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Haider KH. Priming mesenchymal stem cells to develop "super stem cells". World J Stem Cells 2024; 16:623-640. [PMID: 38948094 PMCID: PMC11212549 DOI: 10.4252/wjsc.v16.i6.623] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Revised: 05/04/2024] [Accepted: 05/20/2024] [Indexed: 06/25/2024] Open
Abstract
The stem cell pre-treatment approaches at cellular and sub-cellular levels encompass physical manipulation of stem cells to growth factor treatment, genetic manipulation, and chemical and pharmacological treatment, each strategy having advantages and limitations. Most of these pre-treatment protocols are non-combinative. This editorial is a continuum of Li et al's published article and Wan et al's editorial focusing on the significance of pre-treatment strategies to enhance their stemness, immunoregulatory, and immunosuppressive properties. They have elaborated on the intricacies of the combinative pre-treatment protocol using pro-inflammatory cytokines and hypoxia. Applying a well-defined multi-pronged combinatorial strategy of mesenchymal stem cells (MSCs), pre-treatment based on the mechanistic understanding is expected to develop "Super MSCs", which will create a transformative shift in MSC-based therapies in clinical settings, potentially revolutionizing the field. Once optimized, the standardized protocols may be used with slight modifications to pre-treat different stem cells to develop "super stem cells" with augmented stemness, functionality, and reparability for diverse clinical applications with better outcomes.
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Affiliation(s)
- Khawaja Husnain Haider
- Department of Basic Sciences, Sulaiman AlRajhi University, AlQaseem 52736, Saudi Arabia.
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2
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Peng C, Yan J, Jiang Y, Wu L, Li M, Fan X. Exploring Cutting-Edge Approaches to Potentiate Mesenchymal Stem Cell and Exosome Therapy for Myocardial Infarction. J Cardiovasc Transl Res 2024; 17:356-375. [PMID: 37819538 DOI: 10.1007/s12265-023-10438-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Accepted: 09/12/2023] [Indexed: 10/13/2023]
Abstract
Cardiovascular diseases (CVDs) continue to be a significant global health concern. Many studies have reported promising outcomes from using MSCs and their secreted exosomes in managing various cardiovascular-related diseases like myocardial infarction (MI). MSCs and exosomes have demonstrated considerable potential in promoting regeneration and neovascularization, as well as exerting beneficial effects against apoptosis, remodeling, and inflammation in cases of myocardial infarction. Nonetheless, ensuring the durability and effectiveness of MSCs and exosomes following in vivo transplantation remains a significant concern. Recently, novel methods have emerged to improve their effectiveness and robustness, such as employing preconditioning statuses, modifying MSC and their exosomes, targeted drug delivery with exosomes, biomaterials, and combination therapy. Herein, we summarize the novel approaches that intensify the therapeutic application of MSC and their derived exosomes in treating MI.
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Affiliation(s)
- Chendong Peng
- Department of Cardiology, the Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, China
| | - Jie Yan
- Department of Cardiology, the Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, China
| | - Yu'ang Jiang
- Department of Cardiology, the Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, China
| | - Lin Wu
- Key Laboratory of Medical Electrophysiology of Ministry of Education and Medical Electrophysiological, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease, Institute of Cardiovascular Research, Key Laboratory of Sichuan Province, Southwest Medical University, Luzhou, 646000, Sichuan, China
- Department of Cardiology, Peking University First Hospital, Beijing, 100000, China
| | - Miaoling Li
- Department of Cardiology, the Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, China.
- Key Laboratory of Medical Electrophysiology of Ministry of Education and Medical Electrophysiological, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease, Institute of Cardiovascular Research, Key Laboratory of Sichuan Province, Southwest Medical University, Luzhou, 646000, Sichuan, China.
| | - Xinrong Fan
- Department of Cardiology, the Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, China.
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3
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Gupta A. Cardiac 31P MR spectroscopy: development of the past five decades and future vision-will it be of diagnostic use in clinics? Heart Fail Rev 2023; 28:485-532. [PMID: 36427161 DOI: 10.1007/s10741-022-10287-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/16/2022] [Indexed: 11/27/2022]
Abstract
In the past five decades, the use of the magnetic resonance (MR) technique for cardiovascular diseases has engendered much attention and raised the opportunity that the technique could be useful for clinical applications. MR has two arrows in its quiver: One is magnetic resonance imaging (MRI), and the other is magnetic resonance spectroscopy (MRS). Non-invasively, highly advanced MRI provides unique and profound information about the anatomical changes of the heart. Excellently developed MRS provides irreplaceable and insightful evidence of the real-time biochemistry of cardiac metabolism of underpinning diseases. Compared to MRI, which has already been successfully applied in routine clinical practice, MRS still has a long way to travel to be incorporated into routine diagnostics. Considering the exceptional potential of 31P MRS to measure the real-time metabolic changes of energetic molecules qualitatively and quantitatively, how far its powerful technique should be waited before a successful transition from "bench-to-bedside" is enticing. The present review highlights the seminal studies on the chronological development of cardiac 31P MRS in the past five decades and the future vision and challenges to incorporating it for routine diagnostics of cardiovascular disease.
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Affiliation(s)
- Ashish Gupta
- Centre of Biomedical Research, SGPGIMS Campus, Lucknow, 226014, India.
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4
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Sun Y, Xu H, Tan B, Yi Q, Liu H, Chen T, Xiang H, Wang R, Xie Q, Tian J, Zhu J. Andrographolide protects bone marrow mesenchymal stem cells against glucose and serum deprivation under hypoxia via the NRF2 signaling pathway. Stem Cell Res Ther 2022; 13:326. [PMID: 35850702 PMCID: PMC9290240 DOI: 10.1186/s13287-022-03016-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2021] [Accepted: 11/24/2021] [Indexed: 12/15/2022] Open
Abstract
Background Bone marrow mesenchymal stem cell (BMSCs) therapy is an important cell transplantation strategy in the regenerative medicine field. However, a severely ischemic microenvironment, such as nutrient depletion and hypoxia, causes a lower survival rate of transplanted BMSCs, limiting the application of BMSCs. Therefore, improving BMSCs viability in adverse microenvironments is an important means to improve the effectiveness of BMSCs therapy. Objective To illustrate the protective effect of andrographolide (AG) against glucose and serum deprivation under hypoxia (1% O2) (GSDH)-induced cell injury in BMSCs and investigate the possible underlying mechanisms. Methods An in vitro primary rat BMSCs cell injury model was established by GSDH, and cellular viability, proliferation and apoptosis were observed after AG treatment under GSDH. Reactive oxygen species levels and oxidative stress-related genes and proteins were measured by flow cytometry, RT-qPCR and Western blotting. Mitochondrial morphology, function and number were further assessed by laser confocal microscopy and flow cytometry. Results AG protected BMSCs against GSDH-induced cell injury, as indicated by increases in cell viability and proliferation and mitochondrial number and decreases in apoptosis and oxidative stress. The metabolic status of BMSCs was changed from glycolysis to oxidative phosphorylation to increase the ATP supply. We further observed that the NRF2 pathway was activated by AG, and treatment of BMSCs with a specific NRF2 inhibitor (ML385) blocked the protective effect of AG. Conclusion Our results suggest that AG is a promising agent to improve the therapeutic effect of BMSCs. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-022-03016-6.
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Affiliation(s)
- Yanting Sun
- Department of Pediatric Research Institute, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, 400014, China
| | - Hao Xu
- Department of Pediatric Research Institute, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, 400014, China.,Department of Clinical Laboratory, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Bin Tan
- Department of Pediatric Research Institute, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, 400014, China
| | - Qin Yi
- Department of Pediatric Research Institute, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, 400014, China
| | - Huiwen Liu
- Department of Pediatric Research Institute, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, 400014, China
| | - Tangtian Chen
- Department of Pediatric Research Institute, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, 400014, China
| | - Han Xiang
- Department of Pediatric Research Institute, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, 400014, China
| | - Rui Wang
- Department of Pediatric Research Institute, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, 400014, China
| | - Qiumin Xie
- Department of Pediatric Research Institute, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, 400014, China
| | - Jie Tian
- Department of Pediatric Research Institute, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, 400014, China.,Department of Cardiovascular (Internal Medicine), Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Jing Zhu
- Department of Pediatric Research Institute, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, 400014, China.
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Signaling cascades in the failing heart and emerging therapeutic strategies. Signal Transduct Target Ther 2022; 7:134. [PMID: 35461308 PMCID: PMC9035186 DOI: 10.1038/s41392-022-00972-6] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Revised: 03/13/2022] [Accepted: 03/20/2022] [Indexed: 12/11/2022] Open
Abstract
Chronic heart failure is the end stage of cardiac diseases. With a high prevalence and a high mortality rate worldwide, chronic heart failure is one of the heaviest health-related burdens. In addition to the standard neurohormonal blockade therapy, several medications have been developed for chronic heart failure treatment, but the population-wide improvement in chronic heart failure prognosis over time has been modest, and novel therapies are still needed. Mechanistic discovery and technical innovation are powerful driving forces for therapeutic development. On the one hand, the past decades have witnessed great progress in understanding the mechanism of chronic heart failure. It is now known that chronic heart failure is not only a matter involving cardiomyocytes. Instead, chronic heart failure involves numerous signaling pathways in noncardiomyocytes, including fibroblasts, immune cells, vascular cells, and lymphatic endothelial cells, and crosstalk among these cells. The complex regulatory network includes protein-protein, protein-RNA, and RNA-RNA interactions. These achievements in mechanistic studies provide novel insights for future therapeutic targets. On the other hand, with the development of modern biological techniques, targeting a protein pharmacologically is no longer the sole option for treating chronic heart failure. Gene therapy can directly manipulate the expression level of genes; gene editing techniques provide hope for curing hereditary cardiomyopathy; cell therapy aims to replace dysfunctional cardiomyocytes; and xenotransplantation may solve the problem of donor heart shortages. In this paper, we reviewed these two aspects in the field of failing heart signaling cascades and emerging therapeutic strategies based on modern biological techniques.
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Scott SR, March KL, Wang IW, Singh K, Liu J, Turrentine M, Sen CK, Wang M. Bone marrow- or adipose-mesenchymal stromal cell secretome preserves myocardial transcriptome profile and ameliorates cardiac damage following ex vivo cold storage. J Mol Cell Cardiol 2022; 164:1-12. [PMID: 34774548 PMCID: PMC8860861 DOI: 10.1016/j.yjmcc.2021.11.002] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2021] [Revised: 10/24/2021] [Accepted: 11/03/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND Heart transplantation, a life-saving approach for patients with end-stage heart disease, is limited by shortage of donor organs. While prolonged storage provides more organs, it increases the extent of ischemia. Therefore, we seek to understand molecular mechanisms underlying pathophysiological changes of donor hearts during prolonged storage. Additionally, considering mesenchymal stromal cell (MSC)-derived paracrine protection, we aim to test if MSC secretome preserves myocardial transcriptome profile and whether MSC secretome from a certain source provides the optimal protection in donor hearts during cold storage. METHODS AND RESULTS Isolated mouse hearts were divided into: no cold storage (control), 6 h cold storage (6 h-I), 6 h-I + conditioned media from bone marrow MSCs (BM-MSC CM), and 6 h-I + adipose-MSC CM (Ad-MSC CM). Deep RNA sequencing analysis revealed that compared to control, 6 h-I led to 266 differentially expressed genes, many of which were implicated in modulating mitochondrial performance, oxidative stress response, myocardial function, and apoptosis. BM-MSC CM and Ad-MSC CM restored these gene expression towards control. They also improved 6 h-I-induced myocardial functional depression, reduced inflammatory cytokine production, decreased apoptosis, and reduced myocardial H2O2. However, neither MSC-exosomes nor exosome-depleted CM recapitulated MSC CM-ameliorated apoptosis and CM-improved mitochondrial preservation during cold ischemia. Knockdown of Per2 by specific siRNA abolished MSC CM-mediated these protective effects in cardiomyocytes following 6 h cold storage. CONCLUSIONS Our results demonstrated that using MSC secretome (BM-MSCs and Ad-MSCs) during prolonged cold storage confers preservation of the normal transcriptional "fingerprint", and reduces donor heart damage. MSC-released soluble factors and exosomes may synergistically act for donor heart protection.
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Affiliation(s)
- Susan R Scott
- Department of Surgery, IU School of Medicine, Indianapolis, IN, U.S.A
| | - Keith L March
- Division of Cardiovascular Medicine, Department of Medicine, IU School of Medicine, Indianapolis, IN, U.S.A,Division of Cardiovascular Medicine, Center for Regenerative Medicine, University of Florida, Gainesville, FL, U.S.A
| | - I-wen Wang
- Department of Surgery, IU School of Medicine, Indianapolis, IN, U.S.A,Methodist Hospital, IU Health, IU School of Medicine, Indianapolis, IN, U.S.A
| | - Kanhaiya Singh
- Department of Surgery, IU School of Medicine, Indianapolis, IN, U.S.A,Indiana Center for Regenerative Medicine and Engineering, Indiana University School of Medicine, Indianapolis, Indiana, U.S.A
| | - Jianyun Liu
- Department of Surgery, IU School of Medicine, Indianapolis, IN, U.S.A
| | - Mark Turrentine
- Department of Surgery, IU School of Medicine, Indianapolis, IN, U.S.A
| | - Chandan K Sen
- Department of Surgery, IU School of Medicine, Indianapolis, IN, U.S.A,Indiana Center for Regenerative Medicine and Engineering, Indiana University School of Medicine, Indianapolis, Indiana, U.S.A
| | - Meijing Wang
- Department of Surgery, IU School of Medicine, Indianapolis, IN, USA.
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7
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Bone Marrow Mesenchymal Stem Cells and Their Derived Extracellular Vesicles Attenuate Non-Alcoholic Steatohepatitis-Induced Cardiotoxicity via Modulating Cardiac Mechanisms. Life (Basel) 2022; 12:life12030355. [PMID: 35330106 PMCID: PMC8952775 DOI: 10.3390/life12030355] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2022] [Revised: 02/22/2022] [Accepted: 02/23/2022] [Indexed: 12/12/2022] Open
Abstract
Cardiovascular-disease (CVD)-related mortality has been fueled by the upsurge of non-alcoholic steatohepatitis (NASH). Mesenchymal stem cells (MSCs) were extensively studied for their reparative power in ameliorating different CVDs via direct and paracrine effects. Several reports pointed to the importance of bone marrow mesenchymal stem cells (BM-MSCs) as a reliable therapeutic approach for several CVDs. Nevertheless, their therapeutic potential has not yet been investigated in the cardiotoxic state that is induced by NASH. Thus, this study sought to investigate the molecular mechanisms associated with cardiotoxicity that accompany NASH. Besides, we aimed to comparatively study the therapeutic effects of bone-marrow mesenchymal-stem-cell-derived extracellular vesicles (BM-MSCs-EV) and BM-MSCs in a cardiotoxic model that is induced by NASH in rats. Rats were fed with high-fat diet (HFD) for 12 weeks. At the seventh week, BM-MSCs-EV were given a dose of 120 µg/kg i.v., twice a week for six weeks (12 doses per 6 weeks). Another group was treated with BM-MSCs at a dose of 1 × 106 cell i.v., per rat once every 2 weeks for 6 weeks (3 doses per 6 weeks). BM-MSCs-EV demonstrated superior cardioprotective effects through decreasing serum cardiotoxic markers, cardiac hypoxic state (HIF-1) and cardiac inflammation (NF-κB p65, TNF-α, IL-6). This was accompanied by increased vascular endothelial growth factor (VEGF) and improved cardiac histopathological alterations. Both BM-MSCs-EV and BM-MSCs restored the mitochondrial antioxidant state through the upregulation of UCP2 and MnSOD genes. Besides, mitochondrial Parkin-dependent and -independent mitophagies were regained through the upregulation of (Parkin, PINK1, ULK1, BNIP3L, FUNDC1) and (LC3B). These effects were mediated through the regulation of pAKT, PI3K, Hypoxia, VEGF and NF-κB signaling pathways by an array of secreted microRNAs (miRNAs). Our findings unravel the potential ameliorative effects of BM-MSCs-EV as a comparable new avenue for BM-MSCs for modulating cardiotoxicity that is induced by NASH.
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Pittenger MF, Eghtesad S, Sanchez PG, Liu X, Wu Z, Chen L, Griffith BP. MSC Pretreatment for Improved Transplantation Viability Results in Improved Ventricular Function in Infarcted Hearts. Int J Mol Sci 2022; 23:694. [PMID: 35054878 PMCID: PMC8775864 DOI: 10.3390/ijms23020694] [Citation(s) in RCA: 3] [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: 12/09/2021] [Revised: 01/04/2022] [Accepted: 01/05/2022] [Indexed: 12/22/2022] Open
Abstract
Many clinical studies utilizing MSCs (mesenchymal stem cells, mesenchymal stromal cells, or multipotential stromal cells) are underway in multiple clinical settings; however, the ideal approach to prepare these cells in vitro and to deliver them to injury sites in vivo with maximal effectiveness remains a challenge. Here, pretreating MSCs with agents that block the apoptotic pathways were compared with untreated MSCs. The treatment effects were evaluated in the myocardial infarct setting following direct injection, and physiological parameters were examined at 4 weeks post-infarct in a rat permanent ligation model. The prosurvival treated MSCs were detected in the hearts in greater abundance at 1 week and 4 weeks than the untreated MSCs. The untreated MSCs improved ejection fraction in infarcted hearts from 61% to 77% and the prosurvival treated MSCs further improved ejection fraction to 83% of normal. The untreated MSCs improved fractional shortening in the infarcted heart from 52% to 68%, and the prosurvival treated MSCs further improved fractional shortening to 77% of normal. Further improvements in survival of the MSC dose seems possible. Thus, pretreating MSCs for improved in vivo survival has implications for MSC-based cardiac therapies and in other indications where improved cell survival may improve effectiveness.
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Affiliation(s)
- Mark F. Pittenger
- Department of Surgery, School of Medicine, University of Maryland, Baltimore, MD 21201, USA; (S.E.); (P.G.S.); (X.L.); (Z.W.)
| | - Saman Eghtesad
- Department of Surgery, School of Medicine, University of Maryland, Baltimore, MD 21201, USA; (S.E.); (P.G.S.); (X.L.); (Z.W.)
- Department of Biochemistry, School of Medicine, University of Maryland, Baltimore, MD 21201, USA
| | - Pablo G. Sanchez
- Department of Surgery, School of Medicine, University of Maryland, Baltimore, MD 21201, USA; (S.E.); (P.G.S.); (X.L.); (Z.W.)
- Department of Cardiothoracic Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15260, USA
| | - Xiaoyan Liu
- Department of Surgery, School of Medicine, University of Maryland, Baltimore, MD 21201, USA; (S.E.); (P.G.S.); (X.L.); (Z.W.)
| | - Zhongjun Wu
- Department of Surgery, School of Medicine, University of Maryland, Baltimore, MD 21201, USA; (S.E.); (P.G.S.); (X.L.); (Z.W.)
| | - Ling Chen
- Departments of Physiology and Medicine, School of Medicine, University of Maryland, Baltimore, MD 21201, USA;
| | - Bartley P. Griffith
- Department of Surgery, School of Medicine, University of Maryland, Baltimore, MD 21201, USA; (S.E.); (P.G.S.); (X.L.); (Z.W.)
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Zhang J, Bolli R, Garry DJ, Marbán E, Menasché P, Zimmermann WH, Kamp TJ, Wu JC, Dzau VJ. Basic and Translational Research in Cardiac Repair and Regeneration: JACC State-of-the-Art Review. J Am Coll Cardiol 2021; 78:2092-2105. [PMID: 34794691 PMCID: PMC9116459 DOI: 10.1016/j.jacc.2021.09.019] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 09/13/2021] [Accepted: 09/13/2021] [Indexed: 12/25/2022]
Abstract
This paper aims to provide an important update on the recent preclinical and clinical trials using cell therapy strategies and engineered heart tissues for the treatment of postinfarction left ventricular remodeling and heart failure. In addition to the authors’ own works and opinions on the roadblocks of the field, they discuss novel approaches for cardiac remuscularization via the activation of proliferative mechanisms in resident cardiomyocytes or direct reprogramming of somatic cells into cardiomyocytes. This paper’s main mindset is to present current and future strategies in light of their implications for the design of future patient trials with the ultimate objective of facilitating the translation of discoveries in regenerative myocardial therapies to the clinic.
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Affiliation(s)
- Jianyi Zhang
- Department of Biomedical Engineering, School of Medicine, School of Engineering, The University of Alabama at Birmingham, Birmingham, Alabama, USA.
| | - Roberto Bolli
- Institute of Molecular Cardiology, University of Louisville, Louisville, Kentucky, USA
| | - Daniel J Garry
- Department of Medicine, Lillehei Heart Institute, University of Minnesota, Minneapolis, Minnesota, USA
| | - Eduardo Marbán
- Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles California, USA
| | - Philippe Menasché
- Department of Cardiovascular Surgery, Hôpital Européen Georges Pompidou, University of Paris, PARCC, INSERM, F-75015, Paris, France
| | - Wolfram-Hubertus Zimmermann
- Institute of Pharmacology and Toxicology, University Medical Center Göttingen, and DZHK (German Center for Cardiovascular Research), partner site Göttingen, Göttingen, Germany
| | - Timothy J Kamp
- Department of Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Joseph C Wu
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, USA
| | - Victor J Dzau
- Mandel Center for Hypertension Research, Duke Cardiovascular Center, Duke University School of Medicine, Durham, North Carolina, USA
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Báez-Díaz C, Blanco-Blázquez V, Sánchez-Margallo FM, López E, Martín H, Espona-Noguera A, Casado JG, Ciriza J, Pedraz JL, Crisóstomo V. Intrapericardial Delivery of APA-Microcapsules as Promising Stem Cell Therapy Carriers in an Experimental Acute Myocardial Infarction Model. Pharmaceutics 2021; 13:1824. [PMID: 34834235 PMCID: PMC8626005 DOI: 10.3390/pharmaceutics13111824] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Revised: 10/15/2021] [Accepted: 10/26/2021] [Indexed: 01/08/2023] Open
Abstract
The administration of cardiosphere-derived cells (CDCs) after acute myocardial infarction (AMI) is very promising. CDC encapsulation in alginate-poly-l-lysine-alginate (APA) could increase cell survival and adherence. The intrapericardial (IP) approach potentially achieves high concentrations of the therapeutic agent in the infarcted area. We aimed to evaluate IP therapy using a saline vehicle as a control (CON), a dose of 30 × 106 CDCs (CDCs) or APA microcapsules containing 30 × 106 CDCs (APA-CDCs) at 72 h in a porcine AMI model. Magnetic resonance imaging (MRI) was used to determine the left ventricular ejection fraction (LVEF), infarct size (IS), and indexed end diastolic and systolic volumes (EDVi; ESVi) pre- and 10 weeks post-injection. Programmed electrical stimulation (PES) was performed to test arrhythmia inducibility before euthanasia. Histopathological analysis was carried out afterwards. The IP infusion was successful in all animals. At 10 weeks, MRI revealed significantly higher LVEF in the APA-CDC group compared with CON. No significant differences were observed among groups in IS, EDVi, ESVi, PES and histopathological analyses. In conclusion, the IP injection of CDCs (microencapsulated or not) was feasible and safe 72 h post-AMI in the porcine model. Moreover, CDCs APA encapsulation could have a beneficial effect on cardiac function, reflected by a higher LVEF at 10 weeks.
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Affiliation(s)
- Claudia Báez-Díaz
- CIBERCV, Instituto de Salud Carlos III, 28029 Madrid, Spain; (V.B.-B.); (F.M.S.-M.); (V.C.)
- Fundación Centro de Cirugía de Mínima Invasión Jesús Usón, 10071 Cáceres, Spain; (E.L.); (H.M.)
| | - Virginia Blanco-Blázquez
- CIBERCV, Instituto de Salud Carlos III, 28029 Madrid, Spain; (V.B.-B.); (F.M.S.-M.); (V.C.)
- Fundación Centro de Cirugía de Mínima Invasión Jesús Usón, 10071 Cáceres, Spain; (E.L.); (H.M.)
| | - Francisco Miguel Sánchez-Margallo
- CIBERCV, Instituto de Salud Carlos III, 28029 Madrid, Spain; (V.B.-B.); (F.M.S.-M.); (V.C.)
- Fundación Centro de Cirugía de Mínima Invasión Jesús Usón, 10071 Cáceres, Spain; (E.L.); (H.M.)
| | - Esther López
- Fundación Centro de Cirugía de Mínima Invasión Jesús Usón, 10071 Cáceres, Spain; (E.L.); (H.M.)
| | - Helena Martín
- Fundación Centro de Cirugía de Mínima Invasión Jesús Usón, 10071 Cáceres, Spain; (E.L.); (H.M.)
| | - Albert Espona-Noguera
- Centro de Investigaciones y Estudios Avanzados Lucio Lascaray (CIEA), Laboratorio de Desarrollo y Evaluación de Medicamentos, 01006 Vitoria Gasteiz, Spain; (A.E.-N.); (J.L.P.)
- CIBER bbn, Instituto de Salud Carlos III, 28029 Madrid, Spain;
| | - Javier G. Casado
- Immunology Unit-Institute of Molecular Pathology Biomarkers, Veterinary Faculty, University of Extremadura, 10003 Cáceres, Spain;
| | - Jesús Ciriza
- CIBER bbn, Instituto de Salud Carlos III, 28029 Madrid, Spain;
- Tissue Microenvironment (TME) Lab, Aragón Institute of Engineering Research (I3A), University of Zaragoza, 50018 Zaragoza, Spain
| | - José Luis Pedraz
- Centro de Investigaciones y Estudios Avanzados Lucio Lascaray (CIEA), Laboratorio de Desarrollo y Evaluación de Medicamentos, 01006 Vitoria Gasteiz, Spain; (A.E.-N.); (J.L.P.)
- CIBER bbn, Instituto de Salud Carlos III, 28029 Madrid, Spain;
| | - Verónica Crisóstomo
- CIBERCV, Instituto de Salud Carlos III, 28029 Madrid, Spain; (V.B.-B.); (F.M.S.-M.); (V.C.)
- Fundación Centro de Cirugía de Mínima Invasión Jesús Usón, 10071 Cáceres, Spain; (E.L.); (H.M.)
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11
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Damasceno PKF, de Santana TA, Santos GC, Orge ID, Silva DN, Albuquerque JF, Golinelli G, Grisendi G, Pinelli M, Ribeiro Dos Santos R, Dominici M, Soares MBP. Genetic Engineering as a Strategy to Improve the Therapeutic Efficacy of Mesenchymal Stem/Stromal Cells in Regenerative Medicine. Front Cell Dev Biol 2020; 8:737. [PMID: 32974331 PMCID: PMC7471932 DOI: 10.3389/fcell.2020.00737] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Accepted: 07/16/2020] [Indexed: 12/14/2022] Open
Abstract
Mesenchymal stem/stromal cells (MSCs) have been widely studied in the field of regenerative medicine for applications in the treatment of several disease settings. The therapeutic potential of MSCs has been evaluated in studies in vitro and in vivo, especially based on their anti-inflammatory and pro-regenerative action, through the secretion of soluble mediators. In many cases, however, insufficient engraftment and limited beneficial effects of MSCs indicate the need of approaches to enhance their survival, migration and therapeutic potential. Genetic engineering emerges as a means to induce the expression of different proteins and soluble factors with a wide range of applications, such as growth factors, cytokines, chemokines, transcription factors, enzymes and microRNAs. Distinct strategies have been applied to induce genetic modifications with the goal to enhance the potential of MCSs. This review aims to contribute to the update of the different genetically engineered tools employed for MSCs modification, as well as the factors investigated in different fields in which genetically engineered MSCs have been tested.
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Affiliation(s)
- Patricia Kauanna Fonseca Damasceno
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Salvador, Brazil.,Health Institute of Technology, SENAI CIMATEC, Salvador, Brazil
| | | | | | - Iasmim Diniz Orge
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Salvador, Brazil.,Health Institute of Technology, SENAI CIMATEC, Salvador, Brazil
| | - Daniela Nascimento Silva
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Salvador, Brazil.,Health Institute of Technology, SENAI CIMATEC, Salvador, Brazil
| | | | - Giulia Golinelli
- Division of Oncology, Laboratory of Cellular Therapy, University of Modena and Reggio Emilia, Modena, Italy
| | - Giulia Grisendi
- Division of Oncology, Laboratory of Cellular Therapy, University of Modena and Reggio Emilia, Modena, Italy
| | - Massimo Pinelli
- Division of Plastic Surgery, Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, Modena, Italy
| | - Ricardo Ribeiro Dos Santos
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Salvador, Brazil.,Health Institute of Technology, SENAI CIMATEC, Salvador, Brazil.,National Institute of Science and Technology for Regenerative Medicine (INCT-REGENERA), Rio de Janeiro, Brazil
| | - Massimo Dominici
- Division of Oncology, Laboratory of Cellular Therapy, University of Modena and Reggio Emilia, Modena, Italy
| | - Milena Botelho Pereira Soares
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Salvador, Brazil.,Health Institute of Technology, SENAI CIMATEC, Salvador, Brazil.,National Institute of Science and Technology for Regenerative Medicine (INCT-REGENERA), Rio de Janeiro, Brazil
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12
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Paracrine Mechanisms of Mesenchymal Stromal Cells in Angiogenesis. Stem Cells Int 2020; 2020:4356359. [PMID: 32215017 PMCID: PMC7085399 DOI: 10.1155/2020/4356359] [Citation(s) in RCA: 157] [Impact Index Per Article: 31.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2019] [Accepted: 02/05/2020] [Indexed: 12/11/2022] Open
Abstract
The role of the mesenchymal stromal cell- (MSC-) derived secretome is becoming increasingly intriguing from a clinical perspective due to its ability to stimulate endogenous tissue repair processes as well as its effective regulation of the immune system, mimicking the therapeutic effects produced by the MSCs. The secretome is a composite product secreted by MSC in vitro (in conditioned medium) and in vivo (in the extracellular milieu), consisting of a protein soluble fraction (mostly growth factors and cytokines) and a vesicular component, extracellular vesicles (EVs), which transfer proteins, lipids, and genetic material. MSC-derived secretome differs based on the tissue from which the MSCs are isolated and under specific conditions (e.g., preconditioning or priming) suggesting that clinical applications should be tailored by choosing the tissue of origin and a priming regimen to specifically correct a given pathology. MSC-derived secretome mediates beneficial angiogenic effects in a variety of tissue injury-related diseases. This supports the current effort to develop cell-free therapeutic products that bring both clinical benefits (reduced immunogenicity, persistence in vivo, and no genotoxicity associated with long-term cell cultures) and manufacturing advantages (reduced costs, availability of large quantities of off-the-shelf products, and lower regulatory burden). In the present review, we aim to give a comprehensive picture of the numerous components of the secretome produced by MSCs derived from the most common tissue sources for clinical use (e.g., AT, BM, and CB). We focus on the factors involved in the complex regulation of angiogenic processes.
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13
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Lin M, Liu X, Zheng H, Huang X, Wu Y, Huang A, Zhu H, Hu Y, Mai W, Huang Y. IGF-1 enhances BMSC viability, migration, and anti-apoptosis in myocardial infarction via secreted frizzled-related protein 2 pathway. Stem Cell Res Ther 2020; 11:22. [PMID: 31918758 PMCID: PMC6953226 DOI: 10.1186/s13287-019-1544-y] [Citation(s) in RCA: 68] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2019] [Revised: 12/16/2019] [Accepted: 12/29/2019] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Bone marrow mesenchymal stem cell (BMSC) transplantation represents a promising therapeutic strategy for ischemic heart disease. However, its effects are hampered by the poor viability of transplanted cells and the hostile microenvironment of the ischemic region. Insulin-like growth factor-1 (IGF-1) is an important paracrine growth factor of BMSC and plays an important role in the properties of BMSC. Here, we investigated whether overexpressing IGF-1 could enhance the BMSC viability, migration, anti-apoptosis, and protective effects of cardiomyocytes, and explore the underlying mechanisms' focus on the role of the AKT/secreted frizzled-related protein 2 (SFRP2)/β-catenin pathway. METHODS We constructed BMSCs overexpressing insulin-like growth factor-1 (BMSCs-IGF-1) or empty vector (BMSCs-NC) using lentivirus, and evaluated cell survival, proliferation, and migration under normoxic and hypoxic conditions. Co-culture of rat cardiomyoblasts with BMSCs was performed to explore the paracrine effect of BMSCs-IGF-1 for rescuing cardiomyoblasts under hypoxia. Transplantation of BMSCs in acute myocardial infarction rats was used to explore the effect of BMSCs-IGF-1 therapy. RESULTS BMSCs-IGF-1 exhibited a higher cell proliferation rate, migration capacity, and stemness, and were more resistant to apoptosis under hypoxia. Overexpression of IGF-1 upregulated the expression of total and nuclear β-catenin via the AKT-secreted frizzled-related protein 2 (SFRP2) pathway, which enhanced cell survival. Inhibition of AKT or SFRP2 knockdown by siRNA significantly antagonized the effect of IGF-1 and decreased the expression of β-catenin. The expression of β-catenin target genes, including cyclin D1 and c-Myc, were accordingly decreased. Moreover, BMSCs-IGF-1 could rescue cardiomyoblasts from hypoxia-induced apoptosis and preserve cell viability under hypoxia. Transplantation of BMSCs-IGF-1 into myocardial infarction rats greatly reduced infarct volume than BMSCs-NC, with significantly greater expression of SFRP2 and β-catenin. CONCLUSIONS These results suggest that in BMSCs overexpressing IGF-1, SFRP2 is an important mediator for the enhancement of stem cell viability via activating, rather than antagonizing, the Wnt/β-catenin pathway.
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Affiliation(s)
- Mingzhuo Lin
- Department of Cardiology, Shunde Hospital, Southern Medical University (the first people's hospital of Shunde), Jiazhi Road, Lunjiao Town, Shunde District, Foshan, 528300, People's Republic of China
| | - Xinyue Liu
- Department of Cardiology, Shunde Hospital, Southern Medical University (the first people's hospital of Shunde), Jiazhi Road, Lunjiao Town, Shunde District, Foshan, 528300, People's Republic of China
| | - Haoxiao Zheng
- Department of Cardiology, Shunde Hospital, Southern Medical University (the first people's hospital of Shunde), Jiazhi Road, Lunjiao Town, Shunde District, Foshan, 528300, People's Republic of China
| | - Xiaohui Huang
- Department of Cardiology, Shunde Hospital, Southern Medical University (the first people's hospital of Shunde), Jiazhi Road, Lunjiao Town, Shunde District, Foshan, 528300, People's Republic of China
| | - Yu Wu
- Department of Cardiology, Shunde Hospital, Southern Medical University (the first people's hospital of Shunde), Jiazhi Road, Lunjiao Town, Shunde District, Foshan, 528300, People's Republic of China
| | - Anqing Huang
- Department of Cardiology, Shunde Hospital, Southern Medical University (the first people's hospital of Shunde), Jiazhi Road, Lunjiao Town, Shunde District, Foshan, 528300, People's Republic of China
| | - Hailan Zhu
- Department of Cardiology, Shunde Hospital, Southern Medical University (the first people's hospital of Shunde), Jiazhi Road, Lunjiao Town, Shunde District, Foshan, 528300, People's Republic of China
| | - Yunzhao Hu
- Department of Cardiology, Shunde Hospital, Southern Medical University (the first people's hospital of Shunde), Jiazhi Road, Lunjiao Town, Shunde District, Foshan, 528300, People's Republic of China
| | - Weiyi Mai
- Department of Cardiology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, People's Republic of China
| | - Yuli Huang
- Department of Cardiology, Shunde Hospital, Southern Medical University (the first people's hospital of Shunde), Jiazhi Road, Lunjiao Town, Shunde District, Foshan, 528300, People's Republic of China.
- The George Institute for Global Health, Sydney, Australia.
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14
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Jahanbani Y, Davaran S, Ghahremani-Nasab M, Aghebati-Maleki L, Yousefi M. Scaffold-based tissue engineering approaches in treating infertility. Life Sci 2019; 240:117066. [PMID: 31738881 DOI: 10.1016/j.lfs.2019.117066] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Revised: 11/03/2019] [Accepted: 11/12/2019] [Indexed: 01/21/2023]
Abstract
Tissue engineering and the use of scaffolds have shown high therapeutic potentialities about male and female infertility. Nowadays, many couples are suffering from infertility problems. There are different causes for infertility including chemotherapy (for male and female), uterine injuries, and intrauterine adhesions. Extra-cellular matrix in tissue engineering provides a supportive medium for blood or lymphatic vessels making it a suitable substrate for cell implantation and growth. Dominant successes in this branch have been in use of patient-derived primary cells, these cells loaded in scaffolds and used to generate tissue for re-implantation. However, this method has limitations, because of the invasive nature of cell collection, also the cells patient-derived may be not healthy and become the source of disease. Therefore, use of stem cells, including embryonic stem (ES) cells, bone marrow mesenchymal stem cells (BM-MSCs) and umbilical cord-derived mesenchymal stem cells (UC-MSCs) have been considered. Cell/scaffold systems have a substantial role in fertility organs or agents repair or regeneration. This review summarizes the novel scaffold-based tissue engineering approaches to treat infertility.
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Affiliation(s)
- Yalda Jahanbani
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Soudabe Davaran
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | | | - Mehdi Yousefi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Endocrine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
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15
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Proteomic analysis of human mesenchymal stromal cell secretomes: a systematic comparison of the angiogenic potential. NPJ Regen Med 2019; 4:8. [PMID: 31016031 PMCID: PMC6467904 DOI: 10.1038/s41536-019-0070-y] [Citation(s) in RCA: 133] [Impact Index Per Article: 22.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Accepted: 03/15/2019] [Indexed: 12/23/2022] Open
Abstract
Human mesenchymal stromal cell (hMSC) secretomes have shown to influence the microenvironment upon injury, promoting cytoprotection, angiogenesis, and tissue repair. The angiogenic potential is of particular interest for the treatment of ischemic diseases. Interestingly, hMSC secretomes isolated from different tissue sources have shown dissimilarities with respect to their angiogenic profile. This study compares angiogenesis of hMSC secretomes from adipose tissue (hADSCs), bone marrow (hBMSCs), and umbilical cord Wharton’s jelly (hWJSCs). hMSC secretomes were obtained under xenofree conditions and analyzed by liquid chromatography tandem mass spectrometry (LC/MS-MS). Biological processes related to angiogenesis were found to be enriched in the proteomic profile of hMSC secretomes. hWJSC secretomes revealed a more complete angiogenic network with higher concentrations of angiogenesis related proteins, followed by hBMSC secretomes. hADSC secretomes lacked central angiogenic proteins and expressed most detected proteins to a significantly lower level. In vivo all secretomes induced vascularization of subcutaneously implanted Matrigel plugs in mice. Differences in secretome composition were functionally analyzed with monocyte and endothelial cell (EC) in vitro co-culture experiments using vi-SNE based multidimensional flow cytometry data analysis. Functional responses between hBMSC and hWJSC secretomes were comparable, with significantly higher migration of CD14++ CD16− monocytes and enhanced macrophage differentiation compared with hADSC secretomes. Both secretomes also induced a more profound pro-angiogenic phenotype of ECs. These results suggest hWJSCs secretome as the most potent hMSC source for inflammation-mediated angiogenesis induction, while the potency of hADSC secretomes was lowest. This systematic analysis may have implication on the selection of hMSCs for future clinical studies.
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16
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Guan Y, Gao X, Tang Q, Huang L, Gao S, Yu S, Huang J, Li J, Zhou D, Zhang Y, Shi D, Liang D, Liu Y, Li L, Cui Y, Xu L, Chen Y. Nucleoporin 107 facilitates the nuclear export of Scn5a mRNA to regulate cardiac bioelectricity. J Cell Mol Med 2019; 23:1448-1457. [PMID: 30506890 PMCID: PMC6349201 DOI: 10.1111/jcmm.14051] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Revised: 10/13/2018] [Accepted: 11/05/2018] [Indexed: 01/02/2023] Open
Abstract
Nucleoporins (Nups) are known to be functional in nucleo-cytoplasmic transport, but the roles of nucleoporins in nonproliferating cells, such as cardiac myocytes, are still poorly understood. In this study, we report that Nup107 regulates cardiac bioelectricity by controlling the nucleo-cytoplasmic trafficking of Scn5a mRNA. Overexpression of Nup107 induced the protein expression of Scn5a rather than that of other ion channels, with no effects of their mRNA levels. The analysis for the protein production demonstrated Nup107-facilitated transport of Scn5a mRNA. Using RIP-PCR and luciferase assay, we found that the 5'-UTR of Scn5a mRNA was not involved in the interaction, whereas the spatial interaction between Nup107 protein and Scn5a mRNA was formed when Scn5a mRNA passing through the nuclear pore. Functionally, Nup107 overexpression in neonatal rat ventricle myocytes significantly increased the currents of Scn5a-encoded INa channel. Moreover, the close correlation between Nup107 and Nav1.5 protein expression was observed in cardiomycytes and heart tissues subjected to hypoxia and ischaemic insults, suggesting a fast regulation of Nup107 on Nav1.5 channel in cardiac myocytes in a posttranscriptional manner. These findings may provide insights into the emergent control of cardiac electrophysiology through Nup-mediated modulation of ion channels.
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17
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Haneef K, Ali A, Khan I, Naeem N, Jamall S, Salim A. Role of interleukin-7 in fusion of rat bone marrow mesenchymal stem cells with cardiomyocytes in vitro and improvement of cardiac function in vivo. Cardiovasc Ther 2018; 36:e12479. [PMID: 30451388 DOI: 10.1111/1755-5922.12479] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2018] [Revised: 11/09/2018] [Accepted: 11/15/2018] [Indexed: 01/27/2023] Open
Abstract
AIMS Mesenchymal stem cells (MSCs) hold significant promise as potential therapeutic candidates following cardiac injury. However, to ensure survival of transplanted cells in ischemic environment, it is beneficial to precondition them with growth factors that play important role in cell survival and proliferation. Aim of this study is to use interleukin-7 (IL-7), a cell survival growth factor, to enhance the potential of rat bone marrow MSCs in terms of cell fusion in vitro and cardiac function in vivo. METHODS Mesenchymal stem cells were transfected with IL-7 gene through retroviral vector. Normal and transfected MSCs were co-cultured with neonatal cardiomyocytes (CMs) and cell fusion was analyzed by flow cytometry and fluorescence microscopy. These MSCs were also transplanted in rat model of myocardial infarction (MI) and changes at tissue level and cardiac function were assessed by histological analysis and echocardiography, respectively. RESULTS Co-culture of IL-7 transfected MSCs and CMs showed significantly higher (P < 0.01) number of fused cells as compared to normal MSCs. Histological analysis of hearts transplanted with IL-7 transfected MSCs showed significant reduction (P < 0.001) in infarct size and better preservation (P < 0.001) of left ventricular wall thickness as compared to normal MSCs. Presence of cardiac-specific proteins, α-actinin, and troponin-T showed that the transplanted MSCs were differentiated into cardiomyocytes. Echocardiographic recordings of the experimental group transplanted with transfected MSCs showed significant increase in the ejection fraction and fractional shortening (P < 0.01), and decrease in diastolic and systolic left ventricular internal diameters (P < 0.001) and end systolic and diastolic volumes (P < 0.01 and P < 0.001, respectively). CONCLUSION Interleukin-7 is able to enhance the fusogenic properties of MSCs and improve cardiac function. This improvement may be attributed to the supportive action of IL-7 on cell proliferation and cell survival contributing to the regeneration of damaged myocardium.
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Affiliation(s)
- Kanwal Haneef
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan
| | - Anwar Ali
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan
| | - Irfan Khan
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan
| | - Nadia Naeem
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan
| | - Siddiqua Jamall
- Department of Biochemistry, University of Karachi, Karachi, Pakistan
| | - Asmat Salim
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan
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18
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Enhancement of the efficacy of mesenchymal stem cells in the treatment of ischemic diseases. Biomed Pharmacother 2018; 109:2022-2034. [PMID: 30551458 DOI: 10.1016/j.biopha.2018.11.068] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2018] [Revised: 11/17/2018] [Accepted: 11/19/2018] [Indexed: 02/05/2023] Open
Abstract
Ischemic diseases refer to a wide range of diseases caused by reduced blood flow and a subsequently deficient oxygen and nutrient supply. The pathogenesis of ischemia is multifaceted and primarily involves inflammation, oxidative stress and an apoptotic response. Over the last decade, mesenchymal stem cells (MSCs) have been widely studied as potential cell therapy agents for ischemic diseases due to their multiple favourable functions. However, the low homing and survival rates of transplanted cells have been concerns limiting for their clinical application. Recently, increasing studies have attempted to enhance the efficacy of MSCs by various strategies including genetic modification, pretreatment, combined application and biomaterial application. The purpose of this review is to summarize these creative strategies and the progress in basic and preclinical studies.
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19
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Brychtova M, Thiele JA, Lysak D, Holubova M, Kralickova M, Vistejnova L. Mesenchymal stem cells as the near future of cardiology medicine - truth or wish? Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2018; 163:8-18. [PMID: 30439932 DOI: 10.5507/bp.2018.071] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2018] [Accepted: 10/28/2018] [Indexed: 12/31/2022] Open
Abstract
Cardiac damage is one of major cause of worldwide morbidity and mortality. Despite the development in pharmacotherapy, cardiosurgery and interventional cardiology, many patients remain at increased risk of developing adverse cardiac remodeling. An alternative treatment approach is the application of stem cells. Mesenchymal stem cells are among the most promising cell types usable for cardiac regeneration. Their homing to the damaged area, differentiation into cardiomyocytes, paracrine and/or immunomodulatory effect on cardiac tissue was investigated extensively. Despite promising preclinical reports, clinical trials on human patients are not convincing. Meta-analyses of these trials open many questions and show that routine clinical application of mesenchymal stem cells as a cardiac treatment may be not as helpful as expected. This review summarizes contemporary knowledge about mesenchymal stem cells role in cardiac tissue repair and discusses the problems and perspectives of this experimental therapeutical approach.
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Affiliation(s)
- Michaela Brychtova
- Biomedical Center, Faculty of Medicine in Pilsen, Charles University in Prague, Alej Svobody 76, 323 00 Pilsen, Czech Republic
| | - Jana-Aletta Thiele
- Biomedical Center, Faculty of Medicine in Pilsen, Charles University in Prague, Alej Svobody 76, 323 00 Pilsen, Czech Republic
| | - Daniel Lysak
- Biomedical Center, Faculty of Medicine in Pilsen, Charles University in Prague, Alej Svobody 76, 323 00 Pilsen, Czech Republic
| | - Monika Holubova
- Biomedical Center, Faculty of Medicine in Pilsen, Charles University in Prague, Alej Svobody 76, 323 00 Pilsen, Czech Republic
| | - Milena Kralickova
- Biomedical Center, Faculty of Medicine in Pilsen, Charles University in Prague, Alej Svobody 76, 323 00 Pilsen, Czech Republic
| | - Lucie Vistejnova
- Biomedical Center, Faculty of Medicine in Pilsen, Charles University in Prague, Alej Svobody 76, 323 00 Pilsen, Czech Republic
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20
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Ishii M, Takahashi M, Murakami J, Yanagisawa T, Nishimura M. Vascular endothelial growth factor-C promotes human mesenchymal stem cell migration via an ERK-and FAK-dependent mechanism. Mol Cell Biochem 2018; 455:185-193. [PMID: 30443854 DOI: 10.1007/s11010-018-3481-y] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2018] [Accepted: 11/10/2018] [Indexed: 01/09/2023]
Abstract
Vascular endothelial cell growth factor-C (VEGF-C) is a member of the VEGF family and plays a role in various biological activities. VEGF-C enhances proliferation and migration of lymphatic endothelial cells and vascular endothelial cells through VEGF receptor 2 (VEGFR2) and/or receptor 3 (VEGFR3), and thereby induces lymphangiogenesis or angiogenesis. However, it remains unclear whether VEGF-C promotes the migration of mesenchymal stem cells (MSCs). Here, we investigated the effects of VEGF-C on the migration of MSCs and evaluated the underlying molecular mechanisms. VEGF-C treatment significantly induced the migration of MSCs, which is accompanied by the promotion of actin cytoskeletal reorganization and focal adhesion assembly. VEGF-C treatment enhanced the phosphorylation of VEGFR2 and VEGFR3 proteins in MSCs, and pretreatment with VEGFR2 and VEGFR3 kinase inhibitors effectively suppressed the VEGF-C-induced MSC migration. In addition, VEGF-C treatment promoted phosphorylation of ERK and FAK proteins in MSCs, and inhibition of VEGFR2 and VEGFR3 signaling pathways abolished the VEGF-C-induced activation of ERK and FAK proteins. Furthermore, treatment with ERK and FAK inhibitors suppressed VEGF-C-induced actin cytoskeletal reorganization and focal adhesion assembly, and then significantly inhibited MSCs migration. These results suggest that VEGF-C-induced MSC migration is mediated via VEGFR2 and VEGFR3, and follows the activation of the ERK and FAK signaling pathway. Thus, VEGF-C may be valuable in tissue regeneration and repair in MSC-based therapy.
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Affiliation(s)
- Masakazu Ishii
- Department of Oral and Maxillofacial Prosthodontics, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan.
| | - Manami Takahashi
- Department of Oral and Maxillofacial Prosthodontics, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan
| | - Juri Murakami
- Department of Oral and Maxillofacial Prosthodontics, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan.,Department of Oral and Maxillofacial Surgery, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, 890-8544, Japan
| | - Takahiro Yanagisawa
- Department of Oral and Maxillofacial Prosthodontics, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan
| | - Masahiro Nishimura
- Department of Oral and Maxillofacial Prosthodontics, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan
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21
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Marofi F, Vahedi G, hasanzadeh A, Salarinasab S, Arzhanga P, Khademi B, Farshdousti Hagh M. Mesenchymal stem cells as the game‐changing tools in the treatment of various organs disorders: Mirage or reality? J Cell Physiol 2018; 234:1268-1288. [DOI: 10.1002/jcp.27152] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2018] [Accepted: 07/05/2018] [Indexed: 12/11/2022]
Affiliation(s)
- Faroogh Marofi
- Department of Hematology Faculty of Medicine, Tabriz University of Medical Sciences Tabriz Iran
| | - Ghasem Vahedi
- Faculty of Veterinary Medicine, University of Tehran Tehran Iran
| | - Ali hasanzadeh
- Department of Hematology Faculty of Medicine, Tabriz University of Medical Sciences Tabriz Iran
| | - Sadegh Salarinasab
- Department of Biochemistry and Clinical Laboratories Faculty of Medicine, Tabriz University of Medical Science Tabriz Iran
| | - Pishva Arzhanga
- Department of Biochemistry and Diet Therapy Faculty of Nutrition and Food Sciences, Tabriz University of Medical Sciences Tabriz Iran
| | - Bahareh Khademi
- Department of Medical Genetic Faculty of Medicine, Tabriz University of Medical Sciences Tabriz Iran
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22
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Jahandideh S, Khatami S, Eslami Far A, Kadivar M. Anti-inflammatory effects of human embryonic stem cell-derived mesenchymal stem cells secretome preconditioned with diazoxide, trimetazidine and MG-132 on LPS-induced systemic inflammation mouse model. ARTIFICIAL CELLS NANOMEDICINE AND BIOTECHNOLOGY 2018; 46:1178-1187. [PMID: 29929400 DOI: 10.1080/21691401.2018.1481862] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Systemic inflammatory response syndrome is a complex pathophysiologic and immunologic response to an insult. Sepsis is a life-threatening condition happening when the body's response to infection causes injury to its own tissues and organs. Stem cell therapy is a new approach to modulate immune responses. Mesenchymal stem cells (MSCs) establish a regenerative niche by secreting secretome and modulating immune responses. MSC secretome can be leveraged for therapeutic applications if production of secretary molecules were optimized. Pharmacological preconditioning using small molecules can increase survival of MSCs after transplantation. The aim of this study was to investigate the effect of secretome of human embryonic-derived mesenchymal stem cells (hESC-MSCs) preconditioned with MG-132,Trimetazidine (TMZ) and Diazoxide (DZ) on immunomodulatory efficiency of these cells in Lipo polysaccharide (LPS) challenged mice models. Mice were injected intraperitoneally with LPS and groups of animals were intraperitoneally given 1 ml 30× secretome 6 h after LPS injection. Serum levels of biochemical parameters were then measured by an auto analyser and serum inflammatory cytokine levels were analysed using commercially available RayBio Mouse Inflammation Antibody Array. Ultimately, histopathology and survival studies were conducted. The results showed that TMZ and DZ-conditioned medium significantly increasing the survival and improvement of histopathological score. We found that MG-132-conditioned medium failed to show significant outcomes. This study demonstrated that human MSC secretome has the potential to control inflammation.
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Affiliation(s)
- Saeed Jahandideh
- a Department of Biochemistry , Pasteur Institute of Iran , Tehran , Iran
| | - Shohreh Khatami
- a Department of Biochemistry , Pasteur Institute of Iran , Tehran , Iran
| | - Ali Eslami Far
- b Department of Clinical Research , Pasteur Institute of Iran , Tehran , Iran
| | - Mehdi Kadivar
- a Department of Biochemistry , Pasteur Institute of Iran , Tehran , Iran
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23
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Xiang Q, Liao Y, Chao H, Huang W, Liu J, Chen H, Hong D, Zou Z, Xiang AP, Li W. ISL1 overexpression enhances the survival of transplanted human mesenchymal stem cells in a murine myocardial infarction model. Stem Cell Res Ther 2018; 9:51. [PMID: 29482621 PMCID: PMC5828309 DOI: 10.1186/s13287-018-0803-7] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2017] [Revised: 02/08/2018] [Accepted: 02/08/2018] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND The LIM-homeobox transcription factor islet-1 (ISL1) has been proposed as a marker for cardiovascular progenitor cells. This study investigated whether forced expression of ISL1 in human mesenchymal stem cells (hMSCs) improves myocardial infarction (MI) treatment outcomes. METHODS The lentiviral vector containing the human elongation factor 1α promoter, which drives the expression of ISL1 (EF1α-ISL1), was constructed using the Multisite Gateway System and used to transduce hMSCs. Flow cytometry, immunofluorescence, Western blotting, TUNEL assay, and RNA sequencing were performed to evaluate the function of ISL1-overexpressing hMSCs (ISL1-hMSCs). RESULTS The in vivo results showed that transplantation of ISL1-hMSCs improved cardiac function in a rat model of MI. Left ventricle ejection fraction and fractional shortening were greater in post-MI hearts after 4 weeks of treatment with ISL1-hMSCs compared with control hMSCs or phosphate-buffered saline. We also found that ISL1 overexpression increased angiogenesis and decreased apoptosis and inflammation. The greater potential of ISL1-hMSCs may be attributable to an increased number of surviving cells after transplantation. Conditioned medium from ISL1-hMSCs decreased the apoptotic effect of H2O2 on the cardiomyocyte cell line H9c2. To clarify the molecular basis of this finding, we employed RNA sequencing to compare the apoptotic-related gene expression profiles of control hMSCs and ISL1-hMSCs. The results showed that insulin-like growth factor binding protein 3 (IGFBP3) was the only gene in ISL1-hMSCs with a RPKM value higher than 100 and that the difference fold-change between ISL1-hMSCs and control hMSCs was greater than 3, suggesting that IGFBP3 might play an important role in the anti-apoptosis effect of ISL1-hMSCs through paracrine effects. Furthermore, the expression of IGFBP3 in the conditioned medium from ISL1-hMSCs was almost fourfold greater than that in conditioned medium from control hMSCs. Moreover, the IGFBP3 neutralization antibody reversed the apoptotic effect of ISL1-hMSCs-CM. CONCLUSIONS These results suggest that overexpression of ISL1 in hMSCs promotes cell survival in a model of MI and enhances their paracrine function to protect cardiomyocytes, which may be mediated through IGFBP3. ISL1 overexpression in hMSCs may represent a novel strategy for enhancing the effectiveness of stem cell therapy after MI.
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Affiliation(s)
- Qiuling Xiang
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou, People's Republic of China.,Zhongshan Medical School, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Yan Liao
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou, People's Republic of China.,Zhongshan Medical School, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Hua Chao
- Zhongshan Medical School, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Weijun Huang
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou, People's Republic of China.,Zhongshan Medical School, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Jia Liu
- Department of Cardiology, the Red Cross hospital of Guangzhou City, the Fourth Affiliated Hospital of Jinan University, Guangzhou, People's Republic of China
| | - Haixuan Chen
- The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Dongxi Hong
- Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Zhengwei Zou
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou, People's Republic of China.,Zhongshan Medical School, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Andy Peng Xiang
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou, People's Republic of China.,Zhongshan Medical School, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Weiqiang Li
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou, People's Republic of China. .,Zhongshan Medical School, Sun Yat-sen University, Guangzhou, People's Republic of China.
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24
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Garikipati VNS, Singh SP, Mohanram Y, Gupta AK, Kapoor D, Nityanand S. Isolation and characterization of mesenchymal stem cells from human fetus heart. PLoS One 2018; 13:e0192244. [PMID: 29420637 PMCID: PMC5805293 DOI: 10.1371/journal.pone.0192244] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2017] [Accepted: 01/18/2018] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) are promising cells for cardiovascular regenerative medicine. However, their potential may be limited, because of their restricted cardiovascular differentiation potential and decline in their number and functional characteristics with increasing donor age. We have previously shown that rat fetus heart harbors primitive MSCs and administration of these cells improved left ventricular (LV) function after ischemia/reperfusion injury in rats. To evaluate their potential as a new cell type for clinical cardiovascular cell therapy, we have undertaken this study on the isolation and characterization of human fetal cardiac MSCs (hfC-MSCs). METHODS MSCs were isolated from the heart of five 14-16-week-old aborted human fetuses and studied for their growth characteristics, karyotypic stability and senescence over successive passages, expression of mesenchymal and embryonal markers by flow cytometry and immunocytochemistry, constitutive expression of cardiovascular genes by RT-PCR, differentiation into cells of the cardiovascular lineage and their immunomodulatory properties. RESULTS The hfC-MSCs grew as adherent monolayer with spindle shaped morphology and exhibited rapid proliferation with an average population doubling time of 34 hours and expansion to up to more than 80 population doublings with maintenance of a normal karyotype and without senescence. Immunophenotyping showed that they had similar phenotype as human bone marrow mesenchymal stem cells (hBM-MSCs) expressing CD73, CD90, CD105 and lacking expression of CD31, CD34, CD45, HLA-DR. However, hfC-MSCs expressed significantly higher levels of CD117 and SSEA-4 compared to hBM-MSCs. In addition, hfC-MSCs expressed the embryonal markers Oct-4, Nanog and Sox-2 as compared to hBM-MSCs. Further, hfC-MSCs had significantly higher expression of the cardiovascular genes viz. ISL-1, flk-1, GATA-4, NKX2.5 and MDR-1 as compared to hBM-MSCs, and could be differentiated into major cardiovascular cells (cardiomyocytes, endothelial cells, smooth muscle cells). Interestingly, hfC-MSCs markedly reduced T-lymphocyte proliferation with an increased secretion of TGF-β and IL-10. CONCLUSIONS Our results show that human fetus heart is a novel source of primitive MSCs with cardiovascular commitment which may have a potential therapeutic application in cardiovascular regenerative medicine.
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Affiliation(s)
- Venkata Naga Srikanth Garikipati
- Stem Cell Research Facility, Department of Hematology, Sanjay Gandhi Post-Graduate Institute of Medical Sciences, Lucknow, India
| | - Saurabh Pratap Singh
- Stem Cell Research Facility, Department of Hematology, Sanjay Gandhi Post-Graduate Institute of Medical Sciences, Lucknow, India
| | - Yamuna Mohanram
- Stem Cell Research Facility, Department of Hematology, Sanjay Gandhi Post-Graduate Institute of Medical Sciences, Lucknow, India
| | - Ashwani Kumar Gupta
- Stem Cell Research Facility, Department of Hematology, Sanjay Gandhi Post-Graduate Institute of Medical Sciences, Lucknow, India
| | - Deepa Kapoor
- General Hospital, Sanjay Gandhi Post-Graduate Institute of Medical Sciences, Lucknow, India
| | - Soniya Nityanand
- Stem Cell Research Facility, Department of Hematology, Sanjay Gandhi Post-Graduate Institute of Medical Sciences, Lucknow, India
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25
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Marotta P, Cianflone E, Aquila I, Vicinanza C, Scalise M, Marino F, Mancuso T, Torella M, Indolfi C, Torella D. Combining cell and gene therapy to advance cardiac regeneration. Expert Opin Biol Ther 2018; 18:409-423. [PMID: 29347847 DOI: 10.1080/14712598.2018.1430762] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
INTRODUCTION The characterization of multipotent endogenous cardiac stem cells (eCSCs) and the breakthroughs of somatic cell reprogramming to boost cardiomyocyte replacement have fostered the prospect of achieving functional heart repair/regeneration. AREAS COVERED Allogeneic CSC therapy through its paracrine stimulation of the endogenous resident reparative/regenerative process produces functional meaningful myocardial regeneration in pre-clinical porcine myocardial infarction models and is currently tested in the first-in-man human trial. The in vivo test of somatic reprogramming and cardioregenerative non-coding RNAs revived the interest in gene therapy for myocardial regeneration. The latter, together with the advent of genome editing, has prompted most recent efforts to produce genetically-modified allogeneic CSCs that secrete cardioregenerative factors to optimize effective myocardial repair. EXPERT OPINION The current war against heart failure epidemics in western countries seeks to find effective treatments to set back the failing hearts prolonging human lifespan. Off-the-shelf allogeneic-genetically-modified CSCs producing regenerative agents are a novel and evolving therapy set to be affordable, safe, effective and available at all times for myocardial regeneration to either prevent or treat heart failure.
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Affiliation(s)
- Pina Marotta
- a Molecular and Cellular Cardiology, Department of Medical and Surgical Sciences , Magna Graecia University , Catanzaro , Italy
| | - Eleonora Cianflone
- a Molecular and Cellular Cardiology, Department of Medical and Surgical Sciences , Magna Graecia University , Catanzaro , Italy
| | - Iolanda Aquila
- a Molecular and Cellular Cardiology, Department of Medical and Surgical Sciences , Magna Graecia University , Catanzaro , Italy
| | - Carla Vicinanza
- a Molecular and Cellular Cardiology, Department of Medical and Surgical Sciences , Magna Graecia University , Catanzaro , Italy
| | - Mariangela Scalise
- a Molecular and Cellular Cardiology, Department of Medical and Surgical Sciences , Magna Graecia University , Catanzaro , Italy
| | - Fabiola Marino
- a Molecular and Cellular Cardiology, Department of Medical and Surgical Sciences , Magna Graecia University , Catanzaro , Italy
| | - Teresa Mancuso
- a Molecular and Cellular Cardiology, Department of Medical and Surgical Sciences , Magna Graecia University , Catanzaro , Italy
| | - Michele Torella
- b Department of Cardiothoracic Sciences , University of Campania "L. Vanvitelli" , Naples , Italy
| | - Ciro Indolfi
- a Molecular and Cellular Cardiology, Department of Medical and Surgical Sciences , Magna Graecia University , Catanzaro , Italy
| | - Daniele Torella
- a Molecular and Cellular Cardiology, Department of Medical and Surgical Sciences , Magna Graecia University , Catanzaro , Italy
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26
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Devetzi M, Goulielmaki M, Khoury N, Spandidos DA, Sotiropoulou G, Christodoulou I, Zoumpourlis V. Genetically‑modified stem cells in treatment of human diseases: Tissue kallikrein (KLK1)‑based targeted therapy (Review). Int J Mol Med 2018; 41:1177-1186. [PMID: 29328364 PMCID: PMC5819898 DOI: 10.3892/ijmm.2018.3361] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2017] [Accepted: 01/02/2018] [Indexed: 12/12/2022] Open
Abstract
The tissue kallikrein-kinin system (KKS) is an endogenous multiprotein metabolic cascade which is implicated in the homeostasis of the cardiovascular, renal and central nervous system. Human tissue kallikrein (KLK1) is a serine protease, component of the KKS that has been demonstrated to exert pleiotropic beneficial effects in protection from tissue injury through its anti-inflammatory, anti-apoptotic, anti-fibrotic and anti-oxidative actions. Mesenchymal stem cells (MSCs) or endothelial progenitor cells (EPCs) constitute populations of well-characterized, readily obtainable multipotent cells with special immunomodulatory, migratory and paracrine properties rendering them appealing potential therapeutics in experimental animal models of various diseases. Genetic modification enhances their inherent properties. MSCs or EPCs are competent cellular vehicles for drug and/or gene delivery in the targeted treatment of diseases. KLK1 gene delivery using adenoviral vectors or KLK1 protein infusion into injured tissues of animal models has provided particularly encouraging results in attenuating or reversing myocardial, renal and cerebrovascular ischemic phenotype and tissue damage, thus paving the way for the administration of genetically modified MSCs or EPCs with the human tissue KLK1 gene. Engraftment of KLK1-modified MSCs and/or KLK1-modified EPCs resulted in advanced beneficial outcome regarding heart and kidney protection and recovery from ischemic insults. Collectively, findings from pre-clinical studies raise the possibility that tissue KLK1 may be a novel future therapeutic target in the treatment of a wide range of cardiovascular, cerebrovascular and renal disorders.
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Affiliation(s)
- Marina Devetzi
- Biomedical Applications Unit, Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, 11635 Athens, Greece
| | - Maria Goulielmaki
- Biomedical Applications Unit, Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, 11635 Athens, Greece
| | - Nicolas Khoury
- Biomedical Applications Unit, Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, 11635 Athens, Greece
| | - Demetrios A Spandidos
- Laboratory of Clinical Virology, Medical School, University of Crete, 71003 Heraklion, Greece
| | | | - Ioannis Christodoulou
- Biomedical Applications Unit, Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, 11635 Athens, Greece
| | - Vassilis Zoumpourlis
- Biomedical Applications Unit, Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, 11635 Athens, Greece
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27
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Gnecchi M, Danieli P, Malpasso G, Ciuffreda MC. Paracrine Mechanisms of Mesenchymal Stem Cells in Tissue Repair. Methods Mol Biol 2017; 1416:123-46. [PMID: 27236669 DOI: 10.1007/978-1-4939-3584-0_7] [Citation(s) in RCA: 294] [Impact Index Per Article: 36.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Tissue regeneration from transplanted mesenchymal stromal cells (MSC) either through transdifferentiation or cell fusion was originally proposed as the principal mechanism underlying their therapeutic action. However, several studies have now shown that both these mechanisms are very inefficient. The low MSC engraftment rate documented in injured areas also refutes the hypothesis that MSC repair tissue damage by replacing cell loss with newly differentiated cells. Indeed, despite evidence of preferential homing of MSC to the site of myocardial ischemia, exogenously administered MSC show poor survival and do not persist in the infarcted area. Therefore, it has been proposed that the functional benefits observed after MSC transplantation in experimental models of tissue injury might be related to the secretion of soluble factors acting in a paracrine fashion. This hypothesis is supported by pre-clinical studies demonstrating equal or even improved organ function upon infusion of MSC-derived conditioned medium (MSC-CM) compared with MSC transplantation. Identifying key MSC-secreted factors and their functional role seems a reasonable approach for a rational design of nextgeneration MSC-based therapeutics. Here, we summarize the major findings regarding both different MSC-mediated paracrine actions and the identification of paracrine mediators.
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Affiliation(s)
- Massimiliano Gnecchi
- Department of Molecular Medicine, Unit of Cardiology, University of Pavia, Pavia, Italy. .,Department of Cardiothoracic and Vascular Sciences - Coronary Care Unit and Laboratory of Clinical and Experimental Cardiology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy. .,Laboratory of Experimental Cardiology for Cell and Molecular Therapy, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy. .,Department of Medicine, University of Cape Town, Cape Town, South Africa.
| | - Patrizia Danieli
- Department of Molecular Medicine, Unit of Cardiology, University of Pavia, Pavia, Italy.,Department of Cardiothoracic and Vascular Sciences - Coronary Care Unit and Laboratory of Clinical and Experimental Cardiology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.,Laboratory of Experimental Cardiology for Cell and Molecular Therapy, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Giuseppe Malpasso
- Department of Molecular Medicine, Unit of Cardiology, University of Pavia, Pavia, Italy.,Department of Cardiothoracic and Vascular Sciences - Coronary Care Unit and Laboratory of Clinical and Experimental Cardiology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.,Laboratory of Experimental Cardiology for Cell and Molecular Therapy, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Maria Chiara Ciuffreda
- Department of Molecular Medicine, Unit of Cardiology, University of Pavia, Pavia, Italy.,Department of Cardiothoracic and Vascular Sciences - Coronary Care Unit and Laboratory of Clinical and Experimental Cardiology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.,Laboratory of Experimental Cardiology for Cell and Molecular Therapy, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
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28
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Shafei AES, Ali MA, Ghanem HG, Shehata AI, Abdelgawad AA, Handal HR, Talaat KA, Ashaal AE, El-Shal AS. Mesenchymal stem cell therapy: A promising cell-based therapy for treatment of myocardial infarction. J Gene Med 2017; 19. [PMID: 29044850 DOI: 10.1002/jgm.2995] [Citation(s) in RCA: 111] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2017] [Revised: 10/07/2017] [Accepted: 10/07/2017] [Indexed: 12/12/2022] Open
Abstract
For decades, mesenchymal stem (MSCs) cells have been used for cardiovascular diseases as regenerative therapy. This review is an attempt to summarize the types of MSCs involved in myocardial infarction (MI) therapy, as well as its possible mechanisms effects, especially the paracrine one in MI focusing on the studies (human and animal) conducted within the last 10 years. Recently, reports showed that MSC therapy could have infarct-limiting effects after MI in both experimental and clinical trials. In this context, various types of MSCs can help cardiac regeneration by either revitalizing the cardiac stem cells or revascularizing the arteries and veins of the heart. Furthermore, MSCs could produce paracrine growth factors that increase the survival of nearby cardiomyocytes, as well as increase angiogenesis through recruitment of stem cell from bone marrow or inducing vessel growth from existing capillaries. Recent research suggests that the paracrine effects of MSCs could be mediated by extracellular vesicles including exosomes. Exosomal microRNAs (miRNAs) released by MSCs are promising therapeutic hotspot target for MI. This could be attributed to the role of miRNA in cardiac biology, including cardiac regeneration, stem cell differentiation, apoptosis, neovascularization, cardiac contractility and cardiac remodeling. Furthermore, gene-modified MSCs could be a recent promising therapy for MI to enhance the paracrine effects of MSCs, including better homing and effective cell targeted tissue regeneration. Although MSC therapy has achieved considerable attention and progress, there are critical challenges that remains to be overcome to achieve the most effective successful cell-based therapy in MI.
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Affiliation(s)
- Ayman El-Sayed Shafei
- Biomedical Research Department, Military Armed Forces College of Medicine, Cairo, Egypt
| | - Mahmoud Ahmed Ali
- Biomedical Research Department, Military Armed Forces College of Medicine, Cairo, Egypt
| | | | | | | | | | | | | | - Amal S El-Shal
- Medical Biochemistry & Molecular Biology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
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29
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Huang D, Yin L, Liu X, Lv B, Xie Z, Wang X, Yu B, Zhang Y. Geraniin protects bone marrow‑derived mesenchymal stem cells against hydrogen peroxide‑induced cellular oxidative stress in vitro. Int J Mol Med 2017; 41:739-748. [PMID: 29207024 PMCID: PMC5752161 DOI: 10.3892/ijmm.2017.3276] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2016] [Accepted: 11/08/2017] [Indexed: 12/23/2022] Open
Abstract
Administration of bone marrow-derived mesenchymal stem cells (MSCs) has emerged as a potential therapeutic approach for the treatment of myocardial infarction (MI). However, the increase in reactive oxygen species (ROS) in ischemic cardiac tissue compromises the survival of transplanted MSCs, thus resulting in limited therapeutic efficiency. Therefore, strategies that attenuate oxidative stress-induced damage and enhance MSC viability are required. Geraniin has been reported to possess potent antioxidative activity and exert protective effects on numerous cell types under certain conditions. Therefore, geraniin may be considered a potential drug used to modulate MSC-based therapy for MI. In the present study, MSCs were pretreated with geraniin for 24 h and were exposed to hydrogen peroxide (H2O2) for 4 h. Cell apoptosis, intracellular ROS levels and mitochondrial membrane potential were measured using Annexin V-fluorescein isothiocyanate/ propidium iodide staining, the 2′,7′-dichlorodihydrofluorescein diacetate fluorescent probe and the membrane permeable dye JC-1, respectively. Glutathione and malondialdehyde levels were also investigated. The expression levels of apoptosis-associated proteins and proteins of the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway were analyzed by western blotting. The results demonstrated that geraniin could significantly attenuate H2O2-induced cell damage by promoting MSC survival, reducing cellular ROS production and maintaining mitochondrial function. Furthermore, geraniin modulated the expression levels of phosphorylated-Akt in a time- and dose-dependent manner. The cytoprotective effects of geraniin were suppressed by LY294002, a specific PI3K inhibitor. In conclusion, the present study revealed that geraniin protects MSCs from H2O2-induced oxidative stress injury via the PI3K/Akt pathway. These findings indicated that cotreatment of MSCs with geraniin may optimize therapeutic efficacy for the clinical treatment of MI.
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Affiliation(s)
- Dan Huang
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Li Yin
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Xinxin Liu
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Bo Lv
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Zulong Xie
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Xuedong Wang
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Bo Yu
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Yao Zhang
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
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Absence of NUCKS augments paracrine effects of mesenchymal stem cells-mediated cardiac protection. Exp Cell Res 2017; 356:74-84. [PMID: 28412246 DOI: 10.1016/j.yexcr.2017.04.012] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2017] [Revised: 04/07/2017] [Accepted: 04/09/2017] [Indexed: 01/06/2023]
Abstract
Bone marrow-derived mesenchymal stem cells (BM-MSCs) contribute to myocardial repair after myocardial infarction (MI) by secreting a panel of growth factors and cytokines. This study was to investigate the potential mechanisms of the nuclear casein kinase and cyclin-dependent kinase substrate 1 (NUCKS) in regulation of the profiles of BM-MSCs secretion and compare the therapeutic efficacy of NUCKS-/-- and wide type-BM-MSCs (WT-BM-MSCs) on MI. The secretion profiles between NUCKS-/-- and WT-BM-MSCs under hypoxia (1%O2) were analyzed. Gene function analysis showed that compared with WT-BM-MSCs-conditioned medium (CdM), some genes over-presented in NUCKS-/--BM-MSCs-CdM were closely associated with inflammatory response, regulation of cell proliferation, death, migration and secretion. Notably, VEGFa in NUCKS-/--BM-MSCs-CdM was higher than that of WT-BM-MSCs-CdM. WT-BM-MSCs and NUCKS-/--BM-MSCs were transplanted into the peri-infarct region in mice of MI. At 4 weeks after cell transplantation, NUCKS-/-- or WT-BM-MSCs group significantly improved heart function and vessels density and reduced infarction size and apoptosis of cardiomyocytes. Furthermore, NUCKS-/--BM-MSCs provided better cardioprotective effects than WT-BM-MSCs against MI. Our study demonstrates that depletion of NUCKS enhances the therapeutic efficacy of BM-MSCs for MI via regulating the secretion.
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31
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Der Sarkissian S, Lévesque T, Noiseux N. Optimizing stem cells for cardiac repair: Current status and new frontiers in regenerative cardiology. World J Stem Cells 2017; 9:9-25. [PMID: 28154736 PMCID: PMC5253186 DOI: 10.4252/wjsc.v9.i1.9] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2016] [Revised: 09/20/2016] [Accepted: 10/24/2016] [Indexed: 02/06/2023] Open
Abstract
Cell therapy has the potential to improve healing of ischemic heart, repopulate injured myocardium and restore cardiac function. The tremendous hope and potential of stem cell therapy is well understood, yet recent trials involving cell therapy for cardiovascular diseases have yielded mixed results with inconsistent data thereby readdressing controversies and unresolved questions regarding stem cell efficacy for ischemic cardiac disease treatment. These controversies are believed to arise by the lack of uniformity of the clinical trial methodologies, uncertainty regarding the underlying reparative mechanisms of stem cells, questions concerning the most appropriate cell population to use, the proper delivery method and timing in relation to the moment of infarction, as well as the poor stem cell survival and engraftment especially in a diseased microenvironment which is collectively acknowledged as a major hindrance to any form of cell therapy. Indeed, the microenvironment of the failing heart exhibits pathological hypoxic, oxidative and inflammatory stressors impairing the survival of transplanted cells. Therefore, in order to observe any significant therapeutic benefit there is a need to increase resilience of stem cells to death in the transplant microenvironment while preserving or better yet improving their reparative functionality. Although stem cell differentiation into cardiomyocytes has been observed in some instance, the prevailing reparative benefits are afforded through paracrine mechanisms that promote angiogenesis, cell survival, transdifferentiate host cells and modulate immune responses. Therefore, to maximize their reparative functionality, ex vivo manipulation of stem cells through physical, genetic and pharmacological means have shown promise to enable cells to thrive in the post-ischemic transplant microenvironment. In the present work, we will overview the current status of stem cell therapy for ischemic heart disease, discuss the most recurring cell populations employed, the mechanisms by which stem cells deliver a therapeutic benefit and strategies that have been used to optimize and increase survival and functionality of stem cells including ex vivo preconditioning with drugs and a novel “pharmaco-optimizer” as well as genetic modifications.
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32
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Lee TM, Harn HJ, Chiou TW, Chuang MH, Chen CH, Lin PC, Lin SZ. Targeting the pathway of GSK-3β/nerve growth factor to attenuate post-infarction arrhythmias by preconditioned adipose-derived stem cells. J Mol Cell Cardiol 2017; 104:17-30. [PMID: 28130118 DOI: 10.1016/j.yjmcc.2017.01.014] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2016] [Revised: 01/01/2017] [Accepted: 01/23/2017] [Indexed: 10/20/2022]
Abstract
Adipose-derived stem cell (ADSC) transplantation is a promising new therapy to improve cardiac function after myocardial infarction. However, its low efficacy of transdifferentiation hampers its usefulness. Glycogen synthase kinase-3β (GSK-3β) signal has been shown to play a role in preconditioning-induced cardioprotection. We assessed whether n-butylidenephthalide (BP) primed ADSCs can attenuate arrhythmias by a GSK-3β-dependent pathway after myocardial infarction. Male Wistar rats after coronary ligation was randomly allocated to receive intramyocardial injection of vehicle, ADSCs, BP-preconditioned ADSCs, (BP+lithium)-preconditioned ADSCs, (BP+SB216763)-preconditioned ADSCs, and (BP+LY294002)-preconditioned ADSCs. ADSCs were primed for 16h before implantation. After 4weeks of implantation, ADSCs were retained in myocardium, reduced fibrosis and improved cardiac function. Sympathetic hyperinnervation was blunted after administering ADSCs, assessed by immunofluorescent analysis, and Western blotting and real-time quantitative RT-PCR of nerve growth factor. Arrhythmic scores during programmed stimulation in the ADSC-treated infarcted rats were significantly lower than vehicle. BP-preconditioned ADSCs had superior cardioprotection, greater ADSC engraftment and transdifferentiation, and antiarrhythmic effects compared with ADSCs alone. Simultaneously, BP increased the levels of phospho-Akt and down-regulated GSK-3β activity. The effects of BP against sympathetic hyperinnervation were blocked by LY294002, a PI3K inhibitor. Addition of either lithium or SB216763 did not have additional effects compared with BP alone. Compared with ADSC alone, BP-primed ADSC implantation improved stem cell engraftment and attenuated sympathetic hyperinnervation and arrhythmias through a PI3K/Akt/GSK-3β-dependent pathway, suggesting that a synergic action was achieved between BP pretreatment and ADSCs.
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Affiliation(s)
- Tsung-Ming Lee
- Department of Medicine, Cardiology Section, China Medical University-An Nan Hospital, Tainan, Taiwan; Department of Medicine, China Medical University, Taichung, Taiwan
| | - Horng-Jyh Harn
- Bioinnovation Center, Tzu Chi Foundation; Department of Pathology, Buddhist Tzu Chi General Hospital, Tzu Chi University
| | - Tzyy-Wen Chiou
- Department of Life Science, Graduate Institute of Biotechnology, National Dong Hwa University, Hualien, Taiwan
| | - Ming-Hsi Chuang
- Gwo Xi Stem Cell Applied Technology, Hsinchu, Taiwan; Department of Bioinformatics, Chung Hua University, Hsinchu, Taiwan
| | | | - Po-Cheng Lin
- Gwo Xi Stem Cell Applied Technology, Hsinchu, Taiwan
| | - Shinn-Zong Lin
- Bioinnovation Center, Tzu Chi Foundation; Department of Neurosurgery, Buddhist Tzu Chi General Hospital, Tzu Chi University.
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Psaltis PJ, Schwarz N, Toledo-Flores D, Nicholls SJ. Cellular Therapy for Heart Failure. Curr Cardiol Rev 2016; 12:195-215. [PMID: 27280304 PMCID: PMC5011188 DOI: 10.2174/1573403x12666160606121858] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2015] [Revised: 12/18/2015] [Accepted: 12/31/1969] [Indexed: 12/12/2022] Open
Abstract
The pathogenesis of cardiomyopathy and heart failure (HF) is underpinned by complex changes at subcellular, cellular and extracellular levels in the ventricular myocardium. For all of the gains that conventional treatments for HF have brought to mortality and morbidity, they do not adequately address the loss of cardiomyocyte numbers in the remodeling ventricle. Originally conceived to address this problem, cellular transplantation for HF has already gone through several stages of evolution over the past two decades. Various cell types and delivery routes have been implemented to positive effect in preclinical models of ischemic and nonischemic cardiomyopathy, with pleiotropic benefits observed in terms of myocardial remodeling, systolic and diastolic performance, perfusion, fibrosis, inflammation, metabolism and electrophysiology. To a large extent, these salubrious effects are now attributed to the indirect, paracrine capacity of transplanted stem cells to facilitate endogenous cardiac repair processes. Promising results have also followed in early phase human studies, although these have been relatively modest and somewhat inconsistent. This review details the preclinical and clinical evidence currently available regarding the use of pluripotent stem cells and adult-derived progenitor cells for cardiomyopathy and HF. It outlines the important lessons that have been learned to this point in time, and balances the promise of this exciting field against the key challenges and questions that still need to be addressed at all levels of research, to ensure that cell therapy realizes its full potential by adding to the armamentarium of HF management.
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Affiliation(s)
- Peter J Psaltis
- Co-Director of Vascular Research Centre, Heart Health Theme, South Australian Health and Medical Research Institute, North Terrace, Adelaide, South Australia, Australia 5000.
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Hodgkinson CP, Bareja A, Gomez JA, Dzau VJ. Emerging Concepts in Paracrine Mechanisms in Regenerative Cardiovascular Medicine and Biology. Circ Res 2016; 118:95-107. [PMID: 26837742 DOI: 10.1161/circresaha.115.305373] [Citation(s) in RCA: 198] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
In the past decade, substantial evidence supports the paradigm that stem cells exert their reparative and regenerative effects, in large part, through the release of biologically active molecules acting in a paracrine fashion on resident cells. The data suggest the existence of a tissue microenvironment where stem cell factors influence cell survival, inflammation, angiogenesis, repair, and regeneration in a temporal and spatial manner.
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Affiliation(s)
- Conrad P Hodgkinson
- From the Department of Medicine, Mandel Center for Hypertension Research and Duke Cardiovascular Research Center, Duke University Medical Center, Durham, NC
| | - Akshay Bareja
- From the Department of Medicine, Mandel Center for Hypertension Research and Duke Cardiovascular Research Center, Duke University Medical Center, Durham, NC
| | - José A Gomez
- From the Department of Medicine, Mandel Center for Hypertension Research and Duke Cardiovascular Research Center, Duke University Medical Center, Durham, NC
| | - Victor J Dzau
- From the Department of Medicine, Mandel Center for Hypertension Research and Duke Cardiovascular Research Center, Duke University Medical Center, Durham, NC.
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35
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Coulson-Thomas VJ, Coulson-Thomas YM, Gesteira TF, Kao WWY. Extrinsic and Intrinsic Mechanisms by Which Mesenchymal Stem Cells Suppress the Immune System. Ocul Surf 2016; 14:121-34. [PMID: 26804815 DOI: 10.1016/j.jtos.2015.11.004] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2015] [Revised: 11/12/2015] [Accepted: 11/23/2015] [Indexed: 12/12/2022]
Abstract
Mesenchymal stem cells (MSCs) are a group of fibroblast-like multipotent mesenchymal stromal cells that have the ability to differentiate into osteoblasts, adipocytes, and chondrocytes. Recent studies have demonstrated that MSCs possess a unique ability to exert suppressive and regulatory effects on both adaptive and innate immunity in an autologous and allogeneic manner. A vital step in stem cell transplantation is overcoming the potential graft-versus-host disease, which is a limiting factor to transplantation success. Given that MSCs attain powerful differentiation capabilities and also present immunosuppressive properties, which enable them to survive host immune rejection, MSCs are of great interest. Due to their ability to differentiate into different cell types and to suppress and modulate the immune system, MSCs are being developed for treating a plethora of diseases, including immune disorders. Moreover, in recent years, MSCs have been genetically engineered to treat and sometimes even cure some diseases, and the use of MSCs for cell therapy presents new perspectives for overcoming tissue rejection. In this review, we discuss the potential extrinsic and intrinsic mechanisms that underlie MSCs' unique ability to modulate inflammation, and both innate and adaptive immunity.
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Affiliation(s)
- Vivien J Coulson-Thomas
- Department of Ophthalmology, University of Cincinnati, Ohio, USA; John van Geest Centre for Brain Repair, University of Cambridge, Cambridge, UK.
| | | | | | - Winston W-Y Kao
- Department of Ophthalmology, University of Cincinnati, Ohio, USA.
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36
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Vu MQ, Der Sarkissian S, Borie M, Bessette PO, Noiseux N. Optimization of Mesenchymal Stem Cells to Increase Their Therapeutic Potential. Methods Mol Biol 2016; 1416:275-88. [PMID: 27236678 DOI: 10.1007/978-1-4939-3584-0_16] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The heart which has limited renewal and regenerative capacity is a prime target for cellular therapy. Stem cell transplantation has emerged as a promising therapeutic strategy to improve healing of the ischemic heart, repopulate the injured myocardium, and restore cardiac function. However, clinical usefulness is impacted by the quality and quantity of delivered cells, the suboptimal manipulations prior to transplantation, and the general poor viability of the cells transferred particularly to an ischemic microenvironment. Focus is now on developing new ways to enhance stem cell renewal and survival capacity before transplant. This can be done by physical, chemical, pharmacological, or genetic manipulation of cells followed by accurate evaluation of conditioning methods by validated tests.This chapter covers the proper handling of mesenchymal stem cells (human and rat lines) and methodologies to evaluate efficacy and the translational potential of conditioning methods. Specifically, we will cover stem cell culture methods, preconditioning protocols, viability assessment in hypoxic and oxidative challenges as encountered in an ischemic microenvironment, and the proliferative capacity of cells.
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Affiliation(s)
- Minh Quan Vu
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, QC, Canada.,Faculté de Médecine, Université de Montréal, Montreal, QC, Canada
| | - Shant Der Sarkissian
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, QC, Canada.,Faculté de Médecine, Université de Montréal, Montreal, QC, Canada
| | - Melanie Borie
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, QC, Canada
| | | | - Nicolas Noiseux
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, QC, Canada. .,Faculté de Médecine, Université de Montréal, Montreal, QC, Canada. .,Division of Cardiac Surgery, Centre Hospitalier de l'Université de Montréal (CHUM), 3840 Saint-Urbain Street, Montreal, QC, Canada, H2W1T8.
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Suzuki G. Translational research of adult stem cell therapy. World J Cardiol 2015; 7:707-718. [PMID: 26635920 PMCID: PMC4660467 DOI: 10.4330/wjc.v7.i11.707] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2015] [Revised: 08/12/2015] [Accepted: 09/28/2015] [Indexed: 02/06/2023] Open
Abstract
Congestive heart failure (CHF) secondary to chronic coronary artery disease is a major cause of morbidity and mortality world-wide. Its prevalence is increasing despite advances in medical and device therapies. Cell based therapies generating new cardiomyocytes and vessels have emerged as a promising treatment to reverse functional deterioration and prevent the progression to CHF. Functional efficacy of progenitor cells isolated from the bone marrow and the heart have been evaluated in preclinical large animal models. Furthermore, several clinical trials using autologous and allogeneic stem cells and progenitor cells have demonstrated their safety in humans yet their clinical relevance is inconclusive. This review will discuss the clinical therapeutic applications of three specific adult stem cells that have shown particularly promising regenerative effects in preclinical studies, bone marrow derived mesenchymal stem cell, heart derived cardiosphere-derived cell and cardiac stem cell. We will also discuss future therapeutic approaches.
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Li F, Niyibizi C. Engraftability of Murine Bone Marrow-Derived Multipotent Mesenchymal Stem Cell Subpopulations in the Tissues of Developing Mice following Systemic Transplantation. Cells Tissues Organs 2015; 201:14-25. [PMID: 26447469 DOI: 10.1159/000438985] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/26/2015] [Indexed: 11/19/2022] Open
Abstract
INTRODUCTION Cell therapies for generalized musculoskeletal diseases would require distribution of cells to all the skeletal tissues; however, there are controversies regarding the transplantability of multipotent mesenchymal stems cells (MSCs). We generated single-cell subpopulations of MSCs from murine bone marrow and assessed them for differences in trafficking through the circulatory system and engraftment in bone and other tissues. MATERIALS AND METHODS Seven single-cell clonal subpopulations were generated by serial dilution of GFP-marked MSCs isolated from bone marrow. The subpopulations were examined for putative MSC surface marker expression, in vitro differentiation toward osteogenic and adipogenic lineages, migration and engraftment in different tissues following intravenous delivery in normal, sublethally irradiated neonatal mice. RESULTS The surface marker expression profile revealed notable differences among clonal cells, specifically CD44 and CD105. All the cell subpopulations differentiated toward osteogenic and adipogenic lineages, with some committed to only one or the other. Two clones enriched in CXCR4 expression were highly efficient in migrating and engrafting in skeletal tissue including bone; this confirmed the role of this chemokine in cell migration. Donor cells retrieved from various tissues displayed different morphologies and potential differentiation into tissue cell type of engraftment, suggesting modification by the tissues in which the donor cells engrafted. CONCLUSION We have reported that, within bone marrow, there are heterogeneous subpopulations of MSCs that may differ in their ability to migrate in the circulatory system and engraft in different tissues.
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Affiliation(s)
- Feng Li
- Division of Musculoskeletal Sciences, Department of Orthopaedics and Rehabilitation, Pennsylvania State University College of Medicine, Hershey, Pa., USA
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D'souza N, Rossignoli F, Golinelli G, Grisendi G, Spano C, Candini O, Osturu S, Catani F, Paolucci P, Horwitz EM, Dominici M. Mesenchymal stem/stromal cells as a delivery platform in cell and gene therapies. BMC Med 2015; 13:186. [PMID: 26265166 PMCID: PMC4534031 DOI: 10.1186/s12916-015-0426-0] [Citation(s) in RCA: 94] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2015] [Accepted: 07/17/2015] [Indexed: 02/07/2023] Open
Abstract
Regenerative medicine relying on cell and gene therapies is one of the most promising approaches to repair tissues. Multipotent mesenchymal stem/stromal cells (MSC), a population of progenitors committing into mesoderm lineages, are progressively demonstrating therapeutic capabilities far beyond their differentiation capacities. The mechanisms by which MSC exert these actions include the release of biomolecules with anti-inflammatory, immunomodulating, anti-fibrogenic, and trophic functions. While we expect the spectra of these molecules with a therapeutic profile to progressively expand, several human pathological conditions have begun to benefit from these biomolecule-delivering properties. In addition, MSC have also been proposed to vehicle genes capable of further empowering these functions. This review deals with the therapeutic properties of MSC, focusing on their ability to secrete naturally produced or gene-induced factors that can be used in the treatment of kidney, lung, heart, liver, pancreas, nervous system, and skeletal diseases. We specifically focus on the different modalities by which MSC can exert these functions. We aim to provide an updated understanding of these paracrine mechanisms as a prerequisite to broadening the therapeutic potential and clinical impact of MSC.
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Affiliation(s)
- Naomi D'souza
- Department of Medical and Surgical Sciences for Children & Adults, University-Hospital of Modena and Reggio Emilia, Via del Pozzo 71, 41124, Modena, Italy
| | - Filippo Rossignoli
- Department of Medical and Surgical Sciences for Children & Adults, University-Hospital of Modena and Reggio Emilia, Via del Pozzo 71, 41124, Modena, Italy
| | - Giulia Golinelli
- Department of Medical and Surgical Sciences for Children & Adults, University-Hospital of Modena and Reggio Emilia, Via del Pozzo 71, 41124, Modena, Italy
| | - Giulia Grisendi
- Department of Medical and Surgical Sciences for Children & Adults, University-Hospital of Modena and Reggio Emilia, Via del Pozzo 71, 41124, Modena, Italy
| | - Carlotta Spano
- Department of Medical and Surgical Sciences for Children & Adults, University-Hospital of Modena and Reggio Emilia, Via del Pozzo 71, 41124, Modena, Italy
| | - Olivia Candini
- Department of Medical and Surgical Sciences for Children & Adults, University-Hospital of Modena and Reggio Emilia, Via del Pozzo 71, 41124, Modena, Italy
| | - Satoru Osturu
- The Division of Hematology/Oncology/BMT, Nationwide Children's Hospital, Departments of Pediatrics and Medicine, The Ohio State University College of Medicine, Columbus, Ohio, USA
| | - Fabio Catani
- Department of Medical and Surgical Sciences for Children & Adults, University-Hospital of Modena and Reggio Emilia, Via del Pozzo 71, 41124, Modena, Italy
| | - Paolo Paolucci
- Department of Medical and Surgical Sciences for Children & Adults, University-Hospital of Modena and Reggio Emilia, Via del Pozzo 71, 41124, Modena, Italy
| | - Edwin M Horwitz
- The Division of Hematology/Oncology/BMT, Nationwide Children's Hospital, Departments of Pediatrics and Medicine, The Ohio State University College of Medicine, Columbus, Ohio, USA
| | - Massimo Dominici
- Department of Medical and Surgical Sciences for Children & Adults, University-Hospital of Modena and Reggio Emilia, Via del Pozzo 71, 41124, Modena, Italy.
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Activation of NRG1-ERBB4 signaling potentiates mesenchymal stem cell-mediated myocardial repairs following myocardial infarction. Cell Death Dis 2015; 6:e1765. [PMID: 25996292 PMCID: PMC4669719 DOI: 10.1038/cddis.2015.91] [Citation(s) in RCA: 63] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2014] [Revised: 01/14/2015] [Accepted: 02/16/2015] [Indexed: 12/31/2022]
Abstract
Mesenchymal stem cell (MSC) transplantation has achieved only modest success in the treatment of ischemic heart disease owing to poor cell viability in the diseased microenvironment. Activation of the NRG1 (neuregulin1)-ERBB4 (v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 4) signaling pathway has been shown to stimulate mature cardiomyocyte cell cycle re-entry and cell division. In this connection, we aimed to determine whether overexpression of ERBB4 in MSCs can enhance their cardio-protective effects following myocardial infarction. NRG1, MSCs or MSC-ERBB4 (MSC with ERBB4 overexpression), were transplanted into mice following myocardial infarction. Superior to that of MSCs and solely NRG1, MSC-ERBB4 transplantation significantly preserved heart functions accompanied with reduced infarct size, enhanced cardiomyocyte division and less apoptosis during early phase of infarction. The transduction of ERBB4 into MSCs indeed increased cell mobility and apoptotic resistance under hypoxic and glucose-deprived conditions via a PI3K/Akt signaling pathway in the presence of NRG1. Unexpectedly, introduction of ERBB4 into MSC in turn potentiates NRG1 synthesis and secretion, thus forming a novel NRG1-ERBB4-NRG1 autocrine loop. Conditioned medium of MSC-ERBB4 containing elevated NRG1, promoted cardiomyocyte growth and division, whereas neutralization of NRG1 blunted this proliferation. These findings collectively suggest that ERBB4 overexpression potentiates MSC survival in the infarcted heart, enhances NRG1 generation to restore declining NRG1 in the infarcted region and stimulates cardiomyocyte division. ERBB4 has an important role in MSC-mediated myocardial repairs.
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Crisostomo V, Baez-Diaz C, Maestre J, Garcia-Lindo M, Sun F, Casado JG, Blazquez R, Abad JL, Palacios I, Rodriguez-Borlado L, Sanchez-Margallo FM. Delayed administration of allogeneic cardiac stem cell therapy for acute myocardial infarction could ameliorate adverse remodeling: experimental study in swine. J Transl Med 2015; 13:156. [PMID: 25964098 PMCID: PMC4458045 DOI: 10.1186/s12967-015-0512-2] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2014] [Accepted: 04/30/2015] [Indexed: 02/07/2023] Open
Abstract
Background The optimal timing of cardiac stem cells administration is still unclear. We assessed the safety of same-day and delayed (one week) delivery and the possible influence of the timing on the therapeutic outcomes of allogeneic porcine cardiac stem cells administration after acute myocardial infarction in a closed-chest ischemia-reperfusion model. Methods Female swine surviving 90 min occlusion of the mid left anterior descending coronary artery received an intracoronary injection of 25x106 porcine cardiac stem cells either two hours (n = 5, D0) or 7 days (n = 6, D7) after reperfusion. Controls received intracoronary injection of vehicle on day 7 (n = 6, CON). Safety was defined in terms of absence of major cardiac events, changes to the ECG during injection, post-administration coronary flow assessed using the TIMI scale and cardiac troponin I determination after the intervention. Cardiac Magnetic Resonance was performed for morphological and functional assessment prior to infarction, before injection (D7 and CON groups only), at one and 10 weeks. Samples were taken from the infarct and transition areas for pathological examination. Results No major adverse cardiac events were seen during injection in any group. Animals receiving the therapy on the same day of infarction (D0 group) showed mild transient ST changes during injection (n = 4) and, in one case, slightly compromised coronary flow (TIMI 2). Cardiac function parameters and infarct sizes were not significantly different between groups, with a trend towards higher ejection fraction in the treated groups. Ventricular volumes indexed to body surface area increased over time in control animals, and decreased by the end of the study in animals receiving the therapy, significantly so when comparing End Diastolic Volume between CON and D7 groups (CON: 121.70 ml/m2 ± 26.09 ml/m2, D7: 98.71 ml/m2 ± 8.30 ml/m2, p = 0.037). The treated groups showed less organization of the collagenous scar, and a significantly (p = 0.019) higher amount of larger, more mature vessels at the infarct border. Conclusions The intracoronary injection of 25x106 allogeneic cardiac stem cells is generally safe, both early and 7 days after experimental infarction, and alleviates myocardial dysfunction, with a greater limitation of left ventricular remodeling when performed at one week. Electronic supplementary material The online version of this article (doi:10.1186/s12967-015-0512-2) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Veronica Crisostomo
- Jesús Usón Minimally Invasive Surgery Centre, Carretera N-521, km 41.8, 10071, Cáceres, Spain.
| | - Claudia Baez-Diaz
- Jesús Usón Minimally Invasive Surgery Centre, Carretera N-521, km 41.8, 10071, Cáceres, Spain.
| | - Juan Maestre
- Jesús Usón Minimally Invasive Surgery Centre, Carretera N-521, km 41.8, 10071, Cáceres, Spain.
| | - Monica Garcia-Lindo
- Jesús Usón Minimally Invasive Surgery Centre, Carretera N-521, km 41.8, 10071, Cáceres, Spain.
| | - Fei Sun
- Jesús Usón Minimally Invasive Surgery Centre, Carretera N-521, km 41.8, 10071, Cáceres, Spain.
| | - Javier G Casado
- Jesús Usón Minimally Invasive Surgery Centre, Carretera N-521, km 41.8, 10071, Cáceres, Spain.
| | - Rebeca Blazquez
- Jesús Usón Minimally Invasive Surgery Centre, Carretera N-521, km 41.8, 10071, Cáceres, Spain.
| | - Jose L Abad
- Coretherapix, Santiago Grisolía, n° 2 Parque Científico de Madrid, 28760, Tres Cantos, Madrid, Spain.
| | - Itziar Palacios
- Coretherapix, Santiago Grisolía, n° 2 Parque Científico de Madrid, 28760, Tres Cantos, Madrid, Spain.
| | - Luis Rodriguez-Borlado
- Coretherapix, Santiago Grisolía, n° 2 Parque Científico de Madrid, 28760, Tres Cantos, Madrid, Spain.
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Danieli P, Malpasso G, Ciuffreda MC, Cervio E, Calvillo L, Copes F, Pisano F, Mura M, Kleijn L, de Boer RA, Viarengo G, Rosti V, Spinillo A, Roccio M, Gnecchi M. Conditioned medium from human amniotic mesenchymal stromal cells limits infarct size and enhances angiogenesis. Stem Cells Transl Med 2015; 4:448-58. [PMID: 25824141 DOI: 10.5966/sctm.2014-0253] [Citation(s) in RCA: 82] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2014] [Accepted: 02/02/2015] [Indexed: 01/08/2023] Open
Abstract
The paracrine properties of human amniotic membrane-derived mesenchymal stromal cells (hAMCs) have not been fully elucidated. The goal of the present study was to elucidate whether hAMCs can exert beneficial paracrine effects on infarcted rat hearts, in particular through cardioprotection and angiogenesis. Moreover, we aimed to identify the putative active paracrine mediators. hAMCs were isolated, expanded, and characterized. In vitro, conditioned medium from hAMC (hAMC-CM) exhibited cytoprotective and proangiogenic properties. In vivo, injection of hAMC-CM into infarcted rat hearts limited the infarct size, reduced cardiomyocyte apoptosis and ventricular remodeling, and strongly promoted capillary formation at the infarct border zone. Gene array analysis led to the identification of 32 genes encoding for the secreted factors overexpressed by hAMCs. Among these, midkine and secreted protein acidic and rich in cysteine were also upregulated at the protein level. Furthermore, high amounts of several proangiogenic factors were detected in hAMC-CM by cytokine array. Our results strongly support the concept that the administration of hAMC-CM favors the repair process after acute myocardial infarction.
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Affiliation(s)
- Patrizia Danieli
- Department of Cardiothoracic and Vascular Sciences, Coronary Care Unit and Laboratory of Clinical and Experimental Cardiology, Laboratory of Experimental Cardiology for Cell and Molecular Therapy, Division of Clinical Immunology, Immunohematology, and Transfusion Service, Center for the Study and Cure of Myelofibrosis, Biotechnology Research Laboratories, and Division of Obstetrics and Gynecology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; Department of Molecular Medicine, Unit of Cardiology, University of Pavia, Pavia, Italy; Laboratory of Cardiovascular Genetics, IRCCS Istituto Auxologico Italiano, Milan, Italy; Department of Cardiology, University Medical Center Groningen, Groningen, The Netherlands; Department of Medicine, University of Cape Town, Cape Town, South Africa
| | - Giuseppe Malpasso
- Department of Cardiothoracic and Vascular Sciences, Coronary Care Unit and Laboratory of Clinical and Experimental Cardiology, Laboratory of Experimental Cardiology for Cell and Molecular Therapy, Division of Clinical Immunology, Immunohematology, and Transfusion Service, Center for the Study and Cure of Myelofibrosis, Biotechnology Research Laboratories, and Division of Obstetrics and Gynecology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; Department of Molecular Medicine, Unit of Cardiology, University of Pavia, Pavia, Italy; Laboratory of Cardiovascular Genetics, IRCCS Istituto Auxologico Italiano, Milan, Italy; Department of Cardiology, University Medical Center Groningen, Groningen, The Netherlands; Department of Medicine, University of Cape Town, Cape Town, South Africa
| | - Maria Chiara Ciuffreda
- Department of Cardiothoracic and Vascular Sciences, Coronary Care Unit and Laboratory of Clinical and Experimental Cardiology, Laboratory of Experimental Cardiology for Cell and Molecular Therapy, Division of Clinical Immunology, Immunohematology, and Transfusion Service, Center for the Study and Cure of Myelofibrosis, Biotechnology Research Laboratories, and Division of Obstetrics and Gynecology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; Department of Molecular Medicine, Unit of Cardiology, University of Pavia, Pavia, Italy; Laboratory of Cardiovascular Genetics, IRCCS Istituto Auxologico Italiano, Milan, Italy; Department of Cardiology, University Medical Center Groningen, Groningen, The Netherlands; Department of Medicine, University of Cape Town, Cape Town, South Africa
| | - Elisabetta Cervio
- Department of Cardiothoracic and Vascular Sciences, Coronary Care Unit and Laboratory of Clinical and Experimental Cardiology, Laboratory of Experimental Cardiology for Cell and Molecular Therapy, Division of Clinical Immunology, Immunohematology, and Transfusion Service, Center for the Study and Cure of Myelofibrosis, Biotechnology Research Laboratories, and Division of Obstetrics and Gynecology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; Department of Molecular Medicine, Unit of Cardiology, University of Pavia, Pavia, Italy; Laboratory of Cardiovascular Genetics, IRCCS Istituto Auxologico Italiano, Milan, Italy; Department of Cardiology, University Medical Center Groningen, Groningen, The Netherlands; Department of Medicine, University of Cape Town, Cape Town, South Africa
| | - Laura Calvillo
- Department of Cardiothoracic and Vascular Sciences, Coronary Care Unit and Laboratory of Clinical and Experimental Cardiology, Laboratory of Experimental Cardiology for Cell and Molecular Therapy, Division of Clinical Immunology, Immunohematology, and Transfusion Service, Center for the Study and Cure of Myelofibrosis, Biotechnology Research Laboratories, and Division of Obstetrics and Gynecology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; Department of Molecular Medicine, Unit of Cardiology, University of Pavia, Pavia, Italy; Laboratory of Cardiovascular Genetics, IRCCS Istituto Auxologico Italiano, Milan, Italy; Department of Cardiology, University Medical Center Groningen, Groningen, The Netherlands; Department of Medicine, University of Cape Town, Cape Town, South Africa
| | - Francesco Copes
- Department of Cardiothoracic and Vascular Sciences, Coronary Care Unit and Laboratory of Clinical and Experimental Cardiology, Laboratory of Experimental Cardiology for Cell and Molecular Therapy, Division of Clinical Immunology, Immunohematology, and Transfusion Service, Center for the Study and Cure of Myelofibrosis, Biotechnology Research Laboratories, and Division of Obstetrics and Gynecology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; Department of Molecular Medicine, Unit of Cardiology, University of Pavia, Pavia, Italy; Laboratory of Cardiovascular Genetics, IRCCS Istituto Auxologico Italiano, Milan, Italy; Department of Cardiology, University Medical Center Groningen, Groningen, The Netherlands; Department of Medicine, University of Cape Town, Cape Town, South Africa
| | - Federica Pisano
- Department of Cardiothoracic and Vascular Sciences, Coronary Care Unit and Laboratory of Clinical and Experimental Cardiology, Laboratory of Experimental Cardiology for Cell and Molecular Therapy, Division of Clinical Immunology, Immunohematology, and Transfusion Service, Center for the Study and Cure of Myelofibrosis, Biotechnology Research Laboratories, and Division of Obstetrics and Gynecology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; Department of Molecular Medicine, Unit of Cardiology, University of Pavia, Pavia, Italy; Laboratory of Cardiovascular Genetics, IRCCS Istituto Auxologico Italiano, Milan, Italy; Department of Cardiology, University Medical Center Groningen, Groningen, The Netherlands; Department of Medicine, University of Cape Town, Cape Town, South Africa
| | - Manuela Mura
- Department of Cardiothoracic and Vascular Sciences, Coronary Care Unit and Laboratory of Clinical and Experimental Cardiology, Laboratory of Experimental Cardiology for Cell and Molecular Therapy, Division of Clinical Immunology, Immunohematology, and Transfusion Service, Center for the Study and Cure of Myelofibrosis, Biotechnology Research Laboratories, and Division of Obstetrics and Gynecology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; Department of Molecular Medicine, Unit of Cardiology, University of Pavia, Pavia, Italy; Laboratory of Cardiovascular Genetics, IRCCS Istituto Auxologico Italiano, Milan, Italy; Department of Cardiology, University Medical Center Groningen, Groningen, The Netherlands; Department of Medicine, University of Cape Town, Cape Town, South Africa
| | - Lennaert Kleijn
- Department of Cardiothoracic and Vascular Sciences, Coronary Care Unit and Laboratory of Clinical and Experimental Cardiology, Laboratory of Experimental Cardiology for Cell and Molecular Therapy, Division of Clinical Immunology, Immunohematology, and Transfusion Service, Center for the Study and Cure of Myelofibrosis, Biotechnology Research Laboratories, and Division of Obstetrics and Gynecology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; Department of Molecular Medicine, Unit of Cardiology, University of Pavia, Pavia, Italy; Laboratory of Cardiovascular Genetics, IRCCS Istituto Auxologico Italiano, Milan, Italy; Department of Cardiology, University Medical Center Groningen, Groningen, The Netherlands; Department of Medicine, University of Cape Town, Cape Town, South Africa
| | - Rudolf A de Boer
- Department of Cardiothoracic and Vascular Sciences, Coronary Care Unit and Laboratory of Clinical and Experimental Cardiology, Laboratory of Experimental Cardiology for Cell and Molecular Therapy, Division of Clinical Immunology, Immunohematology, and Transfusion Service, Center for the Study and Cure of Myelofibrosis, Biotechnology Research Laboratories, and Division of Obstetrics and Gynecology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; Department of Molecular Medicine, Unit of Cardiology, University of Pavia, Pavia, Italy; Laboratory of Cardiovascular Genetics, IRCCS Istituto Auxologico Italiano, Milan, Italy; Department of Cardiology, University Medical Center Groningen, Groningen, The Netherlands; Department of Medicine, University of Cape Town, Cape Town, South Africa
| | - Gianluca Viarengo
- Department of Cardiothoracic and Vascular Sciences, Coronary Care Unit and Laboratory of Clinical and Experimental Cardiology, Laboratory of Experimental Cardiology for Cell and Molecular Therapy, Division of Clinical Immunology, Immunohematology, and Transfusion Service, Center for the Study and Cure of Myelofibrosis, Biotechnology Research Laboratories, and Division of Obstetrics and Gynecology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; Department of Molecular Medicine, Unit of Cardiology, University of Pavia, Pavia, Italy; Laboratory of Cardiovascular Genetics, IRCCS Istituto Auxologico Italiano, Milan, Italy; Department of Cardiology, University Medical Center Groningen, Groningen, The Netherlands; Department of Medicine, University of Cape Town, Cape Town, South Africa
| | - Vittorio Rosti
- Department of Cardiothoracic and Vascular Sciences, Coronary Care Unit and Laboratory of Clinical and Experimental Cardiology, Laboratory of Experimental Cardiology for Cell and Molecular Therapy, Division of Clinical Immunology, Immunohematology, and Transfusion Service, Center for the Study and Cure of Myelofibrosis, Biotechnology Research Laboratories, and Division of Obstetrics and Gynecology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; Department of Molecular Medicine, Unit of Cardiology, University of Pavia, Pavia, Italy; Laboratory of Cardiovascular Genetics, IRCCS Istituto Auxologico Italiano, Milan, Italy; Department of Cardiology, University Medical Center Groningen, Groningen, The Netherlands; Department of Medicine, University of Cape Town, Cape Town, South Africa
| | - Arsenio Spinillo
- Department of Cardiothoracic and Vascular Sciences, Coronary Care Unit and Laboratory of Clinical and Experimental Cardiology, Laboratory of Experimental Cardiology for Cell and Molecular Therapy, Division of Clinical Immunology, Immunohematology, and Transfusion Service, Center for the Study and Cure of Myelofibrosis, Biotechnology Research Laboratories, and Division of Obstetrics and Gynecology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; Department of Molecular Medicine, Unit of Cardiology, University of Pavia, Pavia, Italy; Laboratory of Cardiovascular Genetics, IRCCS Istituto Auxologico Italiano, Milan, Italy; Department of Cardiology, University Medical Center Groningen, Groningen, The Netherlands; Department of Medicine, University of Cape Town, Cape Town, South Africa
| | - Marianna Roccio
- Department of Cardiothoracic and Vascular Sciences, Coronary Care Unit and Laboratory of Clinical and Experimental Cardiology, Laboratory of Experimental Cardiology for Cell and Molecular Therapy, Division of Clinical Immunology, Immunohematology, and Transfusion Service, Center for the Study and Cure of Myelofibrosis, Biotechnology Research Laboratories, and Division of Obstetrics and Gynecology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; Department of Molecular Medicine, Unit of Cardiology, University of Pavia, Pavia, Italy; Laboratory of Cardiovascular Genetics, IRCCS Istituto Auxologico Italiano, Milan, Italy; Department of Cardiology, University Medical Center Groningen, Groningen, The Netherlands; Department of Medicine, University of Cape Town, Cape Town, South Africa
| | - Massimiliano Gnecchi
- Department of Cardiothoracic and Vascular Sciences, Coronary Care Unit and Laboratory of Clinical and Experimental Cardiology, Laboratory of Experimental Cardiology for Cell and Molecular Therapy, Division of Clinical Immunology, Immunohematology, and Transfusion Service, Center for the Study and Cure of Myelofibrosis, Biotechnology Research Laboratories, and Division of Obstetrics and Gynecology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; Department of Molecular Medicine, Unit of Cardiology, University of Pavia, Pavia, Italy; Laboratory of Cardiovascular Genetics, IRCCS Istituto Auxologico Italiano, Milan, Italy; Department of Cardiology, University Medical Center Groningen, Groningen, The Netherlands; Department of Medicine, University of Cape Town, Cape Town, South Africa
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Crisostomo V, Casado JG, Baez-Diaz C, Blazquez R, Sanchez-Margallo FM. Allogeneic cardiac stem cell administration for acute myocardial infarction. Expert Rev Cardiovasc Ther 2015; 13:285-99. [DOI: 10.1586/14779072.2015.1011621] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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Fatkhudinov T, Bolshakova G, Arutyunyan I, Elchaninov A, Makarov A, Kananykhina E, Khokhlova O, Murashev A, Glinkina V, Goldshtein D, Sukhikh G. Bone marrow-derived multipotent stromal cells promote myocardial fibrosis and reverse remodeling of the left ventricle. Stem Cells Int 2015; 2015:746873. [PMID: 25685158 PMCID: PMC4320796 DOI: 10.1155/2015/746873] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2014] [Revised: 12/28/2014] [Accepted: 12/28/2014] [Indexed: 02/07/2023] Open
Abstract
Cell therapy is increasingly recognized as a beneficial practice in various cardiac conditions, but its fundamentals remain largely unclear. The fates of transplanted multipotent stromal cells in postinfarction cardiac microenvironments are particularly understudied. To address this issue, labeled multipotent stromal cells were infused into rat myocardium at day 30 after myocardial infarction, against the background of postinfarction cardiosclerosis. Therapeutic effects of the transplantation were assessed by an exercise tolerance test. Histological examination at 14 or 30 days after the transplantation was conducted by means of immunostaining and quantitative image analysis. An improvement in the functional status of the cardiovascular system was observed after both the autologous and the allogeneic transplantations. Location of the label-positive cells within the heart was restricted to the affected part of myocardium. The transplanted cells could give rise to fibroblasts or myofibroblasts but not to cardiac myocytes or blood vessel cells. Both types of transplantation positively influenced scarring processes, and no expansion of fibrosis to border myocardium was observed. Left ventricular wall thickening associated with reduced dilatation index was promoted by transplantation of the autologous cells. According to the results, multipotent stromal cell transplantation prevents adverse remodeling and stimulates left ventricular reverse remodeling.
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Affiliation(s)
- Timur Fatkhudinov
- Research Center for Obstetrics, Gynecology and Perinatology of Ministry of Healthcare of the Russian Federation, 4 Oparina Street, Moscow 117997, Russia
- Scientific Research Institute of Human Morphology, Russian Academy of Medical Sciences, 3 Tsurupa Street, Moscow 117418, Russia
- Pirogov Russian National Research Medical University, Ministry of Healthcare of the Russian Federation, 1 Ostrovitianov Street, Moscow 117997, Russia
| | - Galina Bolshakova
- Research Center for Obstetrics, Gynecology and Perinatology of Ministry of Healthcare of the Russian Federation, 4 Oparina Street, Moscow 117997, Russia
| | - Irina Arutyunyan
- Research Center for Obstetrics, Gynecology and Perinatology of Ministry of Healthcare of the Russian Federation, 4 Oparina Street, Moscow 117997, Russia
- Scientific Research Institute of Human Morphology, Russian Academy of Medical Sciences, 3 Tsurupa Street, Moscow 117418, Russia
| | - Andrey Elchaninov
- Research Center for Obstetrics, Gynecology and Perinatology of Ministry of Healthcare of the Russian Federation, 4 Oparina Street, Moscow 117997, Russia
- Scientific Research Institute of Human Morphology, Russian Academy of Medical Sciences, 3 Tsurupa Street, Moscow 117418, Russia
- Pirogov Russian National Research Medical University, Ministry of Healthcare of the Russian Federation, 1 Ostrovitianov Street, Moscow 117997, Russia
| | - Andrey Makarov
- Research Center for Obstetrics, Gynecology and Perinatology of Ministry of Healthcare of the Russian Federation, 4 Oparina Street, Moscow 117997, Russia
- Scientific Research Institute of Human Morphology, Russian Academy of Medical Sciences, 3 Tsurupa Street, Moscow 117418, Russia
| | - Evgeniya Kananykhina
- Research Center for Obstetrics, Gynecology and Perinatology of Ministry of Healthcare of the Russian Federation, 4 Oparina Street, Moscow 117997, Russia
- Scientific Research Institute of Human Morphology, Russian Academy of Medical Sciences, 3 Tsurupa Street, Moscow 117418, Russia
| | - Oksana Khokhlova
- Biological Testing Laboratory, Branch of Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 6 Nauki Avenue, Pushchino 142290, Russia
| | - Arkady Murashev
- Biological Testing Laboratory, Branch of Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 6 Nauki Avenue, Pushchino 142290, Russia
| | - Valeria Glinkina
- Pirogov Russian National Research Medical University, Ministry of Healthcare of the Russian Federation, 1 Ostrovitianov Street, Moscow 117997, Russia
| | - Dmitry Goldshtein
- Research Centre of Medical Genetics of the Russian Academy of Medical Sciences, 1 Moskvorechie Street, Moscow 115478, Russia
| | - Gennady Sukhikh
- Research Center for Obstetrics, Gynecology and Perinatology of Ministry of Healthcare of the Russian Federation, 4 Oparina Street, Moscow 117997, Russia
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Lalit PA, Hei DJ, Raval AN, Kamp TJ. Induced pluripotent stem cells for post-myocardial infarction repair: remarkable opportunities and challenges. Circ Res 2014; 114:1328-45. [PMID: 24723658 DOI: 10.1161/circresaha.114.300556] [Citation(s) in RCA: 99] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Coronary artery disease with associated myocardial infarction continues to be a major cause of death and morbidity around the world, despite significant advances in therapy. Patients who have large myocardial infarctions are at highest risk for progressive heart failure and death, and cell-based therapies offer new hope for these patients. A recently discovered cell source for cardiac repair has emerged as a result of a breakthrough reprogramming somatic cells to induced pluripotent stem cells (iPSCs). The iPSCs can proliferate indefinitely in culture and can differentiate into cardiac lineages, including cardiomyocytes, smooth muscle cells, endothelial cells, and cardiac progenitors. Thus, large quantities of desired cell products can be generated without being limited by cellular senescence. The iPSCs can be obtained from patients to allow autologous therapy or, alternatively, banks of human leukocyte antigen diverse iPSCs are possible for allogeneic therapy. Preclinical animal studies using a variety of cell preparations generated from iPSCs have shown evidence of cardiac repair. Methodology for the production of clinical grade products from human iPSCs is in place. Ongoing studies for the safety of various iPSC preparations with regard to the risk of tumor formation, immune rejection, induction of arrhythmias, and formation of stable cardiac grafts are needed as the field advances toward the first-in-man trials of iPSCs after myocardial infarction.
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Affiliation(s)
- Pratik A Lalit
- From the Department of Medicine (P.A.L., A.N.R., T.J.K.), Molecular and Cellular Pharmacology Program (P.A.L., T.J.K.), and Stem Cell and Regenerative Medicine Center (P.A.L., D.J.H., A.N.R., T.J.K.), Waisman Biomanufacturing at University of Wisconsin, Madison (D.J.H.)
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Kim H, Han JW, Lee JY, Choi YJ, Sohn YD, Song M, Yoon YS. Diabetic Mesenchymal Stem Cells Are Ineffective for Improving Limb Ischemia Due to Their Impaired Angiogenic Capability. Cell Transplant 2014; 24:1571-84. [PMID: 25008576 DOI: 10.3727/096368914x682792] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
The purpose of this study was to investigate the effects of diabetes on mesenchymal stem cells (MSCs) in terms of their angiogenic and therapeutic potential for repairing tissue ischemia. We culture-isolated MSCs from streptozotocin-induced diabetic rats (D-MSCs) and compared their proliferation, differentiation, and angiogenic effects with those from normal rats (N-MSCs). The angiogenic effects of MSCs were evaluated by real-time PCR, in vitro tube formation assay, and transplantation of the MSCs into a hindlimb ischemia model followed by laser Doppler perfusion imaging. The number of MSCs derived from diabetic rats was smaller, and their proliferation rate was slower than N-MSCs. Upon induction of differentiation, the osteogenic and angiogenic differentiation of D-MSCs were aberrant compared to N-MSCs. The expression of angiogenic factors was lower in D-MSCs than N-MSCs. D-MSCs cocultured with endothelial cells resulted in decreased tube formation compared to N-MSCs. D-MSCs were ineffective to improve hindlimb ischemia and showed lower capillary density and angiogenic gene expression in ischemic limbs than N-MSCs. D-MSCs have defective proliferation and angiogenic activities and are ineffective for repairing hindlimb ischemia. Newer measures are needed before MSCs can be employed as a source for autologous cell therapy.
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Affiliation(s)
- Hyongbum Kim
- Department of Medicine, Division of Cardiology, Emory University School of Medicine, Atlanta, GA, USA
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Wang X, Li Q, Hu Q, Suntharalingam P, From AHL, Zhang J. Intra-myocardial injection of both growth factors and heart derived Sca-1+/CD31- cells attenuates post-MI LV remodeling more than does cell transplantation alone: neither intervention enhances functionally significant cardiomyocyte regeneration. PLoS One 2014; 9:e95247. [PMID: 24919180 PMCID: PMC4053321 DOI: 10.1371/journal.pone.0095247] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2014] [Accepted: 03/24/2014] [Indexed: 01/24/2023] Open
Abstract
Insulin-like growth factor 1 (IGF-1) and hepatocyte growth factor (HGF) are two potent cell survival and regenerative factors in response to myocardial injury (MI). We hypothesized that simultaneous delivery of IGF+HGF combined with Sca-1+/CD31− cells would improve the outcome of transplantation therapy in response to the altered hostile microenvironment post MI. One million adenovirus nuclear LacZ-labeled Sca-1+/CD31− cells were injected into the peri-infarction area after left anterior descending coronary artery (LAD) ligation in mice. Recombinant mouse IGF-1+HGF was added to the cell suspension prior to the injection. The left ventricular (LV) function was assessed by echocardiography 4 weeks after the transplantation. The cell engraftment, differentiation and cardiomyocyte regeneration were evaluated by histological analysis. Sca-1+/CD31− cells formed viable grafts and improved LV ejection fraction (EF) (Control, 54.5+/−2.4; MI, 17.6+/−3.1; Cell, 28.2+/−4.2, n = 9, P<0.01). IGF+HGF significantly enhanced the benefits of cell transplantation as evidenced by increased EF (38.8+/−2.2; n = 9, P<0.01) and attenuated adverse structural remodeling. Furthermore, IGF+HGF supplementation increased the cell engraftment rate, promoted the transplanted cell survival, enhanced angiogenesis, and minimally stimulated endogenous cardiomyocyte regeneration in vivo. The in vitro experiments showed that IGF+HGF treatment stimulated Sca-1+/CD31− cell proliferation and inhibited serum free medium induced apoptosis. Supperarray profiling of Sca-1+/CD31− cells revealed that Sca-1+/CD31− cells highly expressed various trophic factor mRNAs and IGF+HGF treatment altered the mRNAs expression patterns of these cells. These data indicate that IGF-1+HGF could serve as an adjuvant to cell transplantation for myocardial repair by stimulating donor cell and endogenous cardiac stem cell survival, regeneration and promoting angiogenesis.
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Affiliation(s)
- Xiaohong Wang
- Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, United States of America
- * E-mail: (XW); (JZ)
| | - Qinglu Li
- Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, United States of America
| | - Qingsong Hu
- Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, United States of America
| | - Piradeep Suntharalingam
- Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, United States of America
| | - Arthur H. L. From
- Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, United States of America
| | - Jianyi Zhang
- Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, United States of America
- * E-mail: (XW); (JZ)
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Influence of Egr-1 in cardiac tissue-derived mesenchymal stem cells in response to glucose variations. BIOMED RESEARCH INTERNATIONAL 2014; 2014:254793. [PMID: 24967343 PMCID: PMC4054710 DOI: 10.1155/2014/254793] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/24/2014] [Accepted: 05/06/2014] [Indexed: 01/03/2023]
Abstract
Mesenchymal stem cells (MSCs) represent a promising cell population for cell therapy and regenerative medicine applications. However, how variations in glucose are perceived by MSC pool is still unclear. Since, glucose metabolism is cell type and tissue dependent, this must be considered when MSCs are derived from alternative sources such as the heart. The zinc finger transcription factor Egr-1 is an important early response gene, likely to play a key role in the glucose-induced response. Our aim was to investigate how short-term changes in in vitro glucose concentrations affect multipotent cardiac tissue-derived MSCs (cMSCs) in a mouse model of Egr-1 KO (Egr-1−/−). Results showed that loss of Egr-1 does not significantly influence cMSC proliferation. In contrast, responses to glucose variations were observed in wt but not in Egr-1−/− cMSCs by clonogenic assay. Phenotype analysis by RT-PCR showed that cMSCs Egr-1−/− lost the ability to regulate the glucose transporters GLUT-1 and GLUT-4 and, as expected, the Egr-1 target genes VEGF, TGFβ-1, and p300. Acetylated protein levels of H3 histone were impaired in Egr-1−/− compared to wt cMSCs. We propose that Egr-1 acts as immediate glucose biological sensor in cMSCs after a short period of stimuli, likely inducing epigenetic modifications.
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Injection of mesenchymal stromal cells into a mechanically stimulated in vitro model of cardiac fibrosis has paracrine effects on resident fibroblasts. Cytotherapy 2014; 16:906-14. [PMID: 24713331 DOI: 10.1016/j.jcyt.2014.01.416] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2013] [Revised: 12/18/2013] [Accepted: 01/31/2014] [Indexed: 12/19/2022]
Abstract
BACKGROUND AIMS Myocardial infarction results in the formation of scar tissue populated by myofibroblasts, a phenotype characterized by increased contractility and matrix deposition. Mesenchymal stromal cells (MSC) delivered to the myocardium can attenuate scar growth and restore cardiac function, though the mechanism is unclear. METHODS This study describes a simple yet robust three-dimensional (3D) in vitro co-culture model to examine the paracrine effects of implanted MSC on resident myofibroblasts in a controlled biochemical and mechanical environment. The fibrosis model consisted of fibroblasts embedded in a 3D collagen gel cultured under defined oxygen tensions and exposed to either cyclic strain or interstitial fluid flow. MSC were injected into this model, and the effect on fibroblast phenotype was evaluated 48 h after cell injection. RESULTS Analysis of gene and protein expression of the fibroblasts indicated that injection of MSC attenuated the myofibroblast transition in response to reduced oxygen and mechanical stress. Assessment of vascular endothelial growth factor and insulin-like growth factor-1 levels demonstrated that their release by fibroblasts was markedly upregulated in hypoxic conditions but attenuated by strain or fluid flow. In fibroblast-MSC co-cultures, vascular endothelial growth factor levels were increased by hypoxia but not affected by mechanical stimuli, whereas insulin-like growth factor-1 levels were generally low and not affected by experimental conditions. CONCLUSIONS This study demonstrates how a 3D in vitro model of the cardiac scar can be used to examine paracrine effects of MSC on the phenotype of resident fibroblasts and therefore illuminates the role of injected progenitor cells on the progression of cardiac fibrosis.
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Richardson JD, Psaltis PJ, Frost L, Paton S, Carbone A, Bertaso AG, Nelson AJ, Wong DT, Worthley MI, Gronthos S, Zannettino AC, Worthley SG. Incremental benefits of repeated mesenchymal stromal cell administration compared with solitary intervention after myocardial infarction. Cytotherapy 2014; 16:460-70. [DOI: 10.1016/j.jcyt.2013.07.016] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2013] [Revised: 07/16/2013] [Accepted: 07/29/2013] [Indexed: 12/11/2022]
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