda SS, Papaefthymiou GC, Yi DK. Mechanophysical Cues in Extracellular Matrix Regulation of Cell Behavior. Chembiochem 2020; 21:1254-1264. [DOI: 10.1002/cbic.201900686] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Indexed: 12/22/2022]
Affiliation(s)
- Tuntun Wang
- Department of ChemistryMyongji University Yongin 449-728 Republic of Korea
| | | | | | - Dong Kee Yi
- Department of ChemistryMyongji University Yongin 449-728 Republic of Korea
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Liufu R, Shi G, He X, Lv J, Liu W, Zhu F, Wen C, Zhu Z, Chen H. The therapeutic impact of human neonatal BMSC in a right ventricular pressure overload model in mice. Stem Cell Res Ther 2020; 11:96. [PMID: 32122393 PMCID: PMC7052971 DOI: 10.1186/s13287-020-01593-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2019] [Revised: 01/07/2020] [Accepted: 02/10/2020] [Indexed: 12/12/2022] Open
Abstract
Objective To determine the impact of donor age on the therapeutic effect of bone marrow-derived mesenchymal stem cells (BMSCs) in treating adverse remodeling as the result of right ventricle (RV) pressure overload. Methods BMSCs were isolated from neonatal (< 1 month), infant (1 month to 1 year), and young children (1 year to 5 years) and were compared in their migration potential, surface marker expression, VEGF secretion, and matrix metalloprotein (MMP) 9 expression. Four-week-old male C57 mice underwent pulmonary artery banding and randomized to treatment and untreated control groups. During the surgery, BMSCs were administered to the mice by intramyocardial injection into the RV free wall. Four weeks later, RV function and tissue were analyzed by echocardiography, histology, and quantitative real-time polymerase chain reaction. Results Human neonatal BMSCs demonstrated the greatest migration capacity and secretion of vascular endothelial growth factor but no difference in expression of surface markers. Neonate BMSCs administration resulted in increasing expression of VEGF, a significant reduction in RV wall thickness, and internal diameter in mice after PA banding. These beneficial effects were probably associated with paracrine secretion as no cardiomyocyte transdifferentiation was observed. Conclusions Human BMSCs from different age groups have different characteristics, and the youngest BMSCs may favorably impact the application of stem cell-based therapy to alleviate adverse RV remodeling induced by pressure overload.
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Affiliation(s)
- Rong Liufu
- Cardiovascular Intensive Care Unit, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Guocheng Shi
- Department of Cardiothoracic Surgery, Congenital Heart Center, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Dongfang Road No. 1678, Shanghai, China
| | - Xiaomin He
- Department of Cardiothoracic Surgery, Congenital Heart Center, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Dongfang Road No. 1678, Shanghai, China
| | - Jingjing Lv
- Department of Cardiothoracic Surgery, Congenital Heart Center, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Dongfang Road No. 1678, Shanghai, China
| | - Wei Liu
- Department of Cardiothoracic Surgery, Congenital Heart Center, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Dongfang Road No. 1678, Shanghai, China
| | - Fang Zhu
- Department of Cardiothoracic Surgery, Congenital Heart Center, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Dongfang Road No. 1678, Shanghai, China
| | - Chen Wen
- Department of Cardiothoracic Surgery, Congenital Heart Center, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Dongfang Road No. 1678, Shanghai, China
| | - Zhongqun Zhu
- Department of Cardiothoracic Surgery, Congenital Heart Center, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Dongfang Road No. 1678, Shanghai, China.
| | - Huiwen Chen
- Department of Cardiothoracic Surgery, Congenital Heart Center, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Dongfang Road No. 1678, Shanghai, China.
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18
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Elsaadany B, Zakaria M, Mousa MR. Transplantation of Bone Marrow-Derived Mesenchymal Stem Cells Preserve the Salivary Glands Structure after Head and Neck Radiation in Rats. Open Access Maced J Med Sci 2019; 7:1588-1592. [PMID: 31210805 PMCID: PMC6560309 DOI: 10.3889/oamjms.2019.350] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Revised: 05/18/2019] [Accepted: 05/19/2019] [Indexed: 11/05/2022] Open
Abstract
BACKGROUND The salivary glands are one of the radiation sensitive tissues during radiotherapy in the treatment of head and neck cancer. Within the first weeks of radiotherapy, the radiation causes progressive loss of gland function, then continue throughout the later of the patient's life. AIM The present work was designed to discover the potential effect of bone marrow-derived mesenchymal stem cells (MSCs) injected locally and in decreasing the unwanted effects of radiation on rats salivary gland. MATERIAL AND METHODS 6 rats used as the control group (N) and 12 rats had a single radiation dose of 13Gy in the head and neck then, they were equally allocated into two groups: Irradiated only as a group (C), Irradiated then treated with MSCs as a group (S). The animals were euthanised 7 days post radiation. Then, submandibular salivary glands were cut up; the histological examination was done. RESULTS Histological examination of the treated group(S) shown an apparent improvement in the SG structure and function compared to the irradiated group (C), this improvement represented mainly as preserving acini diameter (mean diameter in µm group (C) 183.1 ± 4.5, in group (S) 356.3 ± 33.5 while, in (N) group 408.9 ± 5.9) and decrease in fibrotic areas in the gland (mean fibrosis parentage in group (C) 26.5 ± 5.9 in (C) group , in group (S) 11.7 ± 4.13 while in (N) group 0.2 ± 0.31). CONCLUSION BM-MSCs has revealed to be promising in mitigating the side effects of radiotherapy on salivary glands structure.
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Affiliation(s)
- Basma Elsaadany
- Oral Medicine and Periodontology Department, Faculty of Dentistry, Cairo University, Cairo, Egypt
| | - Mai Zakaria
- Oral Medicine and Periodontology Department, Faculty of Dentistry, Cairo University, Cairo, Egypt
| | - Mohamed Refat Mousa
- Pathology Department, Faculty of Veterinary Medicine, Cairo University, Cairo, Egypt
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19
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Onoshima D, Yukawa H, Baba Y. Nanobiodevices for Cancer Diagnostics and Stem Cell Therapeutics. Bioanalysis 2019. [DOI: 10.1007/978-981-13-6229-3_10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
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20
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Allen KB, Mahoney A, Aggarwal S, Davis JR, Thompson E, Pak AF, Heimes J, Michael Borkon A. Transmyocardial revascularization (TMR): current status and future directions. Indian J Thorac Cardiovasc Surg 2018; 34:330-339. [PMID: 33060956 DOI: 10.1007/s12055-018-0702-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2018] [Revised: 06/07/2018] [Accepted: 07/13/2018] [Indexed: 01/22/2023] Open
Abstract
Purpose Cardiac surgeons are increasingly faced with a more complex patient who has developed a pattern of diffuse coronary artery disease (CAD), which is refractory to medical, percutaneous, and surgical interventions. This paper will review the clinical science surrounding transmyocardial revascularization (TMR) with an emphasis on the results from randomized controlled trials. Methods Randomized controlled trials which evaluated TMR used as sole therapy and when combined with coronary artery bypass grafting were reviewed. Pertinent basic science papers exploring TMR's possible mechanism of action along with future directions, including the synergism between TMR and cell-based therapies were reviewed. Results Two laser-based systems have been approved by the United States Food and Drug Administration (FDA) to deliver laser therapy to targeted areas of the left ventricle (LV) that cannot be revascularized using conventional methods: the holmium:yttrium-aluminum-garnet (Ho:YAG) laser system (CryoLife, Inc., Kennesaw, GA) and the carbon dioxide (CO2) Heart Laser System (Novadaq Technologies Inc., (Mississauga, Canada). TMR can be performed either as a stand-alone procedure (sole therapy) or in conjunction with coronary artery bypass graft (CABG) surgery in patients who would be incompletely revascularized by CABG alone. Societal practice guidelines have been established and are supportive of using TMR in the difficult population of patients with diffuse CAD. Conclusions Patients with diffuse CAD have increased operative and long-term cardiac risks predicted by incomplete revascularization. The documented operative and long-term benefits associated with sole therapy and adjunctive TMR in randomized trials supports TMR's increased use in this difficult patient population.
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Affiliation(s)
- Keith B Allen
- Saint Luke's Mid America Heart Institute, 4320 Wornall Rd, Medical Plaza II, Suite 50, Kansas City, MO 64111 USA
| | | | - Sanjeev Aggarwal
- Saint Luke's Mid America Heart Institute, 4320 Wornall Rd, Medical Plaza II, Suite 50, Kansas City, MO 64111 USA
| | - John Russell Davis
- Saint Luke's Mid America Heart Institute, 4320 Wornall Rd, Medical Plaza II, Suite 50, Kansas City, MO 64111 USA
| | - Eric Thompson
- Saint Luke's Mid America Heart Institute, 4320 Wornall Rd, Medical Plaza II, Suite 50, Kansas City, MO 64111 USA
| | - Alex F Pak
- Saint Luke's Mid America Heart Institute, 4320 Wornall Rd, Medical Plaza II, Suite 50, Kansas City, MO 64111 USA
| | - Jessica Heimes
- Saint Luke's Mid America Heart Institute, 4320 Wornall Rd, Medical Plaza II, Suite 50, Kansas City, MO 64111 USA
| | - A Michael Borkon
- Saint Luke's Mid America Heart Institute, 4320 Wornall Rd, Medical Plaza II, Suite 50, Kansas City, MO 64111 USA
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21
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Campbell KT, Stilhano RS, Silva EA. Enzymatically degradable alginate hydrogel systems to deliver endothelial progenitor cells for potential revasculature applications. Biomaterials 2018; 179:109-121. [PMID: 29980073 PMCID: PMC6746553 DOI: 10.1016/j.biomaterials.2018.06.038] [Citation(s) in RCA: 58] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2018] [Revised: 06/13/2018] [Accepted: 06/24/2018] [Indexed: 12/11/2022]
Abstract
The objective of this study was to design an injectable biomaterial system that becomes porous in situ to deliver and control vascular progenitor cell release. Alginate hydrogels were loaded with outgrowth endothelial cells (OECs) and alginate lyase, an enzyme which cleaves alginate polymer chains. We postulated and confirmed that higher alginate lyase concentrations mediated loss of hydrogel mechanical properties. Hydrogels incorporating 5 and 50 mU/mL of alginate lyase experienced approximately 28% and 57% loss of mass as well as 81% and 91% reduction in storage modulus respectively after a week. Additionally, computational methods and mechanical analysis revealed that hydrogels with alginate lyase significantly increased in mesh size over time. Furthermore, alginate lyase was not found to inhibit OEC proliferation, viability or sprouting potential. Finally, alginate hydrogels incorporating OECs and alginate lyase promoted up to nearly a 10 fold increase in OEC migration in vitro than nondegradable hydrogels over the course of a week and increased functional vasculature in vivo via a chick chorioallantoic membrane (CAM) assay. Overall, these findings demonstrate that alginate lyase incorporated hydrogels can provide a simple and robust system to promote controlled outward cell migration into native tissue for potential therapeutic revascularization applications.
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Affiliation(s)
- Kevin T Campbell
- Department of Biomedical Engineering, University of California Davis, Davis, CA, USA
| | - Roberta S Stilhano
- Department of Biomedical Engineering, University of California Davis, Davis, CA, USA; Department of Biochemistry, University of Sao Paulo, Sao Paulo, Brazil
| | - Eduardo A Silva
- Department of Biomedical Engineering, University of California Davis, Davis, CA, USA.
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22
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Xu ZM, Huang F, Huang WQ. Angiogenic lncRNAs: A potential therapeutic target for ischaemic heart disease. Life Sci 2018; 211:157-171. [PMID: 30219334 DOI: 10.1016/j.lfs.2018.09.022] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2018] [Revised: 08/31/2018] [Accepted: 09/09/2018] [Indexed: 12/14/2022]
Abstract
Long noncoding RNAs (LncRNAs) are involved in biological processes and the pathology of diseases and represent an important biomarker or therapeutic target for disease. Emerging evidence has suggested that lncRNAs modulate angiogenesis by regulating the angiogenic cell process-including vascular endothelial cells (VECs); stem cells, particularly bone marrow-derived stem cells, endothelial progenitor cells (EPCs) and mesenchymal stem cells (MSCs); and vascular smooth muscle cells (VSMCs)-and participating in ischaemic heart disease (IHD). Therapeutic angiogenesis as an alternative therapy to promote coronary collateral circulation has been demonstrated to significantly improve the prognosis and quality of life of patients with IHD in past decades. Therefore, lncRNAs are likely to represent a novel therapeutic target for IHD through regulation of the angiogenesis process. This review summarizes the classification and functions of lncRNAs and their roles in regulating angiogenesis and in IHD, in the context of an overview of therapeutic angiogenesis in clinical trials.
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Affiliation(s)
- Zhi-Meng Xu
- Department of Geriatric Cardiology & Guangxi Key Laboratory Base of Precision Medicine in Cardio-cerebrovascular Diseases Control and Prevention & Guangxi Clinical Research Center for Cardio-cerebrovascular Diseases, The First Affiliated Hospital of Guangxi Medical University, Nanning, PR China
| | - Feng Huang
- Institute of Cardiovascular Diseases & Guangxi Key Laboratory Base of Precision Medicine in Cardio-cerebrovascular Diseases Control and Prevention & Guangxi Clinical Research Center for Cardio-cerebrovascular Diseases, The First Affiliated Hospital of Guangxi Medical University, Nanning, PR China
| | - Wei-Qiang Huang
- Department of Geriatric Cardiology & Guangxi Key Laboratory Base of Precision Medicine in Cardio-cerebrovascular Diseases Control and Prevention & Guangxi Clinical Research Center for Cardio-cerebrovascular Diseases, The First Affiliated Hospital of Guangxi Medical University, Nanning, PR China.
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23
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Albiero M, Fadini GP. Pharmacologic targeting of the diabetic stem cell mobilopathy. Pharmacol Res 2018; 135:18-24. [PMID: 30030170 DOI: 10.1016/j.phrs.2018.07.017] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2018] [Revised: 06/26/2018] [Accepted: 07/16/2018] [Indexed: 01/01/2023]
Abstract
Diabetes is a chronic metabolic disease characterized by hyperglycemia and several associated biochemical abnormalities. Diabetes leads to multiorgan complications that collectively reduce life expectancy. Hematopoietic stem cells (HSCs) are nested within bone marrow (BM) niches whence they can be mobilized to the peripheral circulation. Clinically, this is done for HSC collection and autologous or allogenic transplantation. A great amount of data from basic and clinical studies support that diabetic patients are poor HSC mobilizers owing to BM remodeling. Dysfunction of the BM shares pathophysiological features and pathways with typical chronic diabetic complications that affect other issues (e.g. the retina and the kidney). From a clinical perspective, impaired HSC mobilization translates into the failure to collect a minimum number of CD34+ cells to achieve a safe engraftment after transplantation. Furthermore, blunted mobilization is associated with reduced steady-state levels of circulating HSCs, which have been consistently described in diabetic patients and associated with increased risk of adverse outcomes, including cardiovascular events and death. In this review, we discuss the most clinically relevant pharmacological options to overcome impaired HSC mobilization in diabetes. These therapeutic strategies may result in an improved outcome of diabetic patients undergoing HSC transplantation and restore circulating HSC levels, thereby protecting from adverse cardiovascular outcomes.
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Affiliation(s)
- M Albiero
- Venetian Institute of Molecular Medicine, Laboratory of Experimental Diabetology, 35100 Padova, Italy; Department of Medicine, Metabolic Division, University of Padova, 35100 Padova, Italy
| | - G P Fadini
- Venetian Institute of Molecular Medicine, Laboratory of Experimental Diabetology, 35100 Padova, Italy; Department of Medicine, Metabolic Division, University of Padova, 35100 Padova, Italy.
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24
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Moonshi SS, Zhang C, Peng H, Puttick S, Rose S, Fisk NM, Bhakoo K, Stringer BW, Qiao GG, Gurr PA, Whittaker AK. A unique 19F MRI agent for the tracking of non phagocytic cells in vivo. NANOSCALE 2018; 10:8226-8239. [PMID: 29682654 DOI: 10.1039/c8nr00703a] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/08/2023]
Abstract
There is currently intense interest in new methods for understanding the fate of therapeutically-relevant cells, such as mesenchymal stem cells (MSCs). The absence of a confounding background signal and consequent unequivocal assignment makes 19F MRI one of the most attractive modalities for the tracking of injected cells in vivo. We describe here the synthesis of novel partly-fluorinated polymeric nanoparticles with small size and high fluorine content as MRI agents. The polymers, constructed from perfluoropolyether methacrylate (PFPEMA) and oligo(ethylene glycol) methacrylate (OEGMA) have favourable cell uptake profiles and excellent MRI performance. To facilitate cell studies the polymer was further conjugated with a fluorescent dye creating a dual-modal imaging agent. The efficacy of labelling of MSCs was assessed using 19F NMR, flow cytometry and confocal microscopy. The labelling efficiency of 2.6 ± 0.1 × 1012 19F atoms per cell, and viability of >90% demonstrates high uptake and good tolerance by the cells. This loading translates to a minimum 19F MRI detection sensitivity of ∼7.4 × 103 cells per voxel. Importantly, preliminary in vivo data demonstrate that labelled cells can be readily detected within a short acquisition scan period (12 minutes). Hence, these copolymers show outstanding potential for 19F MRI cellular tracking and for quantification of non-phagocytic and therapeutically-relevant cells in vivo.
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Affiliation(s)
- Shehzahdi S Moonshi
- Australian Institute for Bioengineering and Nanotechnology and ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, The University of Queensland, QLD 4072, Australia.
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25
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Loisel F, Provost B, Haddad F, Guihaire J, Amsallem M, Vrtovec B, Fadel E, Uzan G, Mercier O. Stem cell therapy targeting the right ventricle in pulmonary arterial hypertension: is it a potential avenue of therapy? Pulm Circ 2018; 8:2045893218755979. [PMID: 29480154 PMCID: PMC5844533 DOI: 10.1177/2045893218755979] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Pulmonary arterial hypertension (PAH) is an incurable disease characterized by an increase in pulmonary arterial pressure due to pathological changes to the pulmonary vascular bed. As a result, the right ventricle (RV) is subject to an increased afterload and undergoes multiple changes, including a decrease in capillary density. All of these dysfunctions lead to RV failure. A number of studies have shown that RV function is one of the main prognostic factors for PAH patients. Many stem cell therapies targeting the left ventricle are currently undergoing development. The promising results observed in animal models have led to clinical trials that have shown an improvement of cardiac function. In contrast to left heart disease, stem cell therapy applied to the RV has remained poorly studied, even though it too may provide a therapeutic benefit. In this review, we discuss stem cell therapy as a treatment for RV failure in PAH. We provide an overview of the results of preclinical and clinical studies for RV cell therapies. Although a large number of studies have targeted the pulmonary circulation rather than the RV directly, there are nonetheless encouraging results in the literature that indicate that cell therapies may have a direct beneficial effect on RV function. This cell therapy strategy may therefore hold great promise and warrants further studies in PAH patients.
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Affiliation(s)
- Fanny Loisel
- 1 36705 Research and Innovation Unit, Inserm UMR-S 999, Marie Lannelongue Hospital, Universite Paris Sud, Paris-Saclay University, Le Plessis Robinson, France.,2 Inserm 1197 Research Unit, Universite Paris Sud, Paris-Saclay University, Villejuif, France
| | - Bastien Provost
- 1 36705 Research and Innovation Unit, Inserm UMR-S 999, Marie Lannelongue Hospital, Universite Paris Sud, Paris-Saclay University, Le Plessis Robinson, France
| | - François Haddad
- 3 Cardiovascular Medicine, Stanford Hospital, Stanford University, CA, USA
| | - Julien Guihaire
- 1 36705 Research and Innovation Unit, Inserm UMR-S 999, Marie Lannelongue Hospital, Universite Paris Sud, Paris-Saclay University, Le Plessis Robinson, France
| | - Myriam Amsallem
- 1 36705 Research and Innovation Unit, Inserm UMR-S 999, Marie Lannelongue Hospital, Universite Paris Sud, Paris-Saclay University, Le Plessis Robinson, France
| | - Bojan Vrtovec
- 4 Department of Cardiology, Advanced Heart Failure and Transplantation Center, University Medical Center Ljubljana, Ljubljana, Slovenia
| | - Elie Fadel
- 1 36705 Research and Innovation Unit, Inserm UMR-S 999, Marie Lannelongue Hospital, Universite Paris Sud, Paris-Saclay University, Le Plessis Robinson, France.,5 Department of Thoracic and Vascular Surgery and Heart-Lung Transplantation, Marie Lannelongue Hospital, Universite Paris Sud, Paris-Saclay University, Le Plessis Robinson, France
| | - Georges Uzan
- 2 Inserm 1197 Research Unit, Universite Paris Sud, Paris-Saclay University, Villejuif, France
| | - Olaf Mercier
- 1 36705 Research and Innovation Unit, Inserm UMR-S 999, Marie Lannelongue Hospital, Universite Paris Sud, Paris-Saclay University, Le Plessis Robinson, France.,5 Department of Thoracic and Vascular Surgery and Heart-Lung Transplantation, Marie Lannelongue Hospital, Universite Paris Sud, Paris-Saclay University, Le Plessis Robinson, France
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Qadura M, Terenzi DC, Verma S, Al-Omran M, Hess DA. Concise Review: Cell Therapy for Critical Limb Ischemia: An Integrated Review of Preclinical and Clinical Studies. Stem Cells 2018; 36:161-171. [DOI: 10.1002/stem.2751] [Citation(s) in RCA: 110] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2017] [Revised: 10/31/2017] [Accepted: 11/19/2017] [Indexed: 12/22/2022]
Affiliation(s)
- Mohammad Qadura
- Division of Vascular Surgery; St. Michael's Hospital; Toronto Ontario Canada
- Department of Surgery; University of Toronto; Toronto Ontario Canada
| | - Daniella C. Terenzi
- Division of Vascular Surgery; St. Michael's Hospital; Toronto Ontario Canada
- Department of Surgery; University of Toronto; Toronto Ontario Canada
| | - Subodh Verma
- Department of Surgery; University of Toronto; Toronto Ontario Canada
- Division of Cardiac Surgery; St. Michael's Hospital; Toronto Ontario Canada
| | - Mohammed Al-Omran
- Division of Vascular Surgery; St. Michael's Hospital; Toronto Ontario Canada
- Department of Surgery; University of Toronto; Toronto Ontario Canada
| | - David A. Hess
- Division of Vascular Surgery; St. Michael's Hospital; Toronto Ontario Canada
- Department of Surgery; University of Toronto; Toronto Ontario Canada
- Molecular Medicine Research Laboratories, Krembil Centre for Stem Cell Biology; Robarts Research Institute; London Ontario Canada
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry; Western University; London Ontario Canada
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27
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Abstract
Every year 13.3 million people suffer acute kidney injury (AKI), which is associated with a high risk of death or development of long-term chronic kidney disease (CKD) in a substantial percentage of patients besides other organ dysfunctions. To date, the mortality rate per year for AKI exceeds 50 % at least in patients requiring early renal replacement therapy and is higher than the mortality for breast and prostate cancer, heart failure and diabetes combined.Until now, no effective treatments able to accelerate renal recovery and improve survival post AKI have been developed. In search of innovative and effective strategies to foster the limited regeneration capacity of the kidney, several studies have evaluated the ability of mesenchymal stem cells (MSCs) of different origin as an attractive therapeutic tool. The results obtained in several models of AKI and CKD document that MSCs have therapeutic potential in repair of renal injury, preserving renal function and structure thus prolonging animal survival through differentiation-independent pathways. In this chapter, we have summarized the mechanisms underlying the regenerative processes triggered by MSC treatment, essentially due to their paracrine activity. The capacity of MSC to migrate to the site of injury and to secrete a pool of growth factors and cytokines with anti-inflammatory, mitogenic, and immunomodulatory effects is described. New modalities of cell-to-cell communication via the release of microvesicles and exosomes by MSCs to injured renal cells will also be discussed. The translation of basic experimental data on MSC biology into effective care is still limited to preliminary phase I clinical trials and further studies are needed to definitively assess the efficacy of MSC-based therapy in humans.
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Affiliation(s)
- Marina Morigi
- IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Via Stezzano 87, 24126, Bergamo, Italy.
| | - Cinzia Rota
- IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Via Stezzano 87, 24126, Bergamo, Italy
| | - Giuseppe Remuzzi
- IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Via Stezzano 87, 24126, Bergamo, Italy
- Unit of Nephrology and Dialysis, A.O. Papa Giovanni XXIII, 24127, Bergamo, Italy
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28
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Serpooshan V, Liu YH, Buikema JW, Galdos FX, Chirikian O, Paige S, Venkatraman S, Kumar A, Rawnsley DR, Huang X, Pijnappels DA, Wu SM. Nkx2.5+ Cardiomyoblasts Contribute to Cardiomyogenesis in the Neonatal Heart. Sci Rep 2017; 7:12590. [PMID: 28974782 PMCID: PMC5626718 DOI: 10.1038/s41598-017-12869-4] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2016] [Accepted: 09/15/2017] [Indexed: 01/26/2023] Open
Abstract
During normal lifespan, the mammalian heart undergoes limited renewal of cardiomyocytes. While the exact mechanism for this renewal remains unclear, two possibilities have been proposed: differentiated myocyte replication and progenitor/immature cell differentiation. This study aimed to characterize a population of cardiomyocyte precursors in the neonatal heart and to determine their requirement for cardiac development. By tracking the expression of an embryonic Nkx2.5 cardiac enhancer, we identified cardiomyoblasts capable of differentiation into striated cardiomyocytes in vitro. Genome-wide expression profile of neonatal Nkx2.5+ cardiomyoblasts showed the absence of sarcomeric gene and the presence of cardiac transcription factors. To determine the lineage contribution of the Nkx2.5+ cardiomyoblasts, we generated a doxycycline suppressible Cre transgenic mouse under the regulation of the Nkx2.5 enhancer and showed that neonatal Nkx2.5+ cardiomyoblasts mature into cardiomyocytes in vivo. Ablation of neonatal cardiomyoblasts resulted in ventricular hypertrophy and dilation, supporting a functional requirement of the Nkx2.5+ cardiomyoblasts. This study provides direct lineage tracing evidence that a cardiomyoblast population contributes to cardiogenesis in the neonatal heart. The cell population identified here may serve as a promising therapeutic for pediatric cardiac regeneration.
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Affiliation(s)
- Vahid Serpooshan
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA
| | - Yuan-Hung Liu
- Cardiovascular Research Center and Department of Medicine, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA, 02114, USA.,Division of Cardiology, Department of Medicine, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA, 02114, USA.,Section of Cardiology, Cardiovascular Center, Far Eastern Memorial Hospital, New Taipei City, Taiwan
| | - Jan W Buikema
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA.,Department of Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Francisco X Galdos
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA
| | - Orlando Chirikian
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA.,Biology Program, California State University Channel Islands, Camarillo, CA, USA
| | - Sharon Paige
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA.,Department of Pediatrics, Division of Pediatric Cardiology, Stanford University School of Medicine, Stanford, CA, USA
| | - Sneha Venkatraman
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA.,Biology Program, California State University Channel Islands, Camarillo, CA, USA
| | - Anusha Kumar
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA
| | - David R Rawnsley
- Cardiovascular Research Center and Department of Medicine, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA, 02114, USA
| | - Xiaojing Huang
- Cardiovascular Research Center and Department of Medicine, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA, 02114, USA
| | - Daniël A Pijnappels
- Cardiovascular Research Center and Department of Medicine, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA, 02114, USA.,Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands
| | - Sean M Wu
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA. .,Department of Medicine, Division of Cardiovascular Medicine, and Stanford University School of Medicine, Stanford, CA, USA. .,Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA.
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29
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Lee DK, Song SU. Immunomodulatory mechanisms of mesenchymal stem cells and their therapeutic applications. Cell Immunol 2017; 326:68-76. [PMID: 28919171 DOI: 10.1016/j.cellimm.2017.08.009] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2017] [Revised: 08/27/2017] [Accepted: 08/27/2017] [Indexed: 02/06/2023]
Abstract
In the recent years, many studies have shown that MSCs must be stimulated by pro-inflammatory cytokines or other immune mediators before they can modulate immune cells in inflamed and damaged tissues. MSCs appear to be involved in inducing several regulatory immune cells, such as Tregs, Bregs, and regulatory NK cells. This new immune milieu created by MSCs may establish a tolerogenic environment that leads to an optimal condition for the treatment of immune diseases. The mechanisms of MSC action to treat immune disorders need to be further investigated in more detail. Since there have been some contradictory outcomes of clinical trials, it is necessary to perform large-scale and randomized clinical studies, such as a phase 3 placebo-controlled double-blind study of a third party MSCs to optimize MSC administration and to prove safety and efficacy of MSC treatment. MSCs offer great therapeutic promise, especially for the treatment of difficult-to-treat immune diseases.
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Affiliation(s)
- Don K Lee
- SCM Lifesciences Co. Ltd., Incheon 22332 Republic of Korea
| | - Sun U Song
- Dept. of Integrated Biomedical Sciences, Inha University School of Medicine, Incheon 22332 Republic of Korea; SCM Lifesciences Co. Ltd., Incheon 22332 Republic of Korea.
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30
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El Gammal ZH, Zaher AM, El-Badri N. Effect of low-level laser-treated mesenchymal stem cells on myocardial infarction. Lasers Med Sci 2017; 32:1637-1646. [PMID: 28681086 DOI: 10.1007/s10103-017-2271-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2016] [Accepted: 06/19/2017] [Indexed: 10/19/2022]
Abstract
Cardiovascular disease is the leading cause of death worldwide. Although cardiac transplantation is considered the most effective therapy for end-stage cardiac diseases, it is limited by the availability of matching donors and the complications of the immune suppressive regimen used to prevent graft rejection. Application of stem cell therapy in experimental animal models was shown to reverse cardiac remodeling, attenuate cardiac fibrosis, improve heart functions, and stimulate angiogenesis. The efficacy of stem cell therapy can be amplified by low-level laser radiation. It is well established that the bio-stimulatory effect of low-level laser is influenced by the following parameters: wavelength, power density, duration, energy density, delivery time, and the type of irradiated target. In this review, we evaluate the available experimental data on treatment of myocardial infarction using low-level laser. Eligible papers were characterized as in vivo experimental studies that evaluated the use of low-level laser therapy on stem cells in order to attenuate myocardial infarction. The following descriptors were used separately and in combination: laser therapy, low-level laser, low-power laser, stem cell, and myocardial infarction. The assessed low-level laser parameters were wavelength (635-804 nm), power density (6-50 mW/cm2), duration (20-150 s), energy density (0.96-1 J/cm2), delivery time (20 min-3 weeks after myocardial infarction), and the type of irradiated target (bone marrow or in vitro-cultured bone marrow mesenchymal stem cells). The analysis focused on the cardioprotective effect of this form of therapy, the attenuation of scar tissue, and the enhancement of angiogenesis as primary targets. Other effects such as cell survival, cell differentiation, and homing are also included. Among the evaluated protocols using different parameters, the best outcome for treating myocardial infarction was achieved by treating the bone marrow by one dose of low-level laser with 804 nm wavelength and 1 J/cm2 energy density within 4 h of the infarction. This approach increased stem cell survival, proliferation, and homing. It has also decreased the infarct size and cell apoptosis, leading to enhanced heart functions. These effects were stable for 6 weeks. However, more studies are still required to assess the effects of low-level laser on the genetic makeup of the cell, the nuclei, and the mitochondria of mesenchymal stromal cells (MSCs).
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Affiliation(s)
- Zaynab H El Gammal
- Center of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, Cairo, 12588, Egypt
| | - Amr M Zaher
- National Institute of Heart, Cairo, 12651, Egypt
| | - Nagwa El-Badri
- Center of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, Cairo, 12588, Egypt.
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31
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Ramos GA, Hare JM. Cardiac Cell-Based Therapy: Cell Types and Mechanisms of Actions. Cell Transplant 2017; 16:951-61. [DOI: 10.3727/096368907783338208] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Over the past decade, the concept that the heart could undergo cardiac regeneration has rapidly evolved. Studies have indicated that numerous sites in the body harbor stem or progenitor cells, prompting clinical trials of these potential therapeutic cell-based approaches. Most notable are the series of trials utilizing either skeletal myoblasts or autologous whole bone marrow. More recently the quest has focused on specific bone marrow constituents, most notably the mesenchymal stem cell, which has several unique advantages including immunoprivilege, immunosuppression, and the ability to home to areas of tissue injury. Most recently, cells have been identified within the heart itself that are capable of self-replication and differentiation. The discovery of cardiac stem cells offers not only a potential therapeutic approach but also provides a plausible target for endogenous activation as a therapeutic strategy. Together the new insights obtained from studies of cell-based cardiac therapy have ushered in new biological paradigms and enormous potential for novel therapeutic strategies for cardiac disease.
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Affiliation(s)
- Geraldo A. Ramos
- The Interdisciplinary Stem Cell Institute, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Joshua M. Hare
- The Interdisciplinary Stem Cell Institute, Miller School of Medicine, University of Miami, Miami, FL, USA
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32
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Putman DM, Cooper TT, Sherman SE, Seneviratne AK, Hewitt M, Bell GI, Hess DA. Expansion of Umbilical Cord Blood Aldehyde Dehydrogenase Expressing Cells Generates Myeloid Progenitor Cells that Stimulate Limb Revascularization. Stem Cells Transl Med 2017; 6:1607-1619. [PMID: 28618138 PMCID: PMC5689765 DOI: 10.1002/sctm.16-0472] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2016] [Revised: 03/30/2017] [Accepted: 05/03/2017] [Indexed: 12/19/2022] Open
Abstract
Uncompromised by chronic disease‐related comorbidities, human umbilical cord blood (UCB) progenitor cells with high aldehyde dehydrogenase activity (ALDHhi cells) stimulate blood vessel regeneration after intra‐muscular transplantation. However, implementation of cellular therapies using UCB ALDHhi cells for critical limb ischemia, the most severe form of severe peripheral artery disease, is limited by the rarity (<0.5%) of these cells. Our goal was to generate a clinically‐translatable, allogeneic cell population for vessel regenerative therapies, via ex vivo expansion of UCB ALDHhi cells without loss of pro‐angiogenic potency. Purified UCB ALDHhi cells were expanded >18‐fold over 6‐days under serum‐free conditions. Consistent with the concept that ALDH‐activity is decreased as progenitor cells differentiate, only 15.1% ± 1.3% of progeny maintained high ALDH‐activity after culture. However, compared to fresh UCB cells, expansion increased the total number of ALDHhi cells (2.7‐fold), CD34+/CD133+ cells (2.8‐fold), and hematopoietic colony forming cells (7.7‐fold). Remarkably, injection of expanded progeny accelerated recovery of perfusion and improved limb usage in immunodeficient mice with femoral artery ligation‐induced limb ischemia. At 7 or 28 days post‐transplantation, mice transplanted with expanded ALDHhi cells showed augmented endothelial cell proliferation and increased capillary density compared to controls. Expanded cells maintained pro‐angiogenic mRNA expression and secreted angiogenesis‐associated growth factors, chemokines, and matrix modifying proteins. Coculture with expanded cells augmented human microvascular endothelial cell survival and tubule formation under serum‐starved, growth factor‐reduced conditions. Expanded UCB‐derived ALDHhi cells represent an alternative to autologous bone marrow as an accessible source of pro‐angiogenic hematopoietic progenitor cells for the refinement of vascular regeneration‐inductive therapies. Stem Cells Translational Medicine2017;6:1607–1619
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Affiliation(s)
- David M Putman
- Molecular Medicine Research Laboratories, Krembil Centre for Stem Cell Biology, Robarts Research Institute, London, Ontario, Canada.,Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
| | - Tyler T Cooper
- Molecular Medicine Research Laboratories, Krembil Centre for Stem Cell Biology, Robarts Research Institute, London, Ontario, Canada.,Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
| | - Stephen E Sherman
- Molecular Medicine Research Laboratories, Krembil Centre for Stem Cell Biology, Robarts Research Institute, London, Ontario, Canada.,Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
| | - Ayesh K Seneviratne
- Molecular Medicine Research Laboratories, Krembil Centre for Stem Cell Biology, Robarts Research Institute, London, Ontario, Canada.,Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
| | - Mark Hewitt
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
| | - Gillian I Bell
- Molecular Medicine Research Laboratories, Krembil Centre for Stem Cell Biology, Robarts Research Institute, London, Ontario, Canada
| | - David A Hess
- Molecular Medicine Research Laboratories, Krembil Centre for Stem Cell Biology, Robarts Research Institute, London, Ontario, Canada.,Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
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33
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Quyyumi AA, Vasquez A, Kereiakes DJ, Klapholz M, Schaer GL, Abdel-Latif A, Frohwein S, Henry TD, Schatz RA, Dib N, Toma C, Davidson CJ, Barsness GW, Shavelle DM, Cohen M, Poole J, Moss T, Hyde P, Kanakaraj AM, Druker V, Chung A, Junge C, Preti RA, Smith RL, Mazzo DJ, Pecora A, Losordo DW. PreSERVE-AMI: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial of Intracoronary Administration of Autologous CD34+ Cells in Patients With Left Ventricular Dysfunction Post STEMI. Circ Res 2017; 120:324-331. [PMID: 27821724 PMCID: PMC5903285 DOI: 10.1161/circresaha.115.308165] [Citation(s) in RCA: 115] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2015] [Revised: 10/04/2016] [Accepted: 11/07/2016] [Indexed: 12/21/2022]
Abstract
RATIONALE Despite direct immediate intervention and therapy, ST-segment-elevation myocardial infarction (STEMI) victims remain at risk for infarct expansion, heart failure, reinfarction, repeat revascularization, and death. OBJECTIVE To evaluate the safety and bioactivity of autologous CD34+ cell (CLBS10) intracoronary infusion in patients with left ventricular dysfunction post STEMI. METHODS AND RESULTS Patients who underwent successful stenting for STEMI and had left ventricular dysfunction (ejection fraction≤48%) ≥4 days poststent were eligible for enrollment. Subjects (N=161) underwent mini bone marrow harvest and were randomized 1:1 to receive (1) autologous CD34+ cells (minimum 10 mol/L±20% cells; N=78) or (2) diluent alone (N=83), via intracoronary infusion. The primary safety end point was adverse events, serious adverse events, and major adverse cardiac event. The primary efficacy end point was change in resting myocardial perfusion over 6 months. No differences in myocardial perfusion or adverse events were observed between the control and treatment groups, although increased perfusion was observed within each group from baseline to 6 months (P<0.001). In secondary analyses, when adjusted for time of ischemia, a consistently favorable cell dose-dependent effect was observed in the change in left ventricular ejection fraction and infarct size, and the duration of time subjects was alive and out of hospital (P=0.05). At 1 year, 3.6% (N=3) and 0% deaths were observed in the control and treatment group, respectively. CONCLUSIONS This PreSERVE-AMI (Phase 2, randomized, double-blind, placebo-controlled trial) represents the largest study of cell-based therapy for STEMI completed in the United States and provides evidence supporting safety and potential efficacy in patients with left ventricular dysfunction post STEMI who are at risk for death and major morbidity. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01495364.
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Affiliation(s)
- Arshed A Quyyumi
- From the Emory Clinical Cardiovascular Research Institute, Cardiology Division, Emory University School of Medicine, Atlanta, GA (A.A.Q., J.P.); Athens Regional Cardiology, GA (J.P.); Division of Cardiology, Huntsville Hospital, Huntsville, AL (A.V.); The Christ Hospital Heart and Vascular Center, Cincinnati, OH (D.J.K.); Rutgers University, New Jersey Medical School, Newark (M.K.); Division of Cardiology, Rush University Medical Center, Chicago, IL (G.L.S.); Department of Medicine, Division of Cardiology, University of Kentucky, Lexington (A.A.-L.); Emory St. Joseph's Hospital, Atlanta, GA (S.F.); Division of Cardiology, Cedars-Sinai Heart Institute, Los Angeles, CA (T.D.H.); Scripps Health, La Jolla, CA (R.A.S.); Heart Sciences Center, Gilbert, AZ (N.D.); University of Pittsburgh Medical Center, PA (C.T.); Bluhm Cardiovascular Institute Northwestern Memorial Hospital, Chicago, IL (C.J.D.); Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN (G.W.B.); Cardiovascular Medicine, University of Southern California, Los Angeles, CA (D.M.S.); Westchester Heart and Vascular, Westchester Medical Center, Valhalla, NY (M.C.); Caladrius Biosciences Inc, Basking Ridge, NJ (T.M., P.H., A.M.K., V.D., A.C., C.J., R.A.P., R.L.S., D.J.M., A.P., D.W.L.); and PCT, LLC, A Caladrius Company, Allendale, NJ (R.A.P.).
| | - Alejandro Vasquez
- From the Emory Clinical Cardiovascular Research Institute, Cardiology Division, Emory University School of Medicine, Atlanta, GA (A.A.Q., J.P.); Athens Regional Cardiology, GA (J.P.); Division of Cardiology, Huntsville Hospital, Huntsville, AL (A.V.); The Christ Hospital Heart and Vascular Center, Cincinnati, OH (D.J.K.); Rutgers University, New Jersey Medical School, Newark (M.K.); Division of Cardiology, Rush University Medical Center, Chicago, IL (G.L.S.); Department of Medicine, Division of Cardiology, University of Kentucky, Lexington (A.A.-L.); Emory St. Joseph's Hospital, Atlanta, GA (S.F.); Division of Cardiology, Cedars-Sinai Heart Institute, Los Angeles, CA (T.D.H.); Scripps Health, La Jolla, CA (R.A.S.); Heart Sciences Center, Gilbert, AZ (N.D.); University of Pittsburgh Medical Center, PA (C.T.); Bluhm Cardiovascular Institute Northwestern Memorial Hospital, Chicago, IL (C.J.D.); Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN (G.W.B.); Cardiovascular Medicine, University of Southern California, Los Angeles, CA (D.M.S.); Westchester Heart and Vascular, Westchester Medical Center, Valhalla, NY (M.C.); Caladrius Biosciences Inc, Basking Ridge, NJ (T.M., P.H., A.M.K., V.D., A.C., C.J., R.A.P., R.L.S., D.J.M., A.P., D.W.L.); and PCT, LLC, A Caladrius Company, Allendale, NJ (R.A.P.)
| | - Dean J Kereiakes
- From the Emory Clinical Cardiovascular Research Institute, Cardiology Division, Emory University School of Medicine, Atlanta, GA (A.A.Q., J.P.); Athens Regional Cardiology, GA (J.P.); Division of Cardiology, Huntsville Hospital, Huntsville, AL (A.V.); The Christ Hospital Heart and Vascular Center, Cincinnati, OH (D.J.K.); Rutgers University, New Jersey Medical School, Newark (M.K.); Division of Cardiology, Rush University Medical Center, Chicago, IL (G.L.S.); Department of Medicine, Division of Cardiology, University of Kentucky, Lexington (A.A.-L.); Emory St. Joseph's Hospital, Atlanta, GA (S.F.); Division of Cardiology, Cedars-Sinai Heart Institute, Los Angeles, CA (T.D.H.); Scripps Health, La Jolla, CA (R.A.S.); Heart Sciences Center, Gilbert, AZ (N.D.); University of Pittsburgh Medical Center, PA (C.T.); Bluhm Cardiovascular Institute Northwestern Memorial Hospital, Chicago, IL (C.J.D.); Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN (G.W.B.); Cardiovascular Medicine, University of Southern California, Los Angeles, CA (D.M.S.); Westchester Heart and Vascular, Westchester Medical Center, Valhalla, NY (M.C.); Caladrius Biosciences Inc, Basking Ridge, NJ (T.M., P.H., A.M.K., V.D., A.C., C.J., R.A.P., R.L.S., D.J.M., A.P., D.W.L.); and PCT, LLC, A Caladrius Company, Allendale, NJ (R.A.P.)
| | - Marc Klapholz
- From the Emory Clinical Cardiovascular Research Institute, Cardiology Division, Emory University School of Medicine, Atlanta, GA (A.A.Q., J.P.); Athens Regional Cardiology, GA (J.P.); Division of Cardiology, Huntsville Hospital, Huntsville, AL (A.V.); The Christ Hospital Heart and Vascular Center, Cincinnati, OH (D.J.K.); Rutgers University, New Jersey Medical School, Newark (M.K.); Division of Cardiology, Rush University Medical Center, Chicago, IL (G.L.S.); Department of Medicine, Division of Cardiology, University of Kentucky, Lexington (A.A.-L.); Emory St. Joseph's Hospital, Atlanta, GA (S.F.); Division of Cardiology, Cedars-Sinai Heart Institute, Los Angeles, CA (T.D.H.); Scripps Health, La Jolla, CA (R.A.S.); Heart Sciences Center, Gilbert, AZ (N.D.); University of Pittsburgh Medical Center, PA (C.T.); Bluhm Cardiovascular Institute Northwestern Memorial Hospital, Chicago, IL (C.J.D.); Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN (G.W.B.); Cardiovascular Medicine, University of Southern California, Los Angeles, CA (D.M.S.); Westchester Heart and Vascular, Westchester Medical Center, Valhalla, NY (M.C.); Caladrius Biosciences Inc, Basking Ridge, NJ (T.M., P.H., A.M.K., V.D., A.C., C.J., R.A.P., R.L.S., D.J.M., A.P., D.W.L.); and PCT, LLC, A Caladrius Company, Allendale, NJ (R.A.P.)
| | - Gary L Schaer
- From the Emory Clinical Cardiovascular Research Institute, Cardiology Division, Emory University School of Medicine, Atlanta, GA (A.A.Q., J.P.); Athens Regional Cardiology, GA (J.P.); Division of Cardiology, Huntsville Hospital, Huntsville, AL (A.V.); The Christ Hospital Heart and Vascular Center, Cincinnati, OH (D.J.K.); Rutgers University, New Jersey Medical School, Newark (M.K.); Division of Cardiology, Rush University Medical Center, Chicago, IL (G.L.S.); Department of Medicine, Division of Cardiology, University of Kentucky, Lexington (A.A.-L.); Emory St. Joseph's Hospital, Atlanta, GA (S.F.); Division of Cardiology, Cedars-Sinai Heart Institute, Los Angeles, CA (T.D.H.); Scripps Health, La Jolla, CA (R.A.S.); Heart Sciences Center, Gilbert, AZ (N.D.); University of Pittsburgh Medical Center, PA (C.T.); Bluhm Cardiovascular Institute Northwestern Memorial Hospital, Chicago, IL (C.J.D.); Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN (G.W.B.); Cardiovascular Medicine, University of Southern California, Los Angeles, CA (D.M.S.); Westchester Heart and Vascular, Westchester Medical Center, Valhalla, NY (M.C.); Caladrius Biosciences Inc, Basking Ridge, NJ (T.M., P.H., A.M.K., V.D., A.C., C.J., R.A.P., R.L.S., D.J.M., A.P., D.W.L.); and PCT, LLC, A Caladrius Company, Allendale, NJ (R.A.P.)
| | - Ahmed Abdel-Latif
- From the Emory Clinical Cardiovascular Research Institute, Cardiology Division, Emory University School of Medicine, Atlanta, GA (A.A.Q., J.P.); Athens Regional Cardiology, GA (J.P.); Division of Cardiology, Huntsville Hospital, Huntsville, AL (A.V.); The Christ Hospital Heart and Vascular Center, Cincinnati, OH (D.J.K.); Rutgers University, New Jersey Medical School, Newark (M.K.); Division of Cardiology, Rush University Medical Center, Chicago, IL (G.L.S.); Department of Medicine, Division of Cardiology, University of Kentucky, Lexington (A.A.-L.); Emory St. Joseph's Hospital, Atlanta, GA (S.F.); Division of Cardiology, Cedars-Sinai Heart Institute, Los Angeles, CA (T.D.H.); Scripps Health, La Jolla, CA (R.A.S.); Heart Sciences Center, Gilbert, AZ (N.D.); University of Pittsburgh Medical Center, PA (C.T.); Bluhm Cardiovascular Institute Northwestern Memorial Hospital, Chicago, IL (C.J.D.); Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN (G.W.B.); Cardiovascular Medicine, University of Southern California, Los Angeles, CA (D.M.S.); Westchester Heart and Vascular, Westchester Medical Center, Valhalla, NY (M.C.); Caladrius Biosciences Inc, Basking Ridge, NJ (T.M., P.H., A.M.K., V.D., A.C., C.J., R.A.P., R.L.S., D.J.M., A.P., D.W.L.); and PCT, LLC, A Caladrius Company, Allendale, NJ (R.A.P.)
| | - Stephen Frohwein
- From the Emory Clinical Cardiovascular Research Institute, Cardiology Division, Emory University School of Medicine, Atlanta, GA (A.A.Q., J.P.); Athens Regional Cardiology, GA (J.P.); Division of Cardiology, Huntsville Hospital, Huntsville, AL (A.V.); The Christ Hospital Heart and Vascular Center, Cincinnati, OH (D.J.K.); Rutgers University, New Jersey Medical School, Newark (M.K.); Division of Cardiology, Rush University Medical Center, Chicago, IL (G.L.S.); Department of Medicine, Division of Cardiology, University of Kentucky, Lexington (A.A.-L.); Emory St. Joseph's Hospital, Atlanta, GA (S.F.); Division of Cardiology, Cedars-Sinai Heart Institute, Los Angeles, CA (T.D.H.); Scripps Health, La Jolla, CA (R.A.S.); Heart Sciences Center, Gilbert, AZ (N.D.); University of Pittsburgh Medical Center, PA (C.T.); Bluhm Cardiovascular Institute Northwestern Memorial Hospital, Chicago, IL (C.J.D.); Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN (G.W.B.); Cardiovascular Medicine, University of Southern California, Los Angeles, CA (D.M.S.); Westchester Heart and Vascular, Westchester Medical Center, Valhalla, NY (M.C.); Caladrius Biosciences Inc, Basking Ridge, NJ (T.M., P.H., A.M.K., V.D., A.C., C.J., R.A.P., R.L.S., D.J.M., A.P., D.W.L.); and PCT, LLC, A Caladrius Company, Allendale, NJ (R.A.P.)
| | - Timothy D Henry
- From the Emory Clinical Cardiovascular Research Institute, Cardiology Division, Emory University School of Medicine, Atlanta, GA (A.A.Q., J.P.); Athens Regional Cardiology, GA (J.P.); Division of Cardiology, Huntsville Hospital, Huntsville, AL (A.V.); The Christ Hospital Heart and Vascular Center, Cincinnati, OH (D.J.K.); Rutgers University, New Jersey Medical School, Newark (M.K.); Division of Cardiology, Rush University Medical Center, Chicago, IL (G.L.S.); Department of Medicine, Division of Cardiology, University of Kentucky, Lexington (A.A.-L.); Emory St. Joseph's Hospital, Atlanta, GA (S.F.); Division of Cardiology, Cedars-Sinai Heart Institute, Los Angeles, CA (T.D.H.); Scripps Health, La Jolla, CA (R.A.S.); Heart Sciences Center, Gilbert, AZ (N.D.); University of Pittsburgh Medical Center, PA (C.T.); Bluhm Cardiovascular Institute Northwestern Memorial Hospital, Chicago, IL (C.J.D.); Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN (G.W.B.); Cardiovascular Medicine, University of Southern California, Los Angeles, CA (D.M.S.); Westchester Heart and Vascular, Westchester Medical Center, Valhalla, NY (M.C.); Caladrius Biosciences Inc, Basking Ridge, NJ (T.M., P.H., A.M.K., V.D., A.C., C.J., R.A.P., R.L.S., D.J.M., A.P., D.W.L.); and PCT, LLC, A Caladrius Company, Allendale, NJ (R.A.P.)
| | - Richard A Schatz
- From the Emory Clinical Cardiovascular Research Institute, Cardiology Division, Emory University School of Medicine, Atlanta, GA (A.A.Q., J.P.); Athens Regional Cardiology, GA (J.P.); Division of Cardiology, Huntsville Hospital, Huntsville, AL (A.V.); The Christ Hospital Heart and Vascular Center, Cincinnati, OH (D.J.K.); Rutgers University, New Jersey Medical School, Newark (M.K.); Division of Cardiology, Rush University Medical Center, Chicago, IL (G.L.S.); Department of Medicine, Division of Cardiology, University of Kentucky, Lexington (A.A.-L.); Emory St. Joseph's Hospital, Atlanta, GA (S.F.); Division of Cardiology, Cedars-Sinai Heart Institute, Los Angeles, CA (T.D.H.); Scripps Health, La Jolla, CA (R.A.S.); Heart Sciences Center, Gilbert, AZ (N.D.); University of Pittsburgh Medical Center, PA (C.T.); Bluhm Cardiovascular Institute Northwestern Memorial Hospital, Chicago, IL (C.J.D.); Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN (G.W.B.); Cardiovascular Medicine, University of Southern California, Los Angeles, CA (D.M.S.); Westchester Heart and Vascular, Westchester Medical Center, Valhalla, NY (M.C.); Caladrius Biosciences Inc, Basking Ridge, NJ (T.M., P.H., A.M.K., V.D., A.C., C.J., R.A.P., R.L.S., D.J.M., A.P., D.W.L.); and PCT, LLC, A Caladrius Company, Allendale, NJ (R.A.P.)
| | - Nabil Dib
- From the Emory Clinical Cardiovascular Research Institute, Cardiology Division, Emory University School of Medicine, Atlanta, GA (A.A.Q., J.P.); Athens Regional Cardiology, GA (J.P.); Division of Cardiology, Huntsville Hospital, Huntsville, AL (A.V.); The Christ Hospital Heart and Vascular Center, Cincinnati, OH (D.J.K.); Rutgers University, New Jersey Medical School, Newark (M.K.); Division of Cardiology, Rush University Medical Center, Chicago, IL (G.L.S.); Department of Medicine, Division of Cardiology, University of Kentucky, Lexington (A.A.-L.); Emory St. Joseph's Hospital, Atlanta, GA (S.F.); Division of Cardiology, Cedars-Sinai Heart Institute, Los Angeles, CA (T.D.H.); Scripps Health, La Jolla, CA (R.A.S.); Heart Sciences Center, Gilbert, AZ (N.D.); University of Pittsburgh Medical Center, PA (C.T.); Bluhm Cardiovascular Institute Northwestern Memorial Hospital, Chicago, IL (C.J.D.); Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN (G.W.B.); Cardiovascular Medicine, University of Southern California, Los Angeles, CA (D.M.S.); Westchester Heart and Vascular, Westchester Medical Center, Valhalla, NY (M.C.); Caladrius Biosciences Inc, Basking Ridge, NJ (T.M., P.H., A.M.K., V.D., A.C., C.J., R.A.P., R.L.S., D.J.M., A.P., D.W.L.); and PCT, LLC, A Caladrius Company, Allendale, NJ (R.A.P.)
| | - Catalin Toma
- From the Emory Clinical Cardiovascular Research Institute, Cardiology Division, Emory University School of Medicine, Atlanta, GA (A.A.Q., J.P.); Athens Regional Cardiology, GA (J.P.); Division of Cardiology, Huntsville Hospital, Huntsville, AL (A.V.); The Christ Hospital Heart and Vascular Center, Cincinnati, OH (D.J.K.); Rutgers University, New Jersey Medical School, Newark (M.K.); Division of Cardiology, Rush University Medical Center, Chicago, IL (G.L.S.); Department of Medicine, Division of Cardiology, University of Kentucky, Lexington (A.A.-L.); Emory St. Joseph's Hospital, Atlanta, GA (S.F.); Division of Cardiology, Cedars-Sinai Heart Institute, Los Angeles, CA (T.D.H.); Scripps Health, La Jolla, CA (R.A.S.); Heart Sciences Center, Gilbert, AZ (N.D.); University of Pittsburgh Medical Center, PA (C.T.); Bluhm Cardiovascular Institute Northwestern Memorial Hospital, Chicago, IL (C.J.D.); Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN (G.W.B.); Cardiovascular Medicine, University of Southern California, Los Angeles, CA (D.M.S.); Westchester Heart and Vascular, Westchester Medical Center, Valhalla, NY (M.C.); Caladrius Biosciences Inc, Basking Ridge, NJ (T.M., P.H., A.M.K., V.D., A.C., C.J., R.A.P., R.L.S., D.J.M., A.P., D.W.L.); and PCT, LLC, A Caladrius Company, Allendale, NJ (R.A.P.)
| | - Charles J Davidson
- From the Emory Clinical Cardiovascular Research Institute, Cardiology Division, Emory University School of Medicine, Atlanta, GA (A.A.Q., J.P.); Athens Regional Cardiology, GA (J.P.); Division of Cardiology, Huntsville Hospital, Huntsville, AL (A.V.); The Christ Hospital Heart and Vascular Center, Cincinnati, OH (D.J.K.); Rutgers University, New Jersey Medical School, Newark (M.K.); Division of Cardiology, Rush University Medical Center, Chicago, IL (G.L.S.); Department of Medicine, Division of Cardiology, University of Kentucky, Lexington (A.A.-L.); Emory St. Joseph's Hospital, Atlanta, GA (S.F.); Division of Cardiology, Cedars-Sinai Heart Institute, Los Angeles, CA (T.D.H.); Scripps Health, La Jolla, CA (R.A.S.); Heart Sciences Center, Gilbert, AZ (N.D.); University of Pittsburgh Medical Center, PA (C.T.); Bluhm Cardiovascular Institute Northwestern Memorial Hospital, Chicago, IL (C.J.D.); Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN (G.W.B.); Cardiovascular Medicine, University of Southern California, Los Angeles, CA (D.M.S.); Westchester Heart and Vascular, Westchester Medical Center, Valhalla, NY (M.C.); Caladrius Biosciences Inc, Basking Ridge, NJ (T.M., P.H., A.M.K., V.D., A.C., C.J., R.A.P., R.L.S., D.J.M., A.P., D.W.L.); and PCT, LLC, A Caladrius Company, Allendale, NJ (R.A.P.)
| | - Gregory W Barsness
- From the Emory Clinical Cardiovascular Research Institute, Cardiology Division, Emory University School of Medicine, Atlanta, GA (A.A.Q., J.P.); Athens Regional Cardiology, GA (J.P.); Division of Cardiology, Huntsville Hospital, Huntsville, AL (A.V.); The Christ Hospital Heart and Vascular Center, Cincinnati, OH (D.J.K.); Rutgers University, New Jersey Medical School, Newark (M.K.); Division of Cardiology, Rush University Medical Center, Chicago, IL (G.L.S.); Department of Medicine, Division of Cardiology, University of Kentucky, Lexington (A.A.-L.); Emory St. Joseph's Hospital, Atlanta, GA (S.F.); Division of Cardiology, Cedars-Sinai Heart Institute, Los Angeles, CA (T.D.H.); Scripps Health, La Jolla, CA (R.A.S.); Heart Sciences Center, Gilbert, AZ (N.D.); University of Pittsburgh Medical Center, PA (C.T.); Bluhm Cardiovascular Institute Northwestern Memorial Hospital, Chicago, IL (C.J.D.); Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN (G.W.B.); Cardiovascular Medicine, University of Southern California, Los Angeles, CA (D.M.S.); Westchester Heart and Vascular, Westchester Medical Center, Valhalla, NY (M.C.); Caladrius Biosciences Inc, Basking Ridge, NJ (T.M., P.H., A.M.K., V.D., A.C., C.J., R.A.P., R.L.S., D.J.M., A.P., D.W.L.); and PCT, LLC, A Caladrius Company, Allendale, NJ (R.A.P.)
| | - David M Shavelle
- From the Emory Clinical Cardiovascular Research Institute, Cardiology Division, Emory University School of Medicine, Atlanta, GA (A.A.Q., J.P.); Athens Regional Cardiology, GA (J.P.); Division of Cardiology, Huntsville Hospital, Huntsville, AL (A.V.); The Christ Hospital Heart and Vascular Center, Cincinnati, OH (D.J.K.); Rutgers University, New Jersey Medical School, Newark (M.K.); Division of Cardiology, Rush University Medical Center, Chicago, IL (G.L.S.); Department of Medicine, Division of Cardiology, University of Kentucky, Lexington (A.A.-L.); Emory St. Joseph's Hospital, Atlanta, GA (S.F.); Division of Cardiology, Cedars-Sinai Heart Institute, Los Angeles, CA (T.D.H.); Scripps Health, La Jolla, CA (R.A.S.); Heart Sciences Center, Gilbert, AZ (N.D.); University of Pittsburgh Medical Center, PA (C.T.); Bluhm Cardiovascular Institute Northwestern Memorial Hospital, Chicago, IL (C.J.D.); Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN (G.W.B.); Cardiovascular Medicine, University of Southern California, Los Angeles, CA (D.M.S.); Westchester Heart and Vascular, Westchester Medical Center, Valhalla, NY (M.C.); Caladrius Biosciences Inc, Basking Ridge, NJ (T.M., P.H., A.M.K., V.D., A.C., C.J., R.A.P., R.L.S., D.J.M., A.P., D.W.L.); and PCT, LLC, A Caladrius Company, Allendale, NJ (R.A.P.)
| | - Martin Cohen
- From the Emory Clinical Cardiovascular Research Institute, Cardiology Division, Emory University School of Medicine, Atlanta, GA (A.A.Q., J.P.); Athens Regional Cardiology, GA (J.P.); Division of Cardiology, Huntsville Hospital, Huntsville, AL (A.V.); The Christ Hospital Heart and Vascular Center, Cincinnati, OH (D.J.K.); Rutgers University, New Jersey Medical School, Newark (M.K.); Division of Cardiology, Rush University Medical Center, Chicago, IL (G.L.S.); Department of Medicine, Division of Cardiology, University of Kentucky, Lexington (A.A.-L.); Emory St. Joseph's Hospital, Atlanta, GA (S.F.); Division of Cardiology, Cedars-Sinai Heart Institute, Los Angeles, CA (T.D.H.); Scripps Health, La Jolla, CA (R.A.S.); Heart Sciences Center, Gilbert, AZ (N.D.); University of Pittsburgh Medical Center, PA (C.T.); Bluhm Cardiovascular Institute Northwestern Memorial Hospital, Chicago, IL (C.J.D.); Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN (G.W.B.); Cardiovascular Medicine, University of Southern California, Los Angeles, CA (D.M.S.); Westchester Heart and Vascular, Westchester Medical Center, Valhalla, NY (M.C.); Caladrius Biosciences Inc, Basking Ridge, NJ (T.M., P.H., A.M.K., V.D., A.C., C.J., R.A.P., R.L.S., D.J.M., A.P., D.W.L.); and PCT, LLC, A Caladrius Company, Allendale, NJ (R.A.P.)
| | - Joseph Poole
- From the Emory Clinical Cardiovascular Research Institute, Cardiology Division, Emory University School of Medicine, Atlanta, GA (A.A.Q., J.P.); Athens Regional Cardiology, GA (J.P.); Division of Cardiology, Huntsville Hospital, Huntsville, AL (A.V.); The Christ Hospital Heart and Vascular Center, Cincinnati, OH (D.J.K.); Rutgers University, New Jersey Medical School, Newark (M.K.); Division of Cardiology, Rush University Medical Center, Chicago, IL (G.L.S.); Department of Medicine, Division of Cardiology, University of Kentucky, Lexington (A.A.-L.); Emory St. Joseph's Hospital, Atlanta, GA (S.F.); Division of Cardiology, Cedars-Sinai Heart Institute, Los Angeles, CA (T.D.H.); Scripps Health, La Jolla, CA (R.A.S.); Heart Sciences Center, Gilbert, AZ (N.D.); University of Pittsburgh Medical Center, PA (C.T.); Bluhm Cardiovascular Institute Northwestern Memorial Hospital, Chicago, IL (C.J.D.); Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN (G.W.B.); Cardiovascular Medicine, University of Southern California, Los Angeles, CA (D.M.S.); Westchester Heart and Vascular, Westchester Medical Center, Valhalla, NY (M.C.); Caladrius Biosciences Inc, Basking Ridge, NJ (T.M., P.H., A.M.K., V.D., A.C., C.J., R.A.P., R.L.S., D.J.M., A.P., D.W.L.); and PCT, LLC, A Caladrius Company, Allendale, NJ (R.A.P.)
| | - Thomas Moss
- From the Emory Clinical Cardiovascular Research Institute, Cardiology Division, Emory University School of Medicine, Atlanta, GA (A.A.Q., J.P.); Athens Regional Cardiology, GA (J.P.); Division of Cardiology, Huntsville Hospital, Huntsville, AL (A.V.); The Christ Hospital Heart and Vascular Center, Cincinnati, OH (D.J.K.); Rutgers University, New Jersey Medical School, Newark (M.K.); Division of Cardiology, Rush University Medical Center, Chicago, IL (G.L.S.); Department of Medicine, Division of Cardiology, University of Kentucky, Lexington (A.A.-L.); Emory St. Joseph's Hospital, Atlanta, GA (S.F.); Division of Cardiology, Cedars-Sinai Heart Institute, Los Angeles, CA (T.D.H.); Scripps Health, La Jolla, CA (R.A.S.); Heart Sciences Center, Gilbert, AZ (N.D.); University of Pittsburgh Medical Center, PA (C.T.); Bluhm Cardiovascular Institute Northwestern Memorial Hospital, Chicago, IL (C.J.D.); Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN (G.W.B.); Cardiovascular Medicine, University of Southern California, Los Angeles, CA (D.M.S.); Westchester Heart and Vascular, Westchester Medical Center, Valhalla, NY (M.C.); Caladrius Biosciences Inc, Basking Ridge, NJ (T.M., P.H., A.M.K., V.D., A.C., C.J., R.A.P., R.L.S., D.J.M., A.P., D.W.L.); and PCT, LLC, A Caladrius Company, Allendale, NJ (R.A.P.)
| | - Pamela Hyde
- From the Emory Clinical Cardiovascular Research Institute, Cardiology Division, Emory University School of Medicine, Atlanta, GA (A.A.Q., J.P.); Athens Regional Cardiology, GA (J.P.); Division of Cardiology, Huntsville Hospital, Huntsville, AL (A.V.); The Christ Hospital Heart and Vascular Center, Cincinnati, OH (D.J.K.); Rutgers University, New Jersey Medical School, Newark (M.K.); Division of Cardiology, Rush University Medical Center, Chicago, IL (G.L.S.); Department of Medicine, Division of Cardiology, University of Kentucky, Lexington (A.A.-L.); Emory St. Joseph's Hospital, Atlanta, GA (S.F.); Division of Cardiology, Cedars-Sinai Heart Institute, Los Angeles, CA (T.D.H.); Scripps Health, La Jolla, CA (R.A.S.); Heart Sciences Center, Gilbert, AZ (N.D.); University of Pittsburgh Medical Center, PA (C.T.); Bluhm Cardiovascular Institute Northwestern Memorial Hospital, Chicago, IL (C.J.D.); Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN (G.W.B.); Cardiovascular Medicine, University of Southern California, Los Angeles, CA (D.M.S.); Westchester Heart and Vascular, Westchester Medical Center, Valhalla, NY (M.C.); Caladrius Biosciences Inc, Basking Ridge, NJ (T.M., P.H., A.M.K., V.D., A.C., C.J., R.A.P., R.L.S., D.J.M., A.P., D.W.L.); and PCT, LLC, A Caladrius Company, Allendale, NJ (R.A.P.)
| | - Anna Maria Kanakaraj
- From the Emory Clinical Cardiovascular Research Institute, Cardiology Division, Emory University School of Medicine, Atlanta, GA (A.A.Q., J.P.); Athens Regional Cardiology, GA (J.P.); Division of Cardiology, Huntsville Hospital, Huntsville, AL (A.V.); The Christ Hospital Heart and Vascular Center, Cincinnati, OH (D.J.K.); Rutgers University, New Jersey Medical School, Newark (M.K.); Division of Cardiology, Rush University Medical Center, Chicago, IL (G.L.S.); Department of Medicine, Division of Cardiology, University of Kentucky, Lexington (A.A.-L.); Emory St. Joseph's Hospital, Atlanta, GA (S.F.); Division of Cardiology, Cedars-Sinai Heart Institute, Los Angeles, CA (T.D.H.); Scripps Health, La Jolla, CA (R.A.S.); Heart Sciences Center, Gilbert, AZ (N.D.); University of Pittsburgh Medical Center, PA (C.T.); Bluhm Cardiovascular Institute Northwestern Memorial Hospital, Chicago, IL (C.J.D.); Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN (G.W.B.); Cardiovascular Medicine, University of Southern California, Los Angeles, CA (D.M.S.); Westchester Heart and Vascular, Westchester Medical Center, Valhalla, NY (M.C.); Caladrius Biosciences Inc, Basking Ridge, NJ (T.M., P.H., A.M.K., V.D., A.C., C.J., R.A.P., R.L.S., D.J.M., A.P., D.W.L.); and PCT, LLC, A Caladrius Company, Allendale, NJ (R.A.P.)
| | - Vitaly Druker
- From the Emory Clinical Cardiovascular Research Institute, Cardiology Division, Emory University School of Medicine, Atlanta, GA (A.A.Q., J.P.); Athens Regional Cardiology, GA (J.P.); Division of Cardiology, Huntsville Hospital, Huntsville, AL (A.V.); The Christ Hospital Heart and Vascular Center, Cincinnati, OH (D.J.K.); Rutgers University, New Jersey Medical School, Newark (M.K.); Division of Cardiology, Rush University Medical Center, Chicago, IL (G.L.S.); Department of Medicine, Division of Cardiology, University of Kentucky, Lexington (A.A.-L.); Emory St. Joseph's Hospital, Atlanta, GA (S.F.); Division of Cardiology, Cedars-Sinai Heart Institute, Los Angeles, CA (T.D.H.); Scripps Health, La Jolla, CA (R.A.S.); Heart Sciences Center, Gilbert, AZ (N.D.); University of Pittsburgh Medical Center, PA (C.T.); Bluhm Cardiovascular Institute Northwestern Memorial Hospital, Chicago, IL (C.J.D.); Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN (G.W.B.); Cardiovascular Medicine, University of Southern California, Los Angeles, CA (D.M.S.); Westchester Heart and Vascular, Westchester Medical Center, Valhalla, NY (M.C.); Caladrius Biosciences Inc, Basking Ridge, NJ (T.M., P.H., A.M.K., V.D., A.C., C.J., R.A.P., R.L.S., D.J.M., A.P., D.W.L.); and PCT, LLC, A Caladrius Company, Allendale, NJ (R.A.P.)
| | - Amy Chung
- From the Emory Clinical Cardiovascular Research Institute, Cardiology Division, Emory University School of Medicine, Atlanta, GA (A.A.Q., J.P.); Athens Regional Cardiology, GA (J.P.); Division of Cardiology, Huntsville Hospital, Huntsville, AL (A.V.); The Christ Hospital Heart and Vascular Center, Cincinnati, OH (D.J.K.); Rutgers University, New Jersey Medical School, Newark (M.K.); Division of Cardiology, Rush University Medical Center, Chicago, IL (G.L.S.); Department of Medicine, Division of Cardiology, University of Kentucky, Lexington (A.A.-L.); Emory St. Joseph's Hospital, Atlanta, GA (S.F.); Division of Cardiology, Cedars-Sinai Heart Institute, Los Angeles, CA (T.D.H.); Scripps Health, La Jolla, CA (R.A.S.); Heart Sciences Center, Gilbert, AZ (N.D.); University of Pittsburgh Medical Center, PA (C.T.); Bluhm Cardiovascular Institute Northwestern Memorial Hospital, Chicago, IL (C.J.D.); Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN (G.W.B.); Cardiovascular Medicine, University of Southern California, Los Angeles, CA (D.M.S.); Westchester Heart and Vascular, Westchester Medical Center, Valhalla, NY (M.C.); Caladrius Biosciences Inc, Basking Ridge, NJ (T.M., P.H., A.M.K., V.D., A.C., C.J., R.A.P., R.L.S., D.J.M., A.P., D.W.L.); and PCT, LLC, A Caladrius Company, Allendale, NJ (R.A.P.)
| | - Candice Junge
- From the Emory Clinical Cardiovascular Research Institute, Cardiology Division, Emory University School of Medicine, Atlanta, GA (A.A.Q., J.P.); Athens Regional Cardiology, GA (J.P.); Division of Cardiology, Huntsville Hospital, Huntsville, AL (A.V.); The Christ Hospital Heart and Vascular Center, Cincinnati, OH (D.J.K.); Rutgers University, New Jersey Medical School, Newark (M.K.); Division of Cardiology, Rush University Medical Center, Chicago, IL (G.L.S.); Department of Medicine, Division of Cardiology, University of Kentucky, Lexington (A.A.-L.); Emory St. Joseph's Hospital, Atlanta, GA (S.F.); Division of Cardiology, Cedars-Sinai Heart Institute, Los Angeles, CA (T.D.H.); Scripps Health, La Jolla, CA (R.A.S.); Heart Sciences Center, Gilbert, AZ (N.D.); University of Pittsburgh Medical Center, PA (C.T.); Bluhm Cardiovascular Institute Northwestern Memorial Hospital, Chicago, IL (C.J.D.); Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN (G.W.B.); Cardiovascular Medicine, University of Southern California, Los Angeles, CA (D.M.S.); Westchester Heart and Vascular, Westchester Medical Center, Valhalla, NY (M.C.); Caladrius Biosciences Inc, Basking Ridge, NJ (T.M., P.H., A.M.K., V.D., A.C., C.J., R.A.P., R.L.S., D.J.M., A.P., D.W.L.); and PCT, LLC, A Caladrius Company, Allendale, NJ (R.A.P.)
| | - Robert A Preti
- From the Emory Clinical Cardiovascular Research Institute, Cardiology Division, Emory University School of Medicine, Atlanta, GA (A.A.Q., J.P.); Athens Regional Cardiology, GA (J.P.); Division of Cardiology, Huntsville Hospital, Huntsville, AL (A.V.); The Christ Hospital Heart and Vascular Center, Cincinnati, OH (D.J.K.); Rutgers University, New Jersey Medical School, Newark (M.K.); Division of Cardiology, Rush University Medical Center, Chicago, IL (G.L.S.); Department of Medicine, Division of Cardiology, University of Kentucky, Lexington (A.A.-L.); Emory St. Joseph's Hospital, Atlanta, GA (S.F.); Division of Cardiology, Cedars-Sinai Heart Institute, Los Angeles, CA (T.D.H.); Scripps Health, La Jolla, CA (R.A.S.); Heart Sciences Center, Gilbert, AZ (N.D.); University of Pittsburgh Medical Center, PA (C.T.); Bluhm Cardiovascular Institute Northwestern Memorial Hospital, Chicago, IL (C.J.D.); Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN (G.W.B.); Cardiovascular Medicine, University of Southern California, Los Angeles, CA (D.M.S.); Westchester Heart and Vascular, Westchester Medical Center, Valhalla, NY (M.C.); Caladrius Biosciences Inc, Basking Ridge, NJ (T.M., P.H., A.M.K., V.D., A.C., C.J., R.A.P., R.L.S., D.J.M., A.P., D.W.L.); and PCT, LLC, A Caladrius Company, Allendale, NJ (R.A.P.)
| | - Robin L Smith
- From the Emory Clinical Cardiovascular Research Institute, Cardiology Division, Emory University School of Medicine, Atlanta, GA (A.A.Q., J.P.); Athens Regional Cardiology, GA (J.P.); Division of Cardiology, Huntsville Hospital, Huntsville, AL (A.V.); The Christ Hospital Heart and Vascular Center, Cincinnati, OH (D.J.K.); Rutgers University, New Jersey Medical School, Newark (M.K.); Division of Cardiology, Rush University Medical Center, Chicago, IL (G.L.S.); Department of Medicine, Division of Cardiology, University of Kentucky, Lexington (A.A.-L.); Emory St. Joseph's Hospital, Atlanta, GA (S.F.); Division of Cardiology, Cedars-Sinai Heart Institute, Los Angeles, CA (T.D.H.); Scripps Health, La Jolla, CA (R.A.S.); Heart Sciences Center, Gilbert, AZ (N.D.); University of Pittsburgh Medical Center, PA (C.T.); Bluhm Cardiovascular Institute Northwestern Memorial Hospital, Chicago, IL (C.J.D.); Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN (G.W.B.); Cardiovascular Medicine, University of Southern California, Los Angeles, CA (D.M.S.); Westchester Heart and Vascular, Westchester Medical Center, Valhalla, NY (M.C.); Caladrius Biosciences Inc, Basking Ridge, NJ (T.M., P.H., A.M.K., V.D., A.C., C.J., R.A.P., R.L.S., D.J.M., A.P., D.W.L.); and PCT, LLC, A Caladrius Company, Allendale, NJ (R.A.P.)
| | - David J Mazzo
- From the Emory Clinical Cardiovascular Research Institute, Cardiology Division, Emory University School of Medicine, Atlanta, GA (A.A.Q., J.P.); Athens Regional Cardiology, GA (J.P.); Division of Cardiology, Huntsville Hospital, Huntsville, AL (A.V.); The Christ Hospital Heart and Vascular Center, Cincinnati, OH (D.J.K.); Rutgers University, New Jersey Medical School, Newark (M.K.); Division of Cardiology, Rush University Medical Center, Chicago, IL (G.L.S.); Department of Medicine, Division of Cardiology, University of Kentucky, Lexington (A.A.-L.); Emory St. Joseph's Hospital, Atlanta, GA (S.F.); Division of Cardiology, Cedars-Sinai Heart Institute, Los Angeles, CA (T.D.H.); Scripps Health, La Jolla, CA (R.A.S.); Heart Sciences Center, Gilbert, AZ (N.D.); University of Pittsburgh Medical Center, PA (C.T.); Bluhm Cardiovascular Institute Northwestern Memorial Hospital, Chicago, IL (C.J.D.); Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN (G.W.B.); Cardiovascular Medicine, University of Southern California, Los Angeles, CA (D.M.S.); Westchester Heart and Vascular, Westchester Medical Center, Valhalla, NY (M.C.); Caladrius Biosciences Inc, Basking Ridge, NJ (T.M., P.H., A.M.K., V.D., A.C., C.J., R.A.P., R.L.S., D.J.M., A.P., D.W.L.); and PCT, LLC, A Caladrius Company, Allendale, NJ (R.A.P.)
| | - Andrew Pecora
- From the Emory Clinical Cardiovascular Research Institute, Cardiology Division, Emory University School of Medicine, Atlanta, GA (A.A.Q., J.P.); Athens Regional Cardiology, GA (J.P.); Division of Cardiology, Huntsville Hospital, Huntsville, AL (A.V.); The Christ Hospital Heart and Vascular Center, Cincinnati, OH (D.J.K.); Rutgers University, New Jersey Medical School, Newark (M.K.); Division of Cardiology, Rush University Medical Center, Chicago, IL (G.L.S.); Department of Medicine, Division of Cardiology, University of Kentucky, Lexington (A.A.-L.); Emory St. Joseph's Hospital, Atlanta, GA (S.F.); Division of Cardiology, Cedars-Sinai Heart Institute, Los Angeles, CA (T.D.H.); Scripps Health, La Jolla, CA (R.A.S.); Heart Sciences Center, Gilbert, AZ (N.D.); University of Pittsburgh Medical Center, PA (C.T.); Bluhm Cardiovascular Institute Northwestern Memorial Hospital, Chicago, IL (C.J.D.); Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN (G.W.B.); Cardiovascular Medicine, University of Southern California, Los Angeles, CA (D.M.S.); Westchester Heart and Vascular, Westchester Medical Center, Valhalla, NY (M.C.); Caladrius Biosciences Inc, Basking Ridge, NJ (T.M., P.H., A.M.K., V.D., A.C., C.J., R.A.P., R.L.S., D.J.M., A.P., D.W.L.); and PCT, LLC, A Caladrius Company, Allendale, NJ (R.A.P.)
| | - Douglas W Losordo
- From the Emory Clinical Cardiovascular Research Institute, Cardiology Division, Emory University School of Medicine, Atlanta, GA (A.A.Q., J.P.); Athens Regional Cardiology, GA (J.P.); Division of Cardiology, Huntsville Hospital, Huntsville, AL (A.V.); The Christ Hospital Heart and Vascular Center, Cincinnati, OH (D.J.K.); Rutgers University, New Jersey Medical School, Newark (M.K.); Division of Cardiology, Rush University Medical Center, Chicago, IL (G.L.S.); Department of Medicine, Division of Cardiology, University of Kentucky, Lexington (A.A.-L.); Emory St. Joseph's Hospital, Atlanta, GA (S.F.); Division of Cardiology, Cedars-Sinai Heart Institute, Los Angeles, CA (T.D.H.); Scripps Health, La Jolla, CA (R.A.S.); Heart Sciences Center, Gilbert, AZ (N.D.); University of Pittsburgh Medical Center, PA (C.T.); Bluhm Cardiovascular Institute Northwestern Memorial Hospital, Chicago, IL (C.J.D.); Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN (G.W.B.); Cardiovascular Medicine, University of Southern California, Los Angeles, CA (D.M.S.); Westchester Heart and Vascular, Westchester Medical Center, Valhalla, NY (M.C.); Caladrius Biosciences Inc, Basking Ridge, NJ (T.M., P.H., A.M.K., V.D., A.C., C.J., R.A.P., R.L.S., D.J.M., A.P., D.W.L.); and PCT, LLC, A Caladrius Company, Allendale, NJ (R.A.P.)
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Hao M, Wang R, Wang W. Cell Therapies in Cardiomyopathy: Current Status of Clinical Trials. Anal Cell Pathol (Amst) 2017; 2017:9404057. [PMID: 28194324 PMCID: PMC5282433 DOI: 10.1155/2017/9404057] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2016] [Revised: 12/06/2016] [Accepted: 12/08/2016] [Indexed: 12/28/2022] Open
Abstract
Because the human heart has limited potential for regeneration, the loss of cardiomyocytes during cardiac myopathy and ischaemic injury can result in heart failure and death. Stem cell therapy has emerged as a promising strategy for the treatment of dead myocardium, directly or indirectly, and seems to offer functional benefits to patients. The ideal candidate donor cell for myocardial reconstitution is a stem-like cell that can be easily obtained, has a robust proliferation capacity and a low risk of tumour formation and immune rejection, differentiates into functionally normal cardiomyocytes, and is suitable for minimally invasive clinical transplantation. The ultimate goal of cardiac repair is to regenerate functionally viable myocardium after myocardial infarction (MI) to prevent or heal heart failure. This review provides a comprehensive overview of treatment with stem-like cells in preclinical and clinical studies to assess the feasibility and efficacy of this novel therapeutic strategy in ischaemic cardiomyopathy.
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Affiliation(s)
- Ming Hao
- Cellular Biomedicine Group, 333 Guiping Road, Shanghai 200233, China
- Cellular Biomedicine Group, 19925 Stevens Creek Blvd, Suite 100, Cupertino, CA 95014, USA
| | - Richard Wang
- Cellular Biomedicine Group, 333 Guiping Road, Shanghai 200233, China
- Cellular Biomedicine Group, 19925 Stevens Creek Blvd, Suite 100, Cupertino, CA 95014, USA
| | - Wen Wang
- Cellular Biomedicine Group, 333 Guiping Road, Shanghai 200233, China
- Cellular Biomedicine Group, 19925 Stevens Creek Blvd, Suite 100, Cupertino, CA 95014, USA
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Wang LT, Ting CH, Yen ML, Liu KJ, Sytwu HK, Wu KK, Yen BL. Human mesenchymal stem cells (MSCs) for treatment towards immune- and inflammation-mediated diseases: review of current clinical trials. J Biomed Sci 2016; 23:76. [PMID: 27809910 PMCID: PMC5095977 DOI: 10.1186/s12929-016-0289-5] [Citation(s) in RCA: 241] [Impact Index Per Article: 26.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2016] [Accepted: 10/12/2016] [Indexed: 12/19/2022] Open
Abstract
Human mesenchymal stem cells (MSCs) are multilineage somatic progenitor/stem cells that have been shown to possess immunomodulatory properties in recent years. Initially met with much skepticism, MSC immunomodulation has now been well reproduced across tissue sources and species to be clinically relevant. This has opened up the use of these versatile cells for application as 3rd party/allogeneic use in cell replacement/tissue regeneration, as well as for immune- and inflammation-mediated disease entities. Most surprisingly, use of MSCs for in immune-/inflammation-mediated diseases appears to yield more efficacy than for regenerative medicine, since engraftment of the exogenous cell does not appear necessary. In this review, we focus on this non-traditional clinical use of a tissue-specific stem cell, and highlight important findings and trends in this exciting area of stem cell therapy.
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Affiliation(s)
- Li-Tzu Wang
- Regenerative Medicine Research Group, Institute of Cellular & System Medicine, National Health Research Institutes (NHRI), 35 Keyan Road, Zhunan, 35053, Taiwan.,Graduate Institute of Life Sciences, National Defense Medical Center (NDMC), Taipei, Taiwan
| | - Chiao-Hsuan Ting
- Regenerative Medicine Research Group, Institute of Cellular & System Medicine, National Health Research Institutes (NHRI), 35 Keyan Road, Zhunan, 35053, Taiwan
| | - Men-Luh Yen
- Department of Ob/Gyn, National Taiwan University Hospital & College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Ko-Jiunn Liu
- National Institute of Cancer Research, NHRI, Tainan, Taiwan
| | - Huey-Kang Sytwu
- Graduate Institute of Life Sciences, National Defense Medical Center (NDMC), Taipei, Taiwan.,Graduate Institute of Microbiology and Immunology, NDMC, Taipei, Taiwan
| | - Kenneth K Wu
- Regenerative Medicine Research Group, Institute of Cellular & System Medicine, National Health Research Institutes (NHRI), 35 Keyan Road, Zhunan, 35053, Taiwan.,Graduate Institute of Basic Medical Sciences, China Medical College, Taichung, Taiwan
| | - B Linju Yen
- Regenerative Medicine Research Group, Institute of Cellular & System Medicine, National Health Research Institutes (NHRI), 35 Keyan Road, Zhunan, 35053, Taiwan.
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Osteoarthritis-derived chondrocytes are a potential source of multipotent progenitor cells for cartilage tissue engineering. Biochem Biophys Res Commun 2016; 479:469-475. [DOI: 10.1016/j.bbrc.2016.09.085] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2016] [Accepted: 09/16/2016] [Indexed: 01/01/2023]
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Fernández-Solà J, Planavila Porta A. New Treatment Strategies for Alcohol-Induced Heart Damage. Int J Mol Sci 2016; 17:E1651. [PMID: 27690014 PMCID: PMC5085684 DOI: 10.3390/ijms17101651] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2016] [Revised: 09/15/2016] [Accepted: 09/16/2016] [Indexed: 02/07/2023] Open
Abstract
High-dose alcohol misuse induces multiple noxious cardiac effects, including myocyte hypertrophy and necrosis, interstitial fibrosis, decreased ventricular contraction and ventricle enlargement. These effects produce diastolic and systolic ventricular dysfunction leading to congestive heart failure, arrhythmias and an increased death rate. There are multiple, dose-dependent, synchronic and synergistic mechanisms of alcohol-induced cardiac damage. Ethanol alters membrane permeability and composition, interferes with receptors and intracellular transients, induces oxidative, metabolic and energy damage, decreases protein synthesis, excitation-contraction coupling and increases cell apoptosis. In addition, ethanol decreases myocyte protective and repair mechanisms and their regeneration. Although there are diverse different strategies to directly target alcohol-induced heart damage, they are partially effective, and can only be used as support medication in a multidisciplinary approach. Alcohol abstinence is the preferred goal, but control drinking is useful in alcohol-addicted subjects not able to abstain. Correction of nutrition, ionic and vitamin deficiencies and control of alcohol-related systemic organ damage are compulsory. Recently, several growth factors (myostatin, IGF-1, leptin, ghrelin, miRNA, and ROCK inhibitors) and new cardiomyokines such as FGF21 have been described to regulate cardiac plasticity and decrease cardiac damage, improving cardiac repair mechanisms, and they are promising agents in this field. New potential therapeutic targets aim to control oxidative damage, myocyte hypertrophy, interstitial fibrosis and persistent apoptosis In addition, stem-cell therapy may improve myocyte regeneration. However, these strategies are not yet approved for clinical use.
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Affiliation(s)
- Joaquim Fernández-Solà
- Alcohol Unit, Department of Internal Medicine, Hospital Clinic, University of Barcelona, Villarroel 170, 08036 Barcelona, Spain.
| | - Ana Planavila Porta
- Departament of Biochemistry and Molecular Biomedicine, Faculty of Biology, Avda Diagonal 643, Universitat de Barcelona, 08028 Barcelona, Spain.
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Characterization of Cellular and Molecular Heterogeneity of Bone Marrow Stromal Cells. Stem Cells Int 2016; 2016:9378081. [PMID: 27610142 PMCID: PMC5004045 DOI: 10.1155/2016/9378081] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2016] [Accepted: 05/26/2016] [Indexed: 01/04/2023] Open
Abstract
Human bone marrow-derived stromal stem cells (hBMSC) exhibit multiple functions, including differentiation into skeletal cells (progenitor function), hematopoiesis support, and immune regulation (nonprogenitor function). We have previously demonstrated the presence of morphological and functional heterogeneity of hBMSC cultures. In the present study, we characterized in detail two hTERT-BMSC clonal cell populations termed here CL1 and CL2 that represent an opposing phenotype with respect to morphology, markers expression: alkaline phosphatase (ALP) and CD146, and ex vivo differentiation potential. CL1 differentiated readily to osteoblasts, adipocytes, and chondrocytes as shown by expression of lineage specific genes and proteins. Whole genome transcriptome profiling of CL1 versus CL2 revealed enrichment in CL1 of bone-, mineralization-, and skeletal muscle-related genes, for example, ALP, POSTN, IGFBP5 BMP4, and CXCL12. On the other hand, CL2 transcriptome was enriched in immune modulatory genes, for example, CD14, CD99, NOTCH3, CXCL6, CFB, and CFI. Furthermore, gene expression microarray analysis of osteoblast differentiated CL1 versus CL2 showed significant upregulation in CL1 of bone development and osteoblast differentiation genes which included several homeobox genes: TBX15, HOXA2 and HOXA10, and IGF1, FGFR3, BMP6, MCAM, ITGA10, IGFBP5, and ALP. siRNA-based downregulation of the ALP gene in CL1 impaired osteoblastic and adipocytic differentiation. Our studies demonstrate the existence of molecular and functional heterogeneity in cultured hBMSC. ALP can be employed to identify osteoblastic and adipocytic progenitor cells in the heterogeneous hBMSC cultures.
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Aonuma T, Takehara N, Maruyama K, Kabara M, Matsuki M, Yamauchi A, Kawabe JI, Hasebe N. Apoptosis-Resistant Cardiac Progenitor Cells Modified With Apurinic/Apyrimidinic Endonuclease/Redox Factor 1 Gene Overexpression Regulate Cardiac Repair After Myocardial Infarction. Stem Cells Transl Med 2016; 5:1067-78. [PMID: 27334489 DOI: 10.5966/sctm.2015-0281] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2015] [Accepted: 03/14/2016] [Indexed: 01/16/2023] Open
Abstract
UNLABELLED : Overcoming the insufficient survival of cell grafts is an essential objective in cell-based therapy. Apurinic/apyrimidinic endonuclease/redox factor 1 (APE1) promotes cell survival and may enhance the therapeutic effect of engrafted cells. The aim of this study is to determine whether APE1 overexpression in cardiac progenitor cells (CPCs) could ameliorate the efficiency of cell-based therapy. CPCs isolated from 8- to 10-week-old C57BL/6 mouse hearts were infected with retrovirus harboring APE1-DsRed (APE1-CPC) or a DsRed control (control-CPC). Oxidative stress-induced apoptosis was then assessed in APE1-CPCs, control-CPCs, and neonatal rat ventricular myocytes (NRVMs) cocultured with these CPCs. This analysis revealed that APE1 overexpression inhibited CPC apoptosis with activation of transforming growth factor β-activated kinase 1 (TAK1) and nuclear factor (NF)-κB. In the coculture model, NRVM apoptosis was inhibited to a greater extent in the presence of APE1-CPCs compared with control-CPCs. Moreover, the number of surviving DsRed-positive CPC grafts was significantly higher 7 days after the transplant of APE1-CPCs into a mouse myocardial infarction model, and the left ventricular ejection fraction showed greater improvement with attenuation of fibrosis 28 days after the transplant of APE1-CPCs compared with control-CPCs. Additionally, fewer inflammatory macrophages and a higher percentage of cardiac α-sarcomeric actinin-positive CPC-grafts were observed in mice injected with APE1-CPCs compared with control-CPCs after 7 days. In conclusion, antiapoptotic APE1-CPC graft, which increased TAK1-NF-κB pathway activation, survived effectively in the ischemic heart, restored cardiac function, and reduced cardiac inflammation and fibrosis. APE1 overexpression in CPCs may serve as a novel strategy to improve cardiac cell therapy. SIGNIFICANCE Improving the survival of cell grafts is essential to maximize the efficacy of cell therapy. The authors investigated the role of APE1 in CPCs under ischemic conditions and evaluated the therapeutic efficacy of transplanted APE1-overexpressing CPCs in a mouse model of myocardial infarction. APE1 hindered apoptosis in CPC grafts subjected to oxidative stress caused in part by increased TAK1-NF-κB pathway activation. Furthermore, APE1-CPC grafts that effectively survived in the ischemic heart restored cardiac function and attenuated fibrosis through pleiotropic mechanisms that remain to be characterized. These findings suggest that APE1 overexpression in CPCs may be a novel strategy to reinforce cardiac cell therapy.
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Affiliation(s)
- Tatsuya Aonuma
- Department of Internal Medicine, Division of Cardiology, Nephrology, Pulmonology, and Neurology, Asahikawa Medical University, Asahikawa, Japan
| | - Naofumi Takehara
- Department of Internal Medicine, Division of Cardiology, Nephrology, Pulmonology, and Neurology, Asahikawa Medical University, Asahikawa, Japan Department of Cardiovascular Regeneration and Innovation, Asahikawa Medical University, Asahikawa, Japan
| | - Keisuke Maruyama
- Department of Internal Medicine, Division of Cardiology, Nephrology, Pulmonology, and Neurology, Asahikawa Medical University, Asahikawa, Japan
| | - Maki Kabara
- Department of Internal Medicine, Division of Cardiology, Nephrology, Pulmonology, and Neurology, Asahikawa Medical University, Asahikawa, Japan Department of Cardiovascular Regeneration and Innovation, Asahikawa Medical University, Asahikawa, Japan
| | - Motoki Matsuki
- Department of Internal Medicine, Division of Cardiology, Nephrology, Pulmonology, and Neurology, Asahikawa Medical University, Asahikawa, Japan
| | - Atsushi Yamauchi
- Department of Internal Medicine, Division of Cardiology, Nephrology, Pulmonology, and Neurology, Asahikawa Medical University, Asahikawa, Japan
| | - Jun-Ichi Kawabe
- Department of Internal Medicine, Division of Cardiology, Nephrology, Pulmonology, and Neurology, Asahikawa Medical University, Asahikawa, Japan Department of Cardiovascular Regeneration and Innovation, Asahikawa Medical University, Asahikawa, Japan
| | - Naoyuki Hasebe
- Department of Internal Medicine, Division of Cardiology, Nephrology, Pulmonology, and Neurology, Asahikawa Medical University, Asahikawa, Japan
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Oh H, Ito H, Sano S. Challenges to success in heart failure: Cardiac cell therapies in patients with heart diseases. J Cardiol 2016; 68:361-367. [PMID: 27341741 DOI: 10.1016/j.jjcc.2016.04.010] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2016] [Accepted: 04/11/2016] [Indexed: 12/18/2022]
Abstract
Heart failure remains the leading cause of death worldwide, and is a burgeoning problem in public health due to the limited capacity of postnatal hearts to self-renew. The pathophysiological changes in injured hearts can sometimes be manifested as scar formation or myocardial degradation, rather than supplemental muscle regeneration to replenish lost tissue during the healing processes. Stem cell therapies have been investigated as a possible treatment approach for children and adults with potentially fatal cardiovascular disease that does not respond to current medical therapies. Although the heart is one of the least regenerative organs in mammals, discoveries made during the past few decades have improved our understanding of cardiac development and resident stem/progenitor pools, which may be lineage-restricted subpopulations during the post-neonatal stage of cardiac morphogenesis. Recently, investigation has specifically focused on factors that activate either endogenous progenitor cells or preexisting cardiomyocytes, to regenerate cardiovascular cells and replace the damaged heart tissues. The discovery of induced pluripotent stem cells has advanced our technological capability to direct cardiac reprogramming by essential factors that are crucial for heart field completion in each stage. Cardiac tissue engineering technology has recently shown progress in generating myocardial tissue on human native cardiac extracellular matrix scaffolds. This review summarizes recent advances in the field of cardiac cell therapies with an emphasis on cellular mechanisms, such as bone marrow stem cells and cardiac progenitor cells, which show the high potential for success in preclinical and clinical meta-analysis studies. Expanding our current understanding of mechanisms of self-renewal in the neonatal mammalian heart may lead to the development of novel cardiovascular regenerative medicines for pediatric heart diseases.
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Affiliation(s)
- Hidemasa Oh
- Department of Regenerative Medicine, Center for Innovative Clinical Medicine, Okayama University Hospital, Okayama, Japan.
| | - Hiroshi Ito
- Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
| | - Shunji Sano
- Department of Cardiovascular Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
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Abstract
Much has changed since our survey of the landscape for myocardial regeneration powered by adult stem cells 4 years ago.(1) The intervening years since that first review has witnessed an explosive expansion of studies that advance both understanding and implementation of adult stem cells in promoting myocardial repair. Painstaking research from innumerable laboratories throughout the world is prying open doors that may lead to restoration of myocardial structure and function in the wake of pathological injury. This global effort has produced deeper mechanistic comprehension coupled with an evolving appreciation for the complexity of myocardial regeneration in the adult context. Undaunted by both known and (as yet) unknown challenges, pursuit of myocardial regenerative medicine mediated by adult stem cell therapy has gathered momentum fueled by tantalizing clues and visionary goals. This concise review takes a somewhat different perspective than our initial treatise, taking stock of the business sector that has become an integral part of the field while concurrently updating state of affairs in cutting edge research. Looking retrospectively at advancement over the years as all reviews eventually must, the fundamental lesson to be learned is best explained by Jonatan Mårtensson: "Success will never be a big step in the future. Success is a small step taken just now."
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Affiliation(s)
- Kathleen M Broughton
- From the San Diego State University Heart Institute and the Integrated Regenerative Research Institute, San Diego, CA
| | - Mark A Sussman
- From the San Diego State University Heart Institute and the Integrated Regenerative Research Institute, San Diego, CA.
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43
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Stem cell therapy for heart failure: Ensuring regenerative proficiency. Trends Cardiovasc Med 2016; 26:395-404. [PMID: 27020904 DOI: 10.1016/j.tcm.2016.01.003] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2015] [Revised: 01/08/2016] [Accepted: 01/20/2016] [Indexed: 02/07/2023]
Abstract
Patient-derived stem cells enable promising regenerative strategies, but display heterogenous cardiac reparative proficiency, leading to unpredictable therapeutic outcomes impeding practice adoption. Means to establish and certify the regenerative potency of emerging biotherapies are thus warranted. In this era of clinomics, deconvolution of variant cytoreparative performance in clinical trials offers an unprecedented opportunity to map pathways that segregate regenerative from non-regenerative states informing the evolution of cardio-regenerative quality systems. A maiden example of this approach is cardiopoiesis-mediated lineage specification developed to ensure regenerative performance. Successfully tested in pre-clinical and early clinical studies, the safety and efficacy of the cardiopoietic stem cell phenotype is undergoing validation in pivotal trials for chronic ischemic cardiomyopathy offering the prospect of a next-generation regenerative solution for heart failure.
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44
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Ryu JK, Kim DH, Song KM, Ryu DS, Kim SN, Shin DH, Yi T, Suh JK, Song SU. Intracavernous delivery of clonal mesenchymal stem cells rescues erectile function in the streptozotocin-induced diabetic mouse. Andrology 2015; 4:172-84. [PMID: 26711324 DOI: 10.1111/andr.12138] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2015] [Revised: 09/02/2015] [Accepted: 10/26/2015] [Indexed: 12/24/2022]
Abstract
The major hurdle for the clinical application of stem cell therapy is the heterogeneous nature of the isolated cells, which may cause different treatment outcomes. The aim of this study was to examine the effectiveness of mouse clonal bone marrow-derived stem cells (BMSCs) obtained from a single colony by using subfractionation culturing method for erectile function in diabetic animals. Twelve-week-old C57BL/6J mice were divided into four groups: controls, diabetic mice, and diabetic mice treated with a single intracavernous injection of PBS (20 μL) or clonal BMSCs (3 × 10(5) cells/20 μL). Clonal BMSCs were isolated from 5-week-old C3H mice. Two weeks after treatment, erectile function was measured by electrical stimulation of the cavernous nerve. The penis was stained with antibodies to PECAM-1, smooth muscle α-actin, neuronal nitric oxide synthase (nNOS), neurofilament, and phosphorylated endothelial NOS (phospho-eNOS). We also performed Western blot for phospho-eNOS, and eNOS in the corpus cavernosum tissue. Local delivery of clonal BMSCs significantly restored cavernous endothelial and smooth muscle cell contents, and penile nNOS and neurofilament contents, and induced eNOS phosphorylation (Ser1177) in diabetic mice. Intracavernous injection of clonal BMSCs induced significant recovery of erectile function, which reached 80-90% of the control values. Clonal BMSCs successfully restored erectile function through dual angiogenic and neurotrophic effects in diabetic mice. The homogenous nature of clonal mesenchymal stem cells may allow their clinical applications and open a new avenue through which to treat diabetic erectile dysfunction.
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Affiliation(s)
- J-K Ryu
- National Research Center for Sexual Medicine and Department of Urology, Inha University School of Medicine, Incheon, Korea.,Inha Research Institute for Medical Sciences, Inha University School of Medicine, Incheon, Korea
| | - D-H Kim
- Translational Research Center, Inha University School of Medicine, Incheon, Korea
| | - K-M Song
- National Research Center for Sexual Medicine and Department of Urology, Inha University School of Medicine, Incheon, Korea
| | - D-S Ryu
- Department of Urology, Sungkyunkwan University School of Medicine, Samsung Changwon Hospital, Changwon, Korea
| | - S-N Kim
- Drug Development Program, Department of Medicine, Inha University School of Medicine, Incheon, Korea
| | - D-H Shin
- SCM Lifescience Co., Ltd., Incheon, Korea
| | - T Yi
- Translational Research Center, Inha University School of Medicine, Incheon, Korea
| | - J-K Suh
- National Research Center for Sexual Medicine and Department of Urology, Inha University School of Medicine, Incheon, Korea
| | - S U Song
- Translational Research Center, Inha University School of Medicine, Incheon, Korea
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Onoshima D, Yukawa H, Baba Y. Multifunctional quantum dots-based cancer diagnostics and stem cell therapeutics for regenerative medicine. Adv Drug Deliv Rev 2015; 95:2-14. [PMID: 26344675 DOI: 10.1016/j.addr.2015.08.004] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2015] [Revised: 07/31/2015] [Accepted: 08/31/2015] [Indexed: 12/19/2022]
Abstract
A field of recent diagnostics and therapeutics has been advanced with quantum dots (QDs). QDs have developed into new formats of biomolecular sensing to push the limits of detection in biology and medicine. QDs can be also utilized as bio-probes or labels for biological imaging of living cells and tissues. More recently, QDs has been demonstrated to construct a multifunctional nanoplatform, where the QDs serve not only as an imaging agent, but also a nanoscaffold for diagnostic and therapeutic modalities. This review highlights the promising applications of multi-functionalized QDs as advanced nanosensors for diagnosing cancer and as innovative fluorescence probes for in vitro or in vivo stem cell imaging in regenerative medicine.
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Yi T, Kim SN, Lee HJ, Kim J, Cho YK, Shin DH, Tak SJ, Moon SH, Kang JE, Ji IM, Lim HJ, Lee DS, Jeon MS, Song SU. Manufacture of Clinical-Grade Human Clonal Mesenchymal Stem Cell Products from Single Colony Forming Unit-Derived Colonies Based on the Subfractionation Culturing Method. Tissue Eng Part C Methods 2015; 21:1251-62. [PMID: 26421757 DOI: 10.1089/ten.tec.2015.0017] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Stem cell products derived from mesenchymal stem cells (MSCs) have been widely used in clinical trials, and a few products have been already commercialized. However, the therapeutic effects of clinical-grade MSCs are still controversial owing to mixed results from recent clinical trials. A potential solution to overcome this hurdle may be to use clonal stem cells as the starting cell material to increase the homogeneity of the final stem cell products. We have previously developed an alternative isolation and culture protocol for establishing a population of clonal MSCs (cMSCs) from single colony forming unit (CFU)-derived colonies. In this study, we established a good manufacturing practice (GMP)-compatible procedure for the clinical-grade production of human bone marrow-derived cMSCs based on the subfractionation culturing method. We optimized the culture procedures to expand and obtain a clonal population of final MSC products from single CFU-derived colonies in a GMP facility. The characterization results of the final cMSC products met our preset criteria. Animal toxicity tests were performed in a good laboratory practice facility, and showed no toxicity or tumor formation in vivo. These tests include single injection toxicity, multiple injection toxicity, biodistribution analysis, and tumorigenicity tests in vivo. No chromosomal abnormalities were detected by in situ karyotyping using oligo-fluorescence in situ hydridization (oligo-FISH), providing evidence of genetic stability of the clinical-grade cMSC products. The manufacture and quality control results indicated that our GMP methodology could produce sufficient clonal population of MSC products from a small amount of bone marrow aspirate to treat a number of patients.
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Affiliation(s)
- TacGhee Yi
- 1 Translational Research Center, Inha University School of Medicine , Incheon, Republic of Korea.,2 Inha Research Institute for Medical Science, Inha University School of Medicine , Incheon, Republic of Korea.,3 SCM Lifescience Co., Ltd. , Incheon, Republic of Korea
| | - Si-na Kim
- 4 Drug Development Program, Department of Biomedical Science, Inha University School of Medicine , Incheon, Republic of Korea
| | - Hyun-Joo Lee
- 4 Drug Development Program, Department of Biomedical Science, Inha University School of Medicine , Incheon, Republic of Korea
| | - Junghee Kim
- 4 Drug Development Program, Department of Biomedical Science, Inha University School of Medicine , Incheon, Republic of Korea
| | - Yun-Kyoung Cho
- 3 SCM Lifescience Co., Ltd. , Incheon, Republic of Korea
| | - Dong-Hee Shin
- 1 Translational Research Center, Inha University School of Medicine , Incheon, Republic of Korea.,2 Inha Research Institute for Medical Science, Inha University School of Medicine , Incheon, Republic of Korea
| | - Sun-Ji Tak
- 1 Translational Research Center, Inha University School of Medicine , Incheon, Republic of Korea
| | - Sun-Hwa Moon
- 3 SCM Lifescience Co., Ltd. , Incheon, Republic of Korea
| | - Ji-Eun Kang
- 3 SCM Lifescience Co., Ltd. , Incheon, Republic of Korea
| | - In-Mi Ji
- 3 SCM Lifescience Co., Ltd. , Incheon, Republic of Korea
| | - Huyn-Ja Lim
- 3 SCM Lifescience Co., Ltd. , Incheon, Republic of Korea
| | - Dong-Soon Lee
- 5 Department of Pathology, Seoul National University School of Medicine , Seoul, Republic of Korea
| | - Myung-Shin Jeon
- 1 Translational Research Center, Inha University School of Medicine , Incheon, Republic of Korea
| | - Sun U Song
- 1 Translational Research Center, Inha University School of Medicine , Incheon, Republic of Korea.,3 SCM Lifescience Co., Ltd. , Incheon, Republic of Korea
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Park JS, Yi TG, Park JM, Han YM, Kim JH, Shin DH, Tak SJ, Lee K, Lee YS, Jeon MS, Hahm KB, Song SU, Park SH. Therapeutic effects of mouse bone marrow-derived clonal mesenchymal stem cells in a mouse model of inflammatory bowel disease. J Clin Biochem Nutr 2015; 57:192-203. [PMID: 26566304 PMCID: PMC4639590 DOI: 10.3164/jcbn.15-56] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2015] [Accepted: 04/20/2015] [Indexed: 12/13/2022] Open
Abstract
Mouse bone marrow-derived clonal mesenchymal stem cells (mcMSCs), which were originated from a single cell by a subfractionation culturing method, are recognized as new paradigm for stem cell therapy featured with its homogenous cell population. Next to proven therapeutic effects against pancreatitis, in the current study we demonstrated that mcMSCs showed significant therapeutic effects in dextran sulfate sodium (DSS)-induced experimental colitis model supported with anti-inflammatory and restorative activities. mcMSCs significantly reduced the disease activity index (DAI) score, including weight loss, stool consistency, and intestinal bleeding and significantly increased survival rates. The pathological scores were also significantly improved with mcMSC. We have demonstrated that especial mucosal regeneration activity accompanied with significantly lowered level of apoptosis as beneficiary actions of mcMSCs in UC models. The levels of inflammatory cytokines including TNF-α, IFN-γ, IL-1β, IL-6, and IL-17 were all significantly concurrent with significantly repressed NF-κB activation compared to the control group and significantly decreased infiltrations of responsible macrophage and neutrophil. Conclusively, our findings provide the rationale that mcMSCs are applicable as a potential source of cell-based therapy in inflammatory bowel diseases, especially contributing either to prevent relapse or to accelerate healing as solution to unmet medical needs in IBD therapy.
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Affiliation(s)
- Jin Seok Park
- Department of Biological Sciences, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon 440-746, Korea
| | - Tac-Ghee Yi
- Translational Research Center and Inha Research Institute for Medical Sciences, Inha University School of Medicine, 100 Inharo, Nam-gu, Incheon 400-711, Korea ; SCM Lifescience Co., Ltd., 366 Saohae-daero, Jung-gu, Incheon 400-711, Korea
| | - Jong-Min Park
- Digestive Disease Center, CHA University Bundang Medical Center, 59 Yatap-ro, Bundang-gu, Seongnam 463-838, Korea
| | - Young Min Han
- Digestive Disease Center, CHA University Bundang Medical Center, 59 Yatap-ro, Bundang-gu, Seongnam 463-838, Korea
| | - Jun-Hyung Kim
- Department of Biological Sciences, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon 440-746, Korea
| | - Dong-Hee Shin
- Translational Research Center and Inha Research Institute for Medical Sciences, Inha University School of Medicine, 100 Inharo, Nam-gu, Incheon 400-711, Korea ; SCM Lifescience Co., Ltd., 366 Saohae-daero, Jung-gu, Incheon 400-711, Korea
| | - Seon Ji Tak
- Translational Research Center and Inha Research Institute for Medical Sciences, Inha University School of Medicine, 100 Inharo, Nam-gu, Incheon 400-711, Korea
| | - Kyuheon Lee
- Translational Research Center and Inha Research Institute for Medical Sciences, Inha University School of Medicine, 100 Inharo, Nam-gu, Incheon 400-711, Korea
| | - Youn Sook Lee
- Department of Biological Sciences, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon 440-746, Korea
| | - Myung-Shin Jeon
- Translational Research Center and Inha Research Institute for Medical Sciences, Inha University School of Medicine, 100 Inharo, Nam-gu, Incheon 400-711, Korea
| | - Ki-Baik Hahm
- Digestive Disease Center, CHA University Bundang Medical Center, 59 Yatap-ro, Bundang-gu, Seongnam 463-838, Korea
| | - Sun U Song
- Translational Research Center and Inha Research Institute for Medical Sciences, Inha University School of Medicine, 100 Inharo, Nam-gu, Incheon 400-711, Korea ; SCM Lifescience Co., Ltd., 366 Saohae-daero, Jung-gu, Incheon 400-711, Korea
| | - Seok Hee Park
- Department of Biological Sciences, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon 440-746, Korea
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Mansour S. Autologous bone marrow mononuclear stem cells for acute myocardial infarction: is it only about time? Eur Heart J 2015; 37:264-6. [DOI: 10.1093/eurheartj/ehv541] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
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Afzal MR, Samanta A, Shah ZI, Jeevanantham V, Abdel-Latif A, Zuba-Surma EK, Dawn B. Adult Bone Marrow Cell Therapy for Ischemic Heart Disease: Evidence and Insights From Randomized Controlled Trials. Circ Res 2015; 117:558-75. [PMID: 26160853 DOI: 10.1161/circresaha.114.304792] [Citation(s) in RCA: 165] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2014] [Accepted: 07/07/2015] [Indexed: 12/30/2022]
Abstract
RATIONALE Notwithstanding the uncertainties about the outcomes of bone marrow cell (BMC) therapy for heart repair, further insights are critically needed to improve this promising approach. OBJECTIVE To delineate the true effect of BMC therapy for cardiac repair and gain insights for future trials through systematic review and meta-analysis of data from eligible randomized controlled trials. METHODS AND RESULTS Database searches through August 2014 identified 48 eligible randomized controlled trials (enrolling 2602 patients). Weighted mean differences for changes in left ventricular (LV) ejection fraction, infarct size, LV end-systolic volume, and LV end-diastolic volume were analyzed with random-effects meta-analysis. Compared with standard therapy, BMC transplantation improved LV ejection fraction (2.92%; 95% confidence interval, 1.91-3.92; P<0.00001), reduced infarct size (-2.25%; 95% confidence interval, -3.55 to -0.95; P=0.0007) and LV end-systolic volume (-6.37 mL; 95% confidence interval, -8.95 to -3.80; P<0.00001), and tended to reduce LV end-diastolic volume (-2.26 mL; 95% confidence interval, -4.59 to 0.07; P=0.06). Similar effects were noted when data were analyzed after excluding studies with discrepancies in reporting of outcomes. The benefits also persisted when cardiac catheterization was performed in control patients as well. Although imaging modalities partly influenced the outcomes, LV ejection fraction improved in BMC-treated patients when assessed by magnetic resonance imaging. Early (<48 hours) BMC injection after myocardial Infarction was more effective in reducing infarct size, whereas BMC injection between 3 and 10 days proved superior toward improving systolic function. A minimum of 50 million BMCs seemed to be necessary, with limited additional benefits seen with increasing cell numbers. BMC therapy was safe and improved clinical outcomes, including all-cause mortality, recurrent myocardial Infarction, ventricular arrhythmia, and cerebrovascular accident during follow-up, albeit with differences between acute myocardial Infarction and chronic ischemic heart disease subgroups. CONCLUSIONS Transplantation of adult BMCs improves LV ejection fraction, reduces infarct size, and ameliorates remodeling in patients with ischemic heart disease. These effects are upheld in the analyses of studies using magnetic resonance imaging and also after excluding studies with discrepant reporting of outcomes. BMC transplantation may also reduce the incidence of death, recurrent myocardial Infarction, ventricular arrhythmia, and cerebrovascular accident during follow-up.
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Affiliation(s)
- Muhammad R Afzal
- From the Division of Cardiovascular Diseases, Cardiovascular Research Institute, and the Midwest Stem Cell Therapy Center, University of Kansas Medical Center, Kansas City (M.R.A., A.S., Z.I.S., B.D.); Heart and Vascular Specialists of Oklahoma, Oklahoma City (V.J.); Division of Cardiology, University of Kentucky, Lexington (A.A.-L.); and Department of Cell Biology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland (E.K.Z.-S)
| | - Anweshan Samanta
- From the Division of Cardiovascular Diseases, Cardiovascular Research Institute, and the Midwest Stem Cell Therapy Center, University of Kansas Medical Center, Kansas City (M.R.A., A.S., Z.I.S., B.D.); Heart and Vascular Specialists of Oklahoma, Oklahoma City (V.J.); Division of Cardiology, University of Kentucky, Lexington (A.A.-L.); and Department of Cell Biology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland (E.K.Z.-S)
| | - Zubair I Shah
- From the Division of Cardiovascular Diseases, Cardiovascular Research Institute, and the Midwest Stem Cell Therapy Center, University of Kansas Medical Center, Kansas City (M.R.A., A.S., Z.I.S., B.D.); Heart and Vascular Specialists of Oklahoma, Oklahoma City (V.J.); Division of Cardiology, University of Kentucky, Lexington (A.A.-L.); and Department of Cell Biology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland (E.K.Z.-S)
| | - Vinodh Jeevanantham
- From the Division of Cardiovascular Diseases, Cardiovascular Research Institute, and the Midwest Stem Cell Therapy Center, University of Kansas Medical Center, Kansas City (M.R.A., A.S., Z.I.S., B.D.); Heart and Vascular Specialists of Oklahoma, Oklahoma City (V.J.); Division of Cardiology, University of Kentucky, Lexington (A.A.-L.); and Department of Cell Biology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland (E.K.Z.-S)
| | - Ahmed Abdel-Latif
- From the Division of Cardiovascular Diseases, Cardiovascular Research Institute, and the Midwest Stem Cell Therapy Center, University of Kansas Medical Center, Kansas City (M.R.A., A.S., Z.I.S., B.D.); Heart and Vascular Specialists of Oklahoma, Oklahoma City (V.J.); Division of Cardiology, University of Kentucky, Lexington (A.A.-L.); and Department of Cell Biology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland (E.K.Z.-S)
| | - Ewa K Zuba-Surma
- From the Division of Cardiovascular Diseases, Cardiovascular Research Institute, and the Midwest Stem Cell Therapy Center, University of Kansas Medical Center, Kansas City (M.R.A., A.S., Z.I.S., B.D.); Heart and Vascular Specialists of Oklahoma, Oklahoma City (V.J.); Division of Cardiology, University of Kentucky, Lexington (A.A.-L.); and Department of Cell Biology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland (E.K.Z.-S)
| | - Buddhadeb Dawn
- From the Division of Cardiovascular Diseases, Cardiovascular Research Institute, and the Midwest Stem Cell Therapy Center, University of Kansas Medical Center, Kansas City (M.R.A., A.S., Z.I.S., B.D.); Heart and Vascular Specialists of Oklahoma, Oklahoma City (V.J.); Division of Cardiology, University of Kentucky, Lexington (A.A.-L.); and Department of Cell Biology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland (E.K.Z.-S).
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50
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Yu Y, Wise SG, Michael PL, Bax DV, Yuen GSC, Hiob MA, Yeo GC, Filipe EC, Dunn LL, Chan KH, Hajian H, Celermajer DS, Weiss AS, Ng MKC. Characterization of Endothelial Progenitor Cell Interactions with Human Tropoelastin. PLoS One 2015; 10:e0131101. [PMID: 26115013 PMCID: PMC4482626 DOI: 10.1371/journal.pone.0131101] [Citation(s) in RCA: 10] [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: 12/09/2013] [Accepted: 05/28/2015] [Indexed: 01/23/2023] Open
Abstract
The deployment of endovascular implants such as stents in the treatment of cardiovascular disease damages the vascular endothelium, increasing the risk of thrombosis and promoting neointimal hyperplasia. The rapid restoration of a functional endothelium is known to reduce these complications. Circulating endothelial progenitor cells (EPCs) are increasingly recognized as important contributors to device re-endothelialization. Extracellular matrix proteins prominent in the vessel wall may enhance EPC-directed re-endothelialization. We examined attachment, spreading and proliferation on recombinant human tropoelastin (rhTE) and investigated the mechanism and site of interaction. EPCs attached and spread on rhTE in a dose dependent manner, reaching a maximal level of 56±3% and 54±3%, respectively. EPC proliferation on rhTE was comparable to vitronectin, fibronectin and collagen. EDTA, but not heparan sulfate or lactose, reduced EPC attachment by 81±3%, while full attachment was recovered after add-back of manganese, inferring a classical integrin-mediated interaction. Integrin αVβ3 blocking antibodies decreased EPC adhesion and spreading on rhTE by 39±3% and 56±10% respectively, demonstrating a large contribution from this specific integrin. Attachment of EPCs on N-terminal rhTE constructs N25 and N18 accounted for most of this interaction, accompanied by comparable spreading. In contrast, attachment and spreading on N10 was negligible. αVβ3 blocking antibodies reduced EPC spreading on both N25 and N18 by 45±4% and 42±14%, respectively. In conclusion, rhTE supports EPC binding via an integrin mechanism involving αVβ3. N25 and N18, but not N10 constructs of rhTE contribute to EPC binding. The regulation of EPC activity by rhTE may have implications for modulation of the vascular biocompatibility of endovascular implants.
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Affiliation(s)
- Young Yu
- Department of Cardiology, Royal Prince Alfred Hospital, Sydney, NSW, 2050, Australia
- The Heart Research Institute, Sydney, NSW, 2042, Australia
- Sydney Medical School, University of Sydney, Sydney, NSW, 2006, Australia
| | - Steven G. Wise
- The Heart Research Institute, Sydney, NSW, 2042, Australia
- Sydney Medical School, University of Sydney, Sydney, NSW, 2006, Australia
- School of Molecular Bioscience, University of Sydney, Sydney, NSW, 2006, Australia
- * E-mail:
| | - Praveesuda L. Michael
- The Heart Research Institute, Sydney, NSW, 2042, Australia
- Sydney Medical School, University of Sydney, Sydney, NSW, 2006, Australia
| | - Daniel V. Bax
- School of Molecular Bioscience, University of Sydney, Sydney, NSW, 2006, Australia
| | - Gloria S. C. Yuen
- The Heart Research Institute, Sydney, NSW, 2042, Australia
- Sydney Medical School, University of Sydney, Sydney, NSW, 2006, Australia
| | - Matti A. Hiob
- The Heart Research Institute, Sydney, NSW, 2042, Australia
- Sydney Medical School, University of Sydney, Sydney, NSW, 2006, Australia
- School of Molecular Bioscience, University of Sydney, Sydney, NSW, 2006, Australia
| | - Giselle C. Yeo
- School of Molecular Bioscience, University of Sydney, Sydney, NSW, 2006, Australia
| | - Elysse C. Filipe
- The Heart Research Institute, Sydney, NSW, 2042, Australia
- Sydney Medical School, University of Sydney, Sydney, NSW, 2006, Australia
| | - Louise L. Dunn
- The Heart Research Institute, Sydney, NSW, 2042, Australia
- Sydney Medical School, University of Sydney, Sydney, NSW, 2006, Australia
| | - Kim H. Chan
- Department of Cardiology, Royal Prince Alfred Hospital, Sydney, NSW, 2050, Australia
- The Heart Research Institute, Sydney, NSW, 2042, Australia
- Sydney Medical School, University of Sydney, Sydney, NSW, 2006, Australia
| | - Hamid Hajian
- The Heart Research Institute, Sydney, NSW, 2042, Australia
- Sydney Medical School, University of Sydney, Sydney, NSW, 2006, Australia
| | - David S. Celermajer
- Department of Cardiology, Royal Prince Alfred Hospital, Sydney, NSW, 2050, Australia
- The Heart Research Institute, Sydney, NSW, 2042, Australia
- Sydney Medical School, University of Sydney, Sydney, NSW, 2006, Australia
| | - Anthony S. Weiss
- School of Molecular Bioscience, University of Sydney, Sydney, NSW, 2006, Australia
- Bosch Institute, University of Sydney, Sydney, NSW, 2006, Australia
- Charles Perkins Centre, University of Sydney, Sydney, NSW, 2006, Australia
| | - Martin K. C. Ng
- Department of Cardiology, Royal Prince Alfred Hospital, Sydney, NSW, 2050, Australia
- The Heart Research Institute, Sydney, NSW, 2042, Australia
- Sydney Medical School, University of Sydney, Sydney, NSW, 2006, Australia
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