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Pezhouman A, Nguyen NB, Kay M, Kanjilal B, Noshadi I, Ardehali R. Cardiac regeneration - Past advancements, current challenges, and future directions. J Mol Cell Cardiol 2023; 182:75-85. [PMID: 37482238 DOI: 10.1016/j.yjmcc.2023.07.009] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Revised: 07/13/2023] [Accepted: 07/18/2023] [Indexed: 07/25/2023]
Abstract
Cardiovascular disease is the leading cause of mortality and morbidity worldwide. Despite improvements in the standard of care for patients with heart diseases, including innovation in pharmacotherapy and surgical interventions, none have yet been proven effective to prevent the progression to heart failure. Cardiac transplantation is the last resort for patients with severe heart failure, but donor shortages remain a roadblock. Cardiac regenerative strategies include cell-based therapeutics, gene therapy, direct reprogramming of non-cardiac cells, acellular biologics, and tissue engineering methods to restore damaged hearts. Significant advancements have been made over the past several decades within each of these fields. This review focuses on the advancements of: 1) cell-based cardiac regenerative therapies, 2) the use of noncoding RNA to induce endogenous cell proliferation, and 3) application of bioengineering methods to promote retention and integration of engrafted cells. Different cell sources have been investigated, including adult stem cells derived from bone marrow and adipose cells, cardiosphere-derived cells, skeletal myoblasts, and pluripotent stem cells. In addition to cell-based transplantation approaches, there have been accumulating interest over the past decade in inducing endogenous CM proliferation for heart regeneration, particularly with the use of noncoding RNAs such as miRNAs and lncRNAs. Bioengineering applications have focused on combining cell-transplantation approaches with fabrication of a porous, vascularized scaffold using biomaterials and advanced bio-fabrication techniques that may offer enhanced retention of transplanted cells, with the hope that these cells would better engraft with host tissue to improve cardiac function. This review summarizes the present status and future challenges of cardiac regenerative therapies.
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Affiliation(s)
- Arash Pezhouman
- Baylor College of Medicine, Department of Medicine, Division of Cardiology, Houston, Texas 77030, United States; Texas Heart Institute, Houston, Texas 77030, United States
| | - Ngoc B Nguyen
- Baylor College of Medicine, Department of Internal Medicine, Houston, Texas 77030, United States
| | - Maryam Kay
- Department of Medicine, Division of Cardiology, University of California, Los Angeles, CA 90095, United States
| | - Baishali Kanjilal
- Department of Bioengineering, University of California, Riverside, Riverside, CA 92521, United States
| | - Iman Noshadi
- Department of Bioengineering, University of California, Riverside, Riverside, CA 92521, United States
| | - Reza Ardehali
- Baylor College of Medicine, Department of Medicine, Division of Cardiology, Houston, Texas 77030, United States; Texas Heart Institute, Houston, Texas 77030, United States.
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Clavellina D, Balkan W, Hare JM. Stem cell therapy for acute myocardial infarction: Mesenchymal Stem Cells and induced Pluripotent Stem Cells. Expert Opin Biol Ther 2023; 23:951-967. [PMID: 37542462 PMCID: PMC10837765 DOI: 10.1080/14712598.2023.2245329] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Revised: 08/01/2023] [Accepted: 08/03/2023] [Indexed: 08/07/2023]
Abstract
INTRODUCTION Acute myocardial infarction (AMI) remains a leading cause of death in the United States. The limited capacity of cardiomyocytes to regenerate and the restricted contractility of scar tissue after AMI are not addressed by current pharmacologic interventions. Mesenchymal stem/stromal cells (MSCs) have emerged as a promising therapeutic approach due to their low antigenicity, ease of harvesting, and efficacy and safety in preclinical and clinical studies, despite their low survival and engraftment rates. Other stem cell types, such as induced pluripotent stem cells (iPSCs) also show promise, and optimizing cardiac repair requires integrating emerging technologies and strategies. AREAS COVERED This review offers insights into advancing cell-based therapies for AMI, emphasizing meticulously planned trials with a standardized definition of AMI, for a bench-to-bedside approach. We critically evaluate fundamental studies and clinical trials to provide a comprehensive overview of the advances, limitations and prospects for cell-based therapy in AMI. EXPERT OPINION MSCs continue to show potential promise for treating AMI and its sequelae, but addressing their low survival and engraftment rates is crucial for clinical success. Integrating emerging technologies such as pluripotent stem cells and conducting well-designed trials will harness the full potential of cell-based therapy in AMI management. Collaborative efforts are vital to developing effective stem cell therapies for AMI patients.
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Affiliation(s)
- Diana Clavellina
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Wayne Balkan
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA
- Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Joshua M Hare
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA
- Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA
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Yu JK, Liang JA, Franceschi WH, Huang Q, Pashakhanloo F, Sung E, Boyle PM, Trayanova NA. Assessment of arrhythmia mechanism and burden of the infarcted ventricles following remuscularization with pluripotent stem cell-derived cardiomyocyte patches using patient-derived models. Cardiovasc Res 2022; 118:1247-1261. [PMID: 33881518 PMCID: PMC8953447 DOI: 10.1093/cvr/cvab140] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 01/14/2021] [Accepted: 04/19/2021] [Indexed: 12/24/2022] Open
Abstract
AIMS Direct remuscularization with pluripotent stem cell-derived cardiomyocytes (PSC-CMs) seeks to address the onset of heart failure post-myocardial infarction (MI) by treating the persistent muscle deficiency that underlies it. However, direct remuscularization with PSC-CMs could potentially be arrhythmogenic. We investigated two possible mechanisms of arrhythmogenesis-focal vs. re-entrant-arising from direct remuscularization with PSC-CM patches in two personalized, human ventricular computer models of post-MI. Moreover, we developed a principled approach for evaluating arrhythmogenicity of direct remuscularization that factors in the VT propensity of the patient-specific post-MI fibrotic substrate and use it to investigate different conditions of patch remuscularization. METHODS AND RESULTS Two personalized, human ventricular models of post-MI (P1 and P2) were constructed from late gadolinium enhanced (LGE)-magnetic resonance images (MRIs). In each model, remuscularization with PSC-CM patches was simulated under different treatment conditions that included patch engraftment, patch myofibril orientation, remuscularization site, patch size (thickness and diameter), and patch maturation. To determine arrhythmogenicity of treatment conditions, VT burden of heart models was quantified prior to and after simulated remuscularization and compared. VT burden was quantified based on inducibility (i.e. weighted sum of pacing sites that induced) and severity (i.e. the number of distinct VT morphologies induced). Prior to remuscularization, VT burden was significant in P1 (0.275) and not in P2 (0.0, not VT inducible). We highlight that re-entrant VT mechanisms would dominate over focal mechanisms; spontaneous beats emerging from PSC-CM grafts were always a fraction of resting sinus rate. Moreover, incomplete patch engraftment can be particularly arrhythmogenic, giving rise to particularly aberrant electrical activation and conduction slowing across the PSC-CM patches along with elevated VT burden when compared with complete engraftment. Under conditions of complete patch engraftment, remuscularization was almost always arrhythmogenic in P2 but certain treatment conditions could be anti-arrhythmogenic in P1. Moreover, the remuscularization site was the most important factor affecting VT burden in both P1 and P2. Complete maturation of PSC-CM patches, both ionically and electrotonically, at the appropriate site could completely alleviate VT burden. CONCLUSION We identified that re-entrant VT would be the primary VT mechanism in patch remuscularization. To evaluate the arrhythmogenicity of remuscularization, we developed a principled approach that factors in the propensity of the patient-specific fibrotic substrate for VT. We showed that arrhythmogenicity is sensitive to the patient-specific fibrotic substrate and remuscularization site. We demonstrate that targeted remuscularization can be safe in the appropriate individual and holds the potential to non-destructively eliminate VT post-MI in addition to addressing muscle deficiency underlying heart failure progression.
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Affiliation(s)
- Joseph K Yu
- Institute for Computational Medicine, Johns Hopkins University, 3400 N Charles Street, 208 Hackerman, Baltimore, MD 21218, USA
- Department of Biomedical Engineering, Johns Hopkins University, 3400 N Charles Street, 208 Hackerman, Baltimore, MD 21218, USA
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Alliance for Cardiovascular Diagnostic and Treatment Innovation (ADVANCE), Johns Hopkins University, 3400 N Charles Street, 216 Hackerman, Baltimore, MD, USA
| | - Jialiu A Liang
- Institute for Computational Medicine, Johns Hopkins University, 3400 N Charles Street, 208 Hackerman, Baltimore, MD 21218, USA
- Department of Biomedical Engineering, Johns Hopkins University, 3400 N Charles Street, 208 Hackerman, Baltimore, MD 21218, USA
| | - William H Franceschi
- Institute for Computational Medicine, Johns Hopkins University, 3400 N Charles Street, 208 Hackerman, Baltimore, MD 21218, USA
- Department of Biomedical Engineering, Johns Hopkins University, 3400 N Charles Street, 208 Hackerman, Baltimore, MD 21218, USA
| | - Qinwen Huang
- Institute for Computational Medicine, Johns Hopkins University, 3400 N Charles Street, 208 Hackerman, Baltimore, MD 21218, USA
- Department of Biomedical Engineering, Johns Hopkins University, 3400 N Charles Street, 208 Hackerman, Baltimore, MD 21218, USA
| | - Farhad Pashakhanloo
- Department of Biomedical Engineering, Johns Hopkins University, 3400 N Charles Street, 208 Hackerman, Baltimore, MD 21218, USA
| | - Eric Sung
- Department of Biomedical Engineering, Johns Hopkins University, 3400 N Charles Street, 208 Hackerman, Baltimore, MD 21218, USA
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Alliance for Cardiovascular Diagnostic and Treatment Innovation (ADVANCE), Johns Hopkins University, 3400 N Charles Street, 216 Hackerman, Baltimore, MD, USA
| | - Patrick M Boyle
- Department of Biomedical Engineering, Johns Hopkins University, 3400 N Charles Street, 208 Hackerman, Baltimore, MD 21218, USA
- Department of Bioengineering, University of Washington, Seattle, WA, USA
- Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, USA
- Center for Cardiovascular Biology, University of Washington, Seattle, WA, USA
| | - Natalia A Trayanova
- Department of Biomedical Engineering, Johns Hopkins University, 3400 N Charles Street, 208 Hackerman, Baltimore, MD 21218, USA
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Alliance for Cardiovascular Diagnostic and Treatment Innovation (ADVANCE), Johns Hopkins University, 3400 N Charles Street, 216 Hackerman, Baltimore, MD, USA
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Kasai-Brunswick TH, Carvalho AB, Campos de Carvalho AC. Stem cell therapies in cardiac diseases: Current status and future possibilities. World J Stem Cells 2021; 13:1231-1247. [PMID: 34630860 PMCID: PMC8474720 DOI: 10.4252/wjsc.v13.i9.1231] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 07/26/2021] [Accepted: 08/10/2021] [Indexed: 02/06/2023] Open
Abstract
Cardiovascular diseases represent the world's leading cause of death. In this heterogeneous group of diseases, ischemic cardiomyopathies are the most devastating and prevalent, estimated to cause 17.9 million deaths per year. Despite all biomedical efforts, there are no effective treatments that can replace the myocytes lost during an ischemic event or progression of the disease to heart failure. In this context, cell therapy is an emerging therapeutic alternative to treat cardiovascular diseases by cell administration, aimed at cardiac regeneration and repair. In this review, we will cover more than 30 years of cell therapy in cardiology, presenting the main milestones and drawbacks in the field and signaling future challenges and perspectives. The outcomes of cardiac cell therapies are discussed in three distinct aspects: The search for remuscularization by replacement of lost cells by exogenous adult cells, the endogenous stem cell era, which pursued the isolation of a progenitor with the ability to induce heart repair, and the utilization of pluripotent stem cells as a rich and reliable source of cardiomyocytes. Acellular therapies using cell derivatives, such as microvesicles and exosomes, are presented as a promising cell-free therapeutic alternative.
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Affiliation(s)
- Tais Hanae Kasai-Brunswick
- National Center of Structural Biology and Bioimaging, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
- National Institute of Science and Technology in Regenerative Medicine, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
| | - Adriana Bastos Carvalho
- National Institute of Science and Technology in Regenerative Medicine, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
- Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
| | - Antonio Carlos Campos de Carvalho
- National Center of Structural Biology and Bioimaging, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
- National Institute of Science and Technology in Regenerative Medicine, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
- Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil.
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Francisco JC, Uemura L, Simeoni RB, da Cunha RC, Mogharbel BF, Simeoni PRB, Naves G, Napimoga MH, Noronha L, Carvalho KAT, Moreira LFP, Guarita-Souza LC. Acellular Human Amniotic Membrane Scaffold with 15d-PGJ 2 Nanoparticles in Postinfarct Rat Model. Tissue Eng Part A 2020; 26:1128-1137. [PMID: 32486914 DOI: 10.1089/ten.tea.2019.0340] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
The difficulty in the regeneration of cardiomyocytes after myocardial infarction is a major cause of heart failure. Together, the amniotic membrane and 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) can help in the recovery of cardiomyocyte, as they present many growth factors and anti-inflammatory effect, respectively. The objective of this study is to compare the efficacy of Human Decellularized Amniotic Membrane Scaffold (AHAS) loaded with 15d-PGJ2 in improving ventricular function in a rat model of postinfarct ventricular dysfunction. Myocardial infarction was induced in 24 rats by left coronary occlusion. After a week, the animals were subjected to echocardiography for evaluation of left ventricle ejection fraction (LVEF), left ventricle end diastolic volume (LVEDV), and left ventricle end systolic volume (LVESV). Animals with ejection fraction <40% were included in the study and were randomized into three groups: control (n = 8), AHAS (n = 8) and AHAS +15d-PGJ2 (n = 8). In the AHAS group only the membrane was implanted, whereas in the AHAS +15d-PGJ2 the membrane +15d-PGJ2 was implanted on myocardial infarction. Echocardiographic evaluation was performed after 1 month. For histological analysis, heart tissue was stained with Gomori trichome, Sirius Red, the antibody against CD31 and connexin 43 (Cx43). There were no significant differences in the baseline LVEF, LVEDV, and LVESV in all groups. After 1 month, ejection fraction decreased in the control group but increased in the AHAS group and in the AHAS +15d-PGJ2 group in comparison with the control group. The LVEDV and LVESV in the AHAS and AHAS +15d-PGJ2 groups decreased compared with the control group, featuring a ventricular antiremodeling effect. Histopathology of the infarcted area identified the reduction of infarct size and collagen type 1 in the AHAS and AHAS +15d-PGJ2 groups. New blood vessels and cardiomyocytes have been identified in an infarcted area by CD31 and Cx43. AHAS +15d-PGJ2 provided an increase in the ejection fraction and prevented ventricular dilation in this postinfarction ventricular dysfunction model. Impact Statement Our study demonstrated reduction of myocardial fibrosis, proliferation of cardiomyocytes and increase in ejection fraction in rats after experimental acellular amniotic membrane scaffold (AHAS) carrying nanoparticles of 15d-PGJ2 scaffold engraftment in infarcted myocardium. AHAS grafts facilitated colonization of fibrotic myocardium regions with new contractile cells, in addition to preventing reduction of left ventricle wall thickness. This contribution is theoretically and practically relevant as current literature describes experimental studies performed on cardiac ischemic models which present conflicting results concerning cell types used in a research model.
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Affiliation(s)
- Julio Cesar Francisco
- Laboratory of Cardiovascular Surgery and Pathophysiology of Circulation, Department of Cardiopneumology, Heart Institute (Incor), Sao Paulo University Medical School, São Paulo, Brazil.,Positivo University (UP), R. Professor Pedro Viriato Parigot de Souza, Curitiba, Brazil
| | - Laercio Uemura
- Experimental Laboratory of Institute of Biological and Health Sciences of Pontifical Catholic University of Paraná (PUCPR), Curitiba, Brazil
| | - Rossana Baggio Simeoni
- Experimental Laboratory of Institute of Biological and Health Sciences of Pontifical Catholic University of Paraná (PUCPR), Curitiba, Brazil.,The Paraná Institute of Technology-TECPAR, Curitiba, Brazil
| | | | - Bassam Felipe Mogharbel
- Cell Therapy and Biotechnology in Regenerative Medicine Department, The Pelé Pequeno Príncipe Institute, Child and Adolescent Health Research and Pequeno Príncipe Faculty, Curitiba, Brazil. São Leopoldo Mandic Institute and Researcher Center, Campinas, Brazil
| | - Paulo Ricardo Baggio Simeoni
- Experimental Laboratory of Institute of Biological and Health Sciences of Pontifical Catholic University of Paraná (PUCPR), Curitiba, Brazil
| | - Guilherme Naves
- Experimental Laboratory of Institute of Biological and Health Sciences of Pontifical Catholic University of Paraná (PUCPR), Curitiba, Brazil
| | - Marcelo Henrique Napimoga
- Laboratory of Immunology and Molecular Biology, São Leopoldo Mandic Institute and Researcher Center, Campinas, Brazil
| | - Lucia Noronha
- Experimental Laboratory of Institute of Biological and Health Sciences of Pontifical Catholic University of Paraná (PUCPR), Curitiba, Brazil
| | - Katherine Athayde Teixeira Carvalho
- Cell Therapy and Biotechnology in Regenerative Medicine Department, The Pelé Pequeno Príncipe Institute, Child and Adolescent Health Research and Pequeno Príncipe Faculty, Curitiba, Brazil. São Leopoldo Mandic Institute and Researcher Center, Campinas, Brazil
| | - Luiz Felipe Pinho Moreira
- Laboratory of Cardiovascular Surgery and Pathophysiology of Circulation, Department of Cardiopneumology, Heart Institute (Incor), Sao Paulo University Medical School, São Paulo, Brazil
| | - Luiz Cesar Guarita-Souza
- Experimental Laboratory of Institute of Biological and Health Sciences of Pontifical Catholic University of Paraná (PUCPR), Curitiba, Brazil
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6
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Machado-Júnior PAB, Blume GG, Francisco JC, Guarita-Souza LC. Cell-Based Therapies for Myocardial Regeneration in Heart Failure: 20 Years of Debate. Braz J Cardiovasc Surg 2020; 35:VIII-XI. [PMID: 32864947 PMCID: PMC7454612 DOI: 10.21470/1678-9741-2020-0362] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Affiliation(s)
| | - Gustavo Gavazzoni Blume
- Post-Graduation program in Health Sciences, Pontifícia Universidade Católica do Paraná (PUCPR), Curitiba, PR, Brazil
| | | | - Luiz César Guarita-Souza
- Post-Graduation program in Health Sciences, Pontifícia Universidade Católica do Paraná (PUCPR), Curitiba, PR, Brazil
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7
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Zhang DY, Gao T, Xu RJ, Sun L, Zhang CF, Bai L, Chen W, Liu KY, Zhou Y, Jiao X, Zhang GH, Guo RL, Li JX, Gao Y, Jiao WJ, Tian H. SIRT3 Transfection of Aged Human Bone Marrow-Derived Mesenchymal Stem Cells Improves Cell Therapy-Mediated Myocardial Repair. Rejuvenation Res 2020; 23:453-464. [PMID: 32228121 DOI: 10.1089/rej.2019.2260] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
Sirtuin 3 (SIRT3) is a deacetylase important for antioxidant protection, cell longevity, and aging. We hypothesized that SIRT3 improve oxidative resistance of aged cells and improve cell therapy in aged patients. In vitro, the proliferation and oxidative resistance of human mesenchymal stem cells (hMSCs) significantly declined with age. The expression and activity of antioxidant enzymes, including catalase (CAT) and manganese superoxide dismutase (MnSOD), increased after transfection of SIRT3 in hMSCs from older donors (O-hMSCs). The protein level of Forkhead box O3a (FOXO3a) in nucleus increased after SIRT3 overexpression. The antioxidant capacity of O-hMSCs increased after SIRT3 overexpression. 3-Amino-1,2,4-triazole (3-AT, CAT inhibitor) or diethyldithiocarbamate (DETC, SOD inhibitor) that was used to inhibit CAT or SOD activity significantly blocked the antioxidant function of SIRT3. When two inhibitors were used together, the antioxidant function of SIRT3 almost disappeared. Following myocardial infarction and intramyocardial injections of O-hMSCs in rats in vivo, the survival rate of O-hMSCs increased by SIRT3 transfection. The cardiac function of rats was improved after SIRT3-overexpressed O-hMSC transplantation. The infarct size, collagen content, and expression levels of matrix metalloproteinase 2 (MMP2) and MMP9 decreased. Besides, the protein level of vascular endothelial growth factor A and vascular density increased after cell transplantation with SIRT3-modified O-hMSCs. These results indicate that damage resistance of hMSCs decline with age and SIRT3 might protect O-hMSCs against oxidative damage by activating CAT and MnSOD through transferring FOXO3a into nucleus. Meanwhile, the therapeutic effect of aged hMSC transplantation can be improved by SIRT3 overexpression.
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Affiliation(s)
- Dong-Yang Zhang
- Department of Thoracic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China.,Future Medical Laboratory, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Tong Gao
- Future Medical Laboratory, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.,Department of Cardiovascular Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Rong-Jian Xu
- Department of Thoracic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Lu Sun
- Future Medical Laboratory, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.,Department of Cardiovascular Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Chun-Feng Zhang
- Future Medical Laboratory, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.,Department of Cardiovascular Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Long Bai
- Future Medical Laboratory, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.,Department of Cardiovascular Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Wei Chen
- Future Medical Laboratory, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.,Department of Cardiovascular Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Kai-Yu Liu
- Future Medical Laboratory, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.,Department of Cardiovascular Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yang Zhou
- Future Medical Laboratory, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.,Department of Cardiovascular Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xuan Jiao
- Future Medical Laboratory, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.,Department of Cardiovascular Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Gui-Huan Zhang
- Future Medical Laboratory, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.,Department of Cardiovascular Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Rui-Lin Guo
- The Second Clinical College of Harbin Medical University, Harbin, China
| | - Jing-Xuan Li
- The Second Clinical College of Harbin Medical University, Harbin, China
| | - Ying Gao
- The Second Clinical College of Harbin Medical University, Harbin, China
| | - Wen-Jie Jiao
- Department of Thoracic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Hai Tian
- Future Medical Laboratory, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.,Department of Cardiovascular Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
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8
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Cell-Based Therapies for Cardiac Regeneration: A Comprehensive Review of Past and Ongoing Strategies. Int J Mol Sci 2018; 19:ijms19103194. [PMID: 30332812 PMCID: PMC6214096 DOI: 10.3390/ijms19103194] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2018] [Revised: 10/11/2018] [Accepted: 10/12/2018] [Indexed: 12/20/2022] Open
Abstract
Despite considerable improvements in the treatment of cardiovascular diseases, heart failure (HF) still represents one of the leading causes of death worldwide. Poor prognosis is mostly due to the limited regenerative capacity of the adult human heart, which ultimately leads to left ventricular dysfunction. As a consequence, heart transplantation is virtually the only alternative for many patients. Therefore, novel regenerative approaches are extremely needed, and several attempts have been performed to improve HF patients’ clinical conditions by promoting the replacement of the lost cardiomyocytes and by activating cardiac repair. In particular, cell-based therapies have been shown to possess a great potential for cardiac regeneration. Different cell types have been extensively tested in clinical trials, demonstrating consistent safety results. However, heterogeneous efficacy data have been reported, probably because precise end-points still need to be clearly defined. Moreover, the principal mechanism responsible for these beneficial effects seems to be the paracrine release of antiapoptotic and immunomodulatory molecules from the injected cells. This review covers past and state-of-the-art strategies in cell-based heart regeneration, highlighting the advantages, challenges, and limitations of each approach.
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Andalousi RBE, Daussin PA, Micallef JP, Roux C, Nougues J, Chammas M, Reyne Y, Bacou F. Changes in Mass and Performance in Rabbit Muscles after Muscle Damage with or without Transplantation of Primary Satellite Cells. Cell Transplant 2017; 11:169-180. [DOI: 10.3727/096020198389898] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Changes in morphology, metabolism, myosin heavy chain gene expression, and functional performances in damaged rabbit muscles with or without transplantation of primary satellite cells were investigated. For this purpose, we damaged bilaterally the fast muscle tibialis anterior (TA) with either 1.5 or 2.6 ml cardiotoxin 10–5 M injections. Primary cultures of satellite cells were autotransplanted unilaterally 5 days after muscle degeneration. Two months postoperation, the masses of damaged TAs, with or without transplantation, were significantly larger than those of the controls. Furthermore, damaged transplanted muscles weighed significantly more than damaged muscles only. The increase in muscle mass was essentially due to increased fiber size. These results were independent of the quantity of cardiotoxin injected into the muscles. Maximal forces were similar in control and 2.6 ml damaged TAs with or without satellite cell transfer. In contrast, 1.5 ml damaged TAs showed a significant decrease in maximal forces that reached the level of controls after transplantation of satellite cells. Fatigue resistance was similar in control and 1.5 ml damaged TAs independently of satellite cell transfer. Fatigue index was significantly higher in 2.6 ml damaged muscles with or without cell transplantation. These changes could be explained in part by muscle metabolism, which shifted towards oxidative activities, and by gene expression of myosin heavy chain isoforms, which presented an increase in type IIa and a decrease in type I and IIb in all damaged muscles with or without cell transfer. Under our experimental conditions, these results show that muscle damage rather than satellite cell transplantation changes muscle metabolism, myosin heavy chain isoform gene expression, and, to a lesser extent, muscle contractile properties. In contrast, muscle weight and fiber size are increased both by muscle damage and by satellite cell transfer.
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Affiliation(s)
| | - Paul-André Daussin
- UMR Différenciation cellulaire et Croissance, INRA, 2 Place Pierre Viala, 34060 Montpellier Cedex 1, France
- Service de Chirurgie Orthopédique 2 et Chirurgie de la Main, Hôpital Lapeyronie, CHU Montpellier, 34295 Montpellier Cedex 5, France
| | - Jean-Paul Micallef
- INSERM ADR 08, Parc Euromédecine, 99 rue Puech Villa, 34197 Montpellier Cedex 5, France
| | - Colette Roux
- Laboratoire de Biométrie, INRA, 2 Place Pierre Viala, 34060 Montpellier Cedex 1, France
| | - Jean Nougues
- UMR Différenciation cellulaire et Croissance, INRA, 2 Place Pierre Viala, 34060 Montpellier Cedex 1, France
| | - Michel Chammas
- Service de Chirurgie Orthopédique 2 et Chirurgie de la Main, Hôpital Lapeyronie, CHU Montpellier, 34295 Montpellier Cedex 5, France
| | - Yves Reyne
- UMR Différenciation cellulaire et Croissance, INRA, 2 Place Pierre Viala, 34060 Montpellier Cedex 1, France
| | - Francis Bacou
- UMR Différenciation cellulaire et Croissance, INRA, 2 Place Pierre Viala, 34060 Montpellier Cedex 1, France
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10
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Wang JF, Yang Y, Wang G, Min J, Sullivan MF, Ping P, Xiao YF, Morgan JP. Embryonic Stem Cells Attenuate Viral Myocarditis in Murine Model. Cell Transplant 2017. [DOI: 10.3727/000000002783985233] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
We used mice to test our hypothesis that in response to viral invasion, stem cells may migrate into the heart and attenuate the effect of viral myocarditis. Male BALB/c mice were divided into three groups: mouse embryonic stem (ES) cell control, encephalomyocarditis virus (EMCV), and EMCV + ES cells. After administration of ES cells via tail vein, mice were immediately inoculated with EMCV. Mice were sacrificed at different days after EMCV inoculation. Mortality was recorded. Inflammatory cell infiltration and necrosis (major pathological changes of viral myocarditis) were evaluated by hematoxylin-eosin staining. ES cell migration and differentiation were identified by immunofluorescence. The survival rate in the EMCV + ES cell group (80%) was significantly increased (p < 0.05) over the EMCV-alone group (64%). Also, the incidence of inflammatory cell infiltration and myocardial lesions was lower in the EMCV + ES cell mice. Furthermore, the result of green fluorescent protein (GFP) and a-actinin analysis indicated that ES cells migrated into the heart and differentiated into myocytes after virus inoculation. In conclusion, ES cells significantly increased the survival of viral myocarditis mice and also decreased the necrosis and infiltration of inflammatory cells. These results demonstrated the ability of stem cells to mitigate the effects of viral infection on the heart and illustrated their potential therapeutic application to other mammalian species, including humans.
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Affiliation(s)
- Ju-Feng Wang
- Cardiovascular Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215
| | - Yingke Yang
- Cardiovascular Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215
| | - Guangwu Wang
- Cardiology Division, Department of Medicine, University of Louisville, Kentucky, KY 40202
| | - Jiangyong Min
- Cardiovascular Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215
| | - Matthew F. Sullivan
- Cardiovascular Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215
| | - Peipei Ping
- Cardiology Division, Department of Medicine, University of Louisville, Kentucky, KY 40202
| | - Yong-Fu Xiao
- Cardiovascular Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215
| | - James P. Morgan
- Cardiovascular Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215
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11
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Huwer H, Winning J, Vollmar B, Welter C, Löhbach C, Menger MD, Schäfers HJ. Long-Term Cell Survival and Hemodynamic Improvements after Neonatal Cardiomyocyte and Satellite Cell Transplantation into Healed Myocardial Cryoinfarcted Lesions in Rats. Cell Transplant 2017; 12:757-67. [PMID: 14653622 DOI: 10.3727/000000003108747361] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Cell engraftment is a new strategy for the repair of ischemic myocardial lesions. The hemodynamic effectiveness of this strategy, however, is not completely elucidated yet. In a rat model of cryothermia-induced myocardial dysfunction, we investigated whether syngeneic transplantation of neonatal cardiomyocytes or satellite cells is able to improve left ventricular performance. Myocardial infarction was induced in female Lewis rats by a standardized cryolesion to the obtuse margin of the left ventricle. After 4 weeks, 5 × 106 genetically male neonatal cardiomyocytes (n= 16) or satellite cells (n = 16) were engrafted into the myocardial scar. Sham-transplanted animals (n = 15) received injections with cell-free medium. Sham-operated animals (n = 15) served as controls. Left ventricular performance was analyzed 4 months after cell engraftment. Chimerism after this sex-mismatched transplantation was evaluated by detection of PCR-amplified DNA of the Y chromosome. The average heart weight of the infarcted animals significantly exceeded that of controls (p < 0.05). In sham-transplanted animals, mean aortic pressure, left ventricular systolic pressure, aortic flow (indicator of cardiac output), and left ventricular systolic reserve were significantly lower (p < 0.05) compared with sham-operated controls. This was associated with deterioration of ventricular diastolic function (maximal negative dP/dt, time constants of isovolumic relaxation; p < 0.05). Transplantation of satellite cells was found more effective than transplantation of neonatal cardiomyocytes, resulting in i) normalization of mean aortic pressure compared with sham-operated controls, and ii) significantly improved left ventricular systolic pressure and aortic flow (p < 0.05) compared with sham-transplanted animals. Left ventricular systolic reserve and diastolic function, however, were improved by neither satellite cell nor neonatal cardiomyocyte transplantation. Analysis of male genomic DNA revealed 3.98 ± 2.70 ng in hearts after neonatal cardiomyocyte engraftment and 6.16 ± 4.05 ng in hearts after satellite cell engraftment, representing approximately 103 viable engrafted cells per heart. Our study demonstrates i) long-term survival of both neonatal cardiomyocytes and satellite cells after transplantation into cryoinfarcted rat hearts, ii) slight superiority of satellite cells over neonatal cardiomyocytes in improving global left ventricular pump performance, and iii) no effect of both transplant procedures on diastolic dysfunction.
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Affiliation(s)
- Hanno Huwer
- Department of Thoracic and Cardiovascular Surgery, University of Saarland, D-66421 Homburg/Saar, Germany
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12
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Rong SL, Wang XL, Zhang CY, Song ZH, Cui LH, He XF, Li XJ, Du HJ, Li B. Transplantation of HGF gene-engineered skeletal myoblasts improve infarction recovery in a rat myocardial ischemia model. PLoS One 2017; 12:e0175807. [PMID: 28459804 PMCID: PMC5411067 DOI: 10.1371/journal.pone.0175807] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2016] [Accepted: 03/31/2017] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Skeletal myoblast transplantation seems a promising approach for the repair of myocardial infarction (MI). However, the low engraftment efficacy and impaired angiogenic ability limit the clinical efficiency of the myoblasts. Gene engineering with angiogenic growth factors promotes angiogenesis and enhances engraftment of transplanted skeletal myoblasts, leading to improved infarction recovery in myocardial ischemia. The present study evaluated the therapeutic effects of hepatocyte growth factor (HGF) gene-engineered skeletal myoblasts on tissue regeneration and restoration of heart function in a rat MI model. METHODS AND RESULTS The skeletal myoblasts were isolated, expanded, and transduced with adenovirus carrying the HGF gene (Ad-HGF). Male SD rats underwent ligation of the left anterior descending coronary artery. After 2 weeks, the surviving rats were randomized into four groups and treated with skeletal myoblasts by direct injection into the myocardium. The survival and engraftment of skeletal myoblasts were determined by real-time PCR and in situ hybridization. The cardiac function with hemodynamic index and left ventricular architecture were monitored; The adenovirus-mediated-HGF gene transfection increases the HGF expression and promotes the proliferation of skeletal myoblasts in vitro. Transplantation of HGF-engineered skeletal myoblasts results in reduced infarct size and collagen deposition, increased vessel density, and improved cardiac function in a rat MI model. HGF gene modification also increases the myocardial levels of HGF, VEGF, and Bcl-2 and enhances the survival and engraftment of skeletal myoblasts. CONCLUSIONS HGF engineering improves the regenerative effect of skeletal myoblasts on MI by enhancing their survival and engraftment ability.
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Affiliation(s)
- Shu-Ling Rong
- Department of Cardiology, Heping Hospital and Institute of cardiovascular disease, Changzhi Medical College, Changzhi, China
- Department of Cardiology, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Xiao-Lin Wang
- Department of Pediatrics, Heping Hospital and Institute of cardiovascular disease, Changzhi Medical College, Changzhi, China
| | - Cui-Ying Zhang
- Department of Physiology, Changzhi Medical College, Changzhi, China
| | - Zhuo-Hui Song
- Department of Physiology, Changzhi Medical College, Changzhi, China
| | - Lu-Hua Cui
- Department of Cardiology, Heping Hospital and Institute of cardiovascular disease, Changzhi Medical College, Changzhi, China
| | - Xiao-Feng He
- Department of Research, Heping Hospital, Changzhi Medical College, Changzhi, China
| | - Xu-Jiong Li
- Department of Physiology, Changzhi Medical College, Changzhi, China
| | - Hui-Jin Du
- Department of Cardiology, Heping Hospital and Institute of cardiovascular disease, Changzhi Medical College, Changzhi, China
| | - Bao Li
- Department of Cardiology, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
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13
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Jiang C, Zheng D, Feng YL, Guo J, Li HR, Zhang AD. Short- and Long-term Therapeutic Efficacies of Intravenous Transplantation of Bone Marrow Stem Cells on Cardiac Function in Rats with Acute Myocardial Infarction: A Meta-analysis of Randomized Controlled Trials. ACTA ACUST UNITED AC 2016; 31:142-8. [PMID: 27733220 DOI: 10.1016/s1001-9294(16)30042-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
<strong>Objective</strong> To investigate the short- and long-term therapeutic efficacies of intravenous trans- plantation of bone marrow stem cells (MSCs) in rats with experimental myocardial infarction by meta- analysis. <strong>Methods</strong> Randomized controlled trials were systematically searched from PubMed, Science Citation Index (SCI), Chinese journal full-text database (CJFD) up to December 2014. While the experimental groups (MSCs groups) were injected MSCs intravenously, the control groups were injected Delubecco's minimum essential medium (DMEM) or phosphate buffered saline (PBS). Subgroup analysis for each outcome measure was performed for the observing time point after the transplantation of MSCs. Weighted mean differences (WMD) and 95% confidence intervals (CI) were calculated for outcome parameters including ejection fraction (EF) and fractional shortening (FS), which were measured by echocardiogram after intravenous injection and analyzed by RevMan 5.2 and STATA 12.0. <strong>Results</strong> Data from 9 studies (190 rats) were included in the meta-analysis. As compared to the control groups, the cardiac function of the experimental groups were not improved at day 7 (EF: WMD=0.08, 95%CI -1.32 to 1.16, P>0.01; FS: WMD=-0.12, 95%CI -0.90 to 0.65, P>0.01) until at day 14 after MSCs' transplantation (EF: WMD=10.79, 95%CI 9.16 to 12.42, P<0.01; FS: WMD=11.34, 95%CI 10.44 to 12.23, P<0.01), and it lasted 4 weeks or more after transplantation of MSCs (EF: WMD=13.94, 95%CI 12.24 to 15.64, P<0.01; FS: WMD=9.64, 95%CI 7.98 to 11.31, P<0.01). <strong>Conclusion</strong> The therapeutic efficacies of MSCs in rats with myocardid infarction become increasing apparent as time advances since 2 weeks after injection.
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Affiliation(s)
- Can Jiang
- Department of Cardiology, the First Affiliated Hospital of Jinan University, Guangzhou 510630, China
| | - Dong Zheng
- Department of Cardiology, the First Affiliated Hospital of Jinan University, Guangzhou 510630, China
| | - Yun-Lu Feng
- Department of Cardiology, the First Affiliated Hospital of Jinan University, Guangzhou 510630, China
| | - Jun Guo
- Department of Cardiology, the First Affiliated Hospital of Jinan University, Guangzhou 510630, China
| | - Hai-Rui Li
- Department of Cardiology, the First Affiliated Hospital of Jinan University, Guangzhou 510630, China
| | - Ai-Dong Zhang
- Department of Cardiology, the First Affiliated Hospital of Jinan University, Guangzhou 510630, China
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14
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Fernandes S, Chong JJH, Paige SL, Iwata M, Torok-Storb B, Keller G, Reinecke H, Murry CE. Comparison of Human Embryonic Stem Cell-Derived Cardiomyocytes, Cardiovascular Progenitors, and Bone Marrow Mononuclear Cells for Cardiac Repair. Stem Cell Reports 2016; 5:753-762. [PMID: 26607951 PMCID: PMC4649260 DOI: 10.1016/j.stemcr.2015.09.011] [Citation(s) in RCA: 76] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2013] [Revised: 09/14/2015] [Accepted: 09/15/2015] [Indexed: 01/04/2023] Open
Abstract
Cardiomyocytes derived from human embryonic stem cells (hESC-CMs) can improve the contractility of injured hearts. We hypothesized that mesodermal cardiovascular progenitors (hESC-CVPs), capable of generating vascular cells in addition to cardiomyocytes, would provide superior repair by contributing to multiple components of myocardium. We performed a head-to-head comparison of hESC-CMs and hESC-CVPs and compared these with the most commonly used clinical cell type, human bone marrow mononuclear cells (hBM-MNCs). In a nude rat model of myocardial infarction, hESC-CMs and hESC-CVPs generated comparable grafts. Both similarly improved systolic function and ventricular dilation. Furthermore, only rare human vessels formed from hESC-CVPs. hBM-MNCs attenuated ventricular dilation and enhanced host vascularization without engrafting long-term or improving contractility. Thus, hESC-CMs and CVPs show similar efficacy for cardiac repair, and both are more efficient than hBM-MNCs. However, hESC-CVPs do not form larger grafts or more significant numbers of human vessels in the infarcted heart.
Transplantation of hBM-MNCs can halt the negative remodeling of the infarcted heart Both hESC-derived cardiovascular progenitors and definitive cardiomyocytes improve contractility hBM-MNCs lead to greater vessel number than hESC-derived cells
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Affiliation(s)
- Sarah Fernandes
- Center for Cardiovascular Biology, University of Washington, Seattle, WA 98109, USA; Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA; Department of Pathology, University of Washington, Seattle, WA 98109, USA
| | - James J H Chong
- Center for Cardiovascular Biology, University of Washington, Seattle, WA 98109, USA; Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA; Department of Pathology, University of Washington, Seattle, WA 98109, USA; School of Medicine, University of Sydney, Sydney, NSW 2006, Australia; Westmead Millennium Institute for Medical Research, University of Sydney, Sydney, NSW 2145, Australia
| | - Sharon L Paige
- Center for Cardiovascular Biology, University of Washington, Seattle, WA 98109, USA; Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA; Department of Pathology, University of Washington, Seattle, WA 98109, USA
| | - Mineo Iwata
- Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
| | | | - Gordon Keller
- McEwen Centre for Regenerative Medicine, Ontario Cancer Institute, Toronto, ON M5G 2M9, Canada
| | - Hans Reinecke
- Center for Cardiovascular Biology, University of Washington, Seattle, WA 98109, USA; Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA; Department of Pathology, University of Washington, Seattle, WA 98109, USA
| | - Charles E Murry
- Center for Cardiovascular Biology, University of Washington, Seattle, WA 98109, USA; Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA; Department of Pathology, University of Washington, Seattle, WA 98109, USA; Department of Bioengineering, University of Washington, Seattle, WA 98109, USA; Department of Medicine/Cardiology, University of Washington, Seattle, WA 98109, USA.
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15
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Figeac F, Lesault PF, Le Coz O, Damy T, Souktani R, Trébeau C, Schmitt A, Ribot J, Mounier R, Guguin A, Manier C, Surenaud M, Hittinger L, Dubois-Randé JL, Rodriguez AM. Nanotubular crosstalk with distressed cardiomyocytes stimulates the paracrine repair function of mesenchymal stem cells. Stem Cells 2014; 32:216-30. [PMID: 24115309 DOI: 10.1002/stem.1560] [Citation(s) in RCA: 92] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2013] [Accepted: 08/05/2013] [Indexed: 01/18/2023]
Abstract
Mesenchymal stem cells (MSC) are known to repair broken heart tissues primarily through a paracrine fashion while emerging evidence indicate that MSC can communicate with cardiomyocytes (CM) through tunneling nanotubes (TNT). Nevertheless, no link has been so far established between these two processes. Here, we addressed whether cell-to-cell communication processes between MSC and suffering cardiomyocytes and more particularly those involving TNT control the MSC paracrine regenerative function. In the attempt to mimic in vitro an injured heart microenvironment, we developed a species mismatch coculture system consisting of terminally differentiated CM from mouse in a distressed state and human multipotent adipose derived stem cells (hMADS). In this setting, we found that crosstalk between hMADS and CM through TNT altered the secretion by hMADS of cardioprotective soluble factors such as VEGF, HGF, SDF-1α, and MCP-3 and thereby maximized the capacity of stem cells to promote angiogenesis and chemotaxis of bone marrow multipotent cells. Additionally, engraftment experiments into mouse infarcted hearts revealed that in vitro preconditioning of hMADS with cardiomyocytes increased the cell therapy efficacy of naïve stem cells. In particular, in comparison with hearts treated with stem cells alone, those treated with cocultured ones exhibited greater cardiac function recovery associated with higher angiogenesis and homing of bone marrow progenitor cells at the infarction site. In conclusion, our findings established the first relationship between the paracrine regenerative action of MSC and the nanotubular crosstalk with CM and emphasize that ex vivo manipulation of these communication processes might be of interest for optimizing current cardiac cell therapies.
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Affiliation(s)
- Florence Figeac
- INSERM, U955, Créteil, France and Université Paris-Est, UMR_S955, UPEC, Créteil, France
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16
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Treskes P, Neef K, Perumal Srinivasan S, Halbach M, Stamm C, Cowan D, Scherner M, Madershahian N, Wittwer T, Hescheler J, Wahlers T, Choi YH. Preconditioning of skeletal myoblast-based engineered tissue constructs enables functional coupling to myocardium in vivo. J Thorac Cardiovasc Surg 2014; 149:348-56. [PMID: 25439779 DOI: 10.1016/j.jtcvs.2014.09.034] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2014] [Revised: 09/05/2014] [Accepted: 09/10/2014] [Indexed: 02/01/2023]
Abstract
OBJECTIVE Skeletal myoblasts fuse to form functional syncytial myotubes as an integral part of the skeletal muscle. During this differentiation process, expression of proteins for mechanical and electrical integration is seized, which is a major drawback for the application of skeletal myoblasts in cardiac regenerative cell therapy, because global heart function depends on intercellular communication. METHODS Mechanically preconditioned engineered tissue constructs containing neonatal mouse skeletal myoblasts were transplanted epicardially. A Y-chromosomal specific polymerase chain reaction (PCR) was undertaken up to 10 weeks after transplantation to confirm the presence of grafted cells. Histologic and electrophysiologic analyses were carried out 1 week after transplantation. RESULTS Cells within the grafted construct expressed connexin 43 at the interface to the host myocardium, indicating electrical coupling, confirmed by sharp electrode recordings. Analyses of the maximum stimulation frequency (5.65 ± 0.37 Hz), conduction velocity (0.087 ± 0.011 m/s) and sensitivity for pharmacologic conduction block (0.736 ± 0.080 mM 1-heptanol) revealed effective electrophysiologic coupling between graft and host cells, although significantly less robust than in native myocardial tissue (maximum stimulation frequency, 11.616 ± 0.238 Hz, P < .001; conduction velocity, 0.300 ± 0.057 m/s, P < .01; conduction block, 1.983 ± 0.077 mM 1-heptanol, P < .001). CONCLUSIONS Although untreated skeletal myoblasts cannot couple to cardiomyocytes, we confirm that mechanical preconditioning enables transplanted skeletal myoblasts to functionally interact with cardiomyocytes in vivo and, thus, reinvigorate the concept of skeletal myoblast-based cardiac cell therapy.
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Affiliation(s)
- Philipp Treskes
- Department of Cardiothoracic Surgery, Heart Center, University of Cologne, Cologne, Germany; Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany; Institute for Neurophysiology, University of Cologne, Cologne, Germany
| | - Klaus Neef
- Department of Cardiothoracic Surgery, Heart Center, University of Cologne, Cologne, Germany; Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
| | - Sureshkumar Perumal Srinivasan
- Department of Cardiothoracic Surgery, Heart Center, University of Cologne, Cologne, Germany; Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany; Institute for Neurophysiology, University of Cologne, Cologne, Germany
| | - Marcel Halbach
- Institute for Neurophysiology, University of Cologne, Cologne, Germany; Department of Internal Medicine III, Heart Center, University of Cologne, Cologne, Germany
| | - Christof Stamm
- Berlin-Brandenburg Center for Regenerative Therapies, Berlin, Germany
| | - Douglas Cowan
- Departments of Anesthesiology and Perioperative and Pain Medicine, Children's Hospital Boston and Harvard Medical School, Boston, Mass
| | - Maximilian Scherner
- Department of Cardiothoracic Surgery, Heart Center, University of Cologne, Cologne, Germany
| | - Navid Madershahian
- Department of Cardiothoracic Surgery, Heart Center, University of Cologne, Cologne, Germany
| | - Thorsten Wittwer
- Department of Cardiothoracic Surgery, Heart Center, University of Cologne, Cologne, Germany
| | - Jürgen Hescheler
- Institute for Neurophysiology, University of Cologne, Cologne, Germany
| | - Thorsten Wahlers
- Department of Cardiothoracic Surgery, Heart Center, University of Cologne, Cologne, Germany; Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
| | - Yeong-Hoon Choi
- Department of Cardiothoracic Surgery, Heart Center, University of Cologne, Cologne, Germany; Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
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17
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In-vivo comparison of the acute retention of stem cell derivatives and fibroblasts after intramyocardial transplantation in the mouse model. Eur J Nucl Med Mol Imaging 2014; 41:2325-36. [DOI: 10.1007/s00259-014-2858-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2014] [Accepted: 07/04/2014] [Indexed: 01/15/2023]
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18
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Abstract
Therapeutic angiogenesis offers promise as a novel treatment for ischemic heart disease, particularly for patients who are not candidates for current methods of revascularization. The goal of treatment is both relief of symptoms of coronary artery disease and improvement of cardiac function by increasing perfusion to the ischemic region. Protein-based therapy with cytokines including vascular endothelial growth factor and fibroblast growth factor demonstrated functionally significant angiogenesis in several animal models. However, clinical trials have yielded largely disappointing results. The attenuated angiogenic response seen in clinical trials of patients with coronary artery disease may be due to multiple factors including endothelial dysfunction, particularly in the context of advanced atherosclerotic disease and associated comorbid conditions, regimens of single agents, as well as inefficiencies of current delivery methods. Gene therapy has several advantages over protein therapy and recent advances in gene transfer techniques have improved the feasibility of this approach. The safety and tolerability of therapeutic angiogenesis by gene transfer has been demonstrated in phase I clinical trials. The utility of therapeutic angiogenesis by gene transfer as a treatment option for ischemic cardiovascular disease will be determined by adequately powered, randomized, placebo-controlled Phase II and III clinical trials. Cell-based therapies offer yet another approach to therapeutic angiogenesis. Although it is a promising therapeutic strategy, additional preclinical studies are warranted to determine the optimal cell type to be administered, as well as the optimal delivery method. It is likely the optimal treatment will involve multiple agents as angiogenesis is a complex process involving a large cascade of cytokines, as well as cells and extracellular matrix, and administration of a single factor may be insufficient. The promise of therapeutic angiogenesis as a novel treatment for no-option patients should be approached with cautious optimism as the field progresses.
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Affiliation(s)
- Audrey Rosinberg
- Division of Cardiothoracic Surgery, Beth Israel Deaconess Medical Center, 110 Francis Street, Suite 2A, Boston, MA 02215, USA
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19
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Young developmental age cardiac extracellular matrix promotes the expansion of neonatal cardiomyocytes in vitro. Acta Biomater 2014; 10:194-204. [PMID: 24012606 DOI: 10.1016/j.actbio.2013.08.037] [Citation(s) in RCA: 132] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2013] [Revised: 08/01/2013] [Accepted: 08/27/2013] [Indexed: 02/02/2023]
Abstract
A major limitation to cardiac tissue engineering and regenerative medicine strategies is the lack of proliferation of postnatal cardiomyocytes. The extracellular matrix (ECM) is altered during heart development, and studies suggest that it plays an important role in regulating myocyte proliferation. Here, the effects of fetal, neonatal and adult cardiac ECM on the expansion of neonatal rat ventricular cells in vitro are studied. At 24h, overall cell attachment was lowest on fetal ECM; however, ~80% of the cells were cardiomyocytes, while many non-myocytes attached to older ECM and poly-l-lysine controls. After 5 days, the cardiomyocyte population remained highest on fetal ECM, with a 4-fold increase in number. Significantly more cardiomyocytes stained positively for the mitotic marker phospho-histone H3 on fetal ECM compared with other substrates at 5 days, suggesting that proliferation may be a major mechanism of cardiomyocyte expansion on young ECM. Further study of the beneficial properties of early developmental aged cardiac ECM could advance the design of novel biomaterials aimed at promoting cardiac regeneration.
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20
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Georgiadis V, Knight RA, Jayasinghe SN, Stephanou A. Cardiac tissue engineering: renewing the arsenal for the battle against heart disease. Integr Biol (Camb) 2014; 6:111-26. [DOI: 10.1039/c3ib40097b] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
The development of therapies that lead to the regeneration or functional repair of compromised cardiac tissue is the most important challenge facing translational cardiovascular research today.
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Affiliation(s)
| | - Richard A. Knight
- Medical Molecular Biology Unit
- University College London
- London WC1E 6JF, UK
| | - Suwan N. Jayasinghe
- BioPhysics Group
- UCL Institute of Biomedical Engineering
- UCL Centre for Stem Cells and Regenerative Medicine and Department of Mechanical Engineering
- University College London
- London WC1E 7JE, UK
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21
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Extracellular vesicles derived from human bone marrow mesenchymal stem cells promote angiogenesis in a rat myocardial infarction model. J Mol Med (Berl) 2013; 92:387-97. [PMID: 24337504 DOI: 10.1007/s00109-013-1110-5] [Citation(s) in RCA: 537] [Impact Index Per Article: 44.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2013] [Revised: 11/19/2013] [Accepted: 11/28/2013] [Indexed: 01/09/2023]
Abstract
UNLABELLED Mesenchymal stem cells (MSCs) have been increasingly tested experimentally and clinically for cardiac repair. However, the underlying mechanisms remain controversial due to the poor viability and considerable death of the engrafted cells in the infracted myocardium. Recent reports have suggested that extracellular vesicles (EVs) released by MSCs have angiogenesis-promoting activity; however, the therapeutic effect of MSC-EVs on an ischemic heart is unclear. In the present study, we reported that MSCs could release a large quantity of EVs around 100 nm in diameter upon hypoxia stimulation though the majority of the cells had not experienced apoptosis. MSC-EVs could be promptly uptaken by human umbilical vein endothelial cells, and the internalization resulted in dose-dependent enhancement of in vitro proliferation, migration, and tube formation of endothelial cells. Using an acute myocardial infarction rat model, we found that intramyocardial injection of MSC-EVs markedly enhanced blood flow recovery, in accordance with reduced infarct size and preserved cardiac systolic and diastolic performance compared to those treated with PBS. These data suggest that like MSCs, MSC-EVs could also protect cardiac tissue from ischemic injury at least by means of promoting blood vessel formation, though further detailed investigations should be performed to define the functionality of MSC-EVs. KEY MESSAGES MSCs released extracellular vesicles (EVs) upon hypoxia stimulation. MSC-EVs were a mixture of microvesicles and exosomes. MSC-EVs could be promptly uptaken by human umbilical vein endothelial cells. MSC-EVs promoted neoangiogenesis in vitro and in vivo. MSC-EVs preserved cardiac performance in an AMI model.
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22
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Abdelwahid E, Siminiak T, Guarita-Souza LC, Teixeira de Carvalho KA, Gallo P, Shim W, Condorelli G. Stem cell therapy in heart diseases: a review of selected new perspectives, practical considerations and clinical applications. Curr Cardiol Rev 2013; 7:201-12. [PMID: 22758618 PMCID: PMC3263484 DOI: 10.2174/157340311798220502] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2010] [Revised: 01/31/2011] [Accepted: 02/03/2011] [Indexed: 12/13/2022] Open
Abstract
Degeneration of cardiac tissues is considered a major cause of mortality in the western world and is expected to be a greater problem in the forthcoming decades. Cardiac damage is associated with dysfunction and irreversible loss of cardiomyocytes. Stem cell therapy for ischemic heart failure is very promising approach in cardiovascular medicine. Initial trials have indicated the ability of cardiomyocytes to regenerate after myocardial injury. These preliminary trials aim to translate cardiac regeneration strategies into clinical practice. In spite of advances, current therapeutic strategies to ischemic heart failure remain very limited. Moreover, major obstacles still need to be solved before stem cell therapy can be fully applied. This review addresses the current state of research and experimental data regarding embryonic stem cells (ESCs), myoblast transplantation, histological and functional analysis of transplantation of co-cultured myoblasts and mesenchymal stem cells, as well as comparison between mononuclear and mesenchymal stem cells in a model of myocardium infarction. We also discuss how research with stem cell transplantation could translate to improvement of cardiac function.
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Affiliation(s)
- Eltyeb Abdelwahid
- CBRC, Massachusetts General Hospital/Harvard Medical School, Charlestown, Massachusetts 02129, USA.
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Mathison M, Gersch RP, Nasser A, Lilo S, Korman M, Fourman M, Hackett N, Shroyer K, Yang J, Ma Y, Crystal RG, Rosengart TK. In vivo cardiac cellular reprogramming efficacy is enhanced by angiogenic preconditioning of the infarcted myocardium with vascular endothelial growth factor. J Am Heart Assoc 2012; 1:e005652. [PMID: 23316332 PMCID: PMC3540681 DOI: 10.1161/jaha.112.005652] [Citation(s) in RCA: 105] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2012] [Accepted: 01/11/2012] [Indexed: 12/12/2022]
Abstract
BACKGROUND In situ cellular reprogramming offers the possibility of regenerating functional cardiomyocytes directly from scar fibroblasts, obviating the challenges of cell implantation. We hypothesized that pretreating scar with gene transfer of the angiogenic vascular endothelial growth factor (VEGF) would enhance the efficacy of this strategy. METHODS AND RESULTS Gata4, Mef2c, and Tbx5 (GMT) administration via lentiviral transduction was demonstrated to transdifferentiate rat fibroblasts into (induced) cardiomyocytes in vitro by cardiomyocyte marker studies. Fisher 344 rats underwent coronary ligation and intramyocardial administration of an adenovirus encoding all 3 major isoforms of VEGF (AdVEGF-All6A(+)) or an AdNull control vector (n=12/group). Lentivirus encoding GMT or a GFP control was administered to each animal 3 weeks later, followed by histologic and echocardiographic analyses. GMT administration reduced the extent of fibrosis by half compared with GFP controls (12 ± 2% vs 24 ± 3%, P<0.01) and reduced the number of myofibroblasts detected in the infarct zone by 4-fold. GMT-treated animals also demonstrated greater density of cardiomyocyte-specific marker beta myosin heavy chain 7(+) cells compared with animals receiving GFP with or without VEGF (P<0.01). Ejection fraction was significantly improved after GMT vs GFP administration (12 ± 3% vs -7 ± 3%, P<0.01). Eight (73%) GFP animals but no GMT animals demonstrated decreased ejection fraction during this interval (P<0.01). Also, improvement in ejection fraction was 4-fold greater in GMT/VEGF vs GMT/null animals (17 ± 2% vs 4 ± 1%, P<0.05). CONCLUSIONS VEGF administration to infarcted myocardium enhances the efficacy of GMT-mediated cellular reprogramming in improving myocardial function and reducing the extent of myocardial fibrosis compared with the use of GMT or VEGF alone.
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Affiliation(s)
- Megumi Mathison
- Department of Surgery, Stony Brook University Medical Center, Stony Brook, NY, USA
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Fernandes S, Kuklok S, McGonigle J, Reinecke H, Murry CE. Synthetic matrices to serve as niches for muscle cell transplantation. Cells Tissues Organs 2011; 195:48-59. [PMID: 22005610 DOI: 10.1159/000331414] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Poor cell retention and limited cell survival after grafting are major limitations of cell therapy. Recent studies showed that the use of matrices as vehicles at the time of cell injection can significantly improve cell engraftment by providing an appropriate structure and physical support for the injected cells. Properly designed matrices can also promote the organization of the cells into a functioning cardiac-like tissue and enhance integration between the host and the engrafted tissue. Furthermore, the use of an injectable biomaterial provides an opportunity to release in situ bioactive molecules that can further enhance the beneficial effects of cell transplantation. In this article we review a large variety of biologically derived synthetic and hybrid materials that have been tested as matrices for cardiac repair. We summarize the optimal parameters required for an ideal matrix including biocompatibility, injectability, degradation rate, and mechanical properties. Using an in vivo subcutaneous grafting model, we also provide novel data involving a side-by-side comparison of six synthetic matrices derived from maltodextrin. By systematically varying polymer molecular weight, cross-link density, and availability of cell adhesion motifs, a synthetic matrix was identified that supported skeletal myotube formation similar to Matrigel™. Our results emphasize not only the need to have a range of tunable matrices for cardiac cell therapy but also the importance of further characterizing the physical properties required for an ideal injectable matrix.
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Affiliation(s)
- Sarah Fernandes
- Center for Cardiovascular Biology, University of Washington, Seattle, USA
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25
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Eun LY, Song H, Choi E, Lee TG, Moon DW, Hwang D, Byun KH, Sul JH, Hwang KC. Implanted bone marrow-derived mesenchymal stem cells fail to metabolically stabilize or recover electromechanical function in infarcted hearts. Tissue Cell 2011; 43:238-45. [PMID: 21700305 DOI: 10.1016/j.tice.2011.04.002] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2010] [Revised: 04/26/2011] [Accepted: 04/27/2011] [Indexed: 11/27/2022]
Abstract
Mesenchymal stem cells (MSCs) have been used with success in several clinical applications for clinical treatment of ischemic hearts. However, the reported effects of MSC-based therapy on myocardial infarction (MI) are inconsistent. In particular, the preventive effects of MSC-based therapy on arrhythmic sudden death and metabolic disorders after infarction remain controversial. Here, we investigated the effects of MSCs on reverse remodeling in an infarcted myocardium, and found that MSC-therapy failed to achieve the complete regeneration of infarcted myocardium. Histological analyses showed that although infarct size and interstitial fibrosis induced by MI recovered significantly after MSC treatment, these improvements were marginal, indicating that a significant amount of damaged tissue was still present. Furthermore, transplanted MSCs had slight anti-apoptotic and anti-inflammatory effects in MSC-implanted regions and no significant improvements in cardiac function were observed, suggesting that naïve MSCs might not be the right cell type to treat myocardial infarction. Furthermore, small ion profiling using ToF-SIMS revealed that the metabolic stabilization provided by the MSCs implantation was not significant compared to the sham group. Together, these results indicate that pretreatment of MSCs is needed to enhance the benefits of MSCs, particularly when MSCs are used to treat arrhythmogenicity and metabolically stabilize infarcted myocardium.
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Affiliation(s)
- L Y Eun
- Yonsei University Graduate School of Medicine, Seoul 120-752, Republic of Korea
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26
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Ayala-Lugo A, Tavares AMV, Paz AHR, Alegretti A, Miquelito L, Bock H, Giugliani R, Clausell N, Cirne-Lima E, Rohde LE. Age-Dependent Availability and Functionality of Bone Marrow Stem Cells in an Experimental Model of Acute and Chronic Myocardial Infarction. Cell Transplant 2011; 20:407-19. [DOI: 10.3727/096368909x519283] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
The aim of this study was to investigate the effect of aging and timing of left ventricular ischemic injury on the availability and functionality of stem cells. We studied young and aged male inbred Lewis rats that were used as donors of bone marrow mononuclear cells (BM-MNCs), divided in four experimental groups: controls, sham operated, 48 h post-myocardial infarction (MI), and 28 days post-MI. In vitro studies included flow cytometry analysis, hematopoietic colony-forming capacity, and invasion assays of migration capacity. BM-MNCs from these groups were transplanted in female rats after MI induction. Late engraftment was evaluated by real-time PCR of the SRY chromosome. Percentage of CD34+/CD45+low cells was similar among different experimental groups in young rats, but was significantly higher in aged animals ( p < 0.001), particularly 28 days post-MI. KDR+/CD34+ cells were increased 48 h after MI and decreased 28 days post-MI in young animals, while they were profoundly reduced in the aged group ( p < 0.001). Triple staining for CD44+/CD29+/CD71+ cells was similar in different groups of aged rats, but we observed an intense increase 48 h post-MI in young animals. Colony-forming units and cytokine-induced migration were significantly attenuated 28 days after the MI. Late engraftment in infarcted transplanted female hearts was present, but considerably heterogeneous. Finally, recovery of left ventricular systolic function in transplanted female recipients was significantly influenced by donors' BM-MNCs groups ( p < 0.01). We have demonstrated that aging and timing of myocardial injury are factors that may act synergistically in determining stem cell availability and function. Such interaction should be considered when planning new cell therapy strategies for acute and chronic ischemic heart disease in the clinical arena.
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Affiliation(s)
- Ana Ayala-Lugo
- Embriology and Cell Differentiation Laboratory, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
- Post-Graduate Program of Genetics and Molecular Biology, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
| | - Angela M. V. Tavares
- Cardiovascular Research Laboratory, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
- Cardiovascular Physiology Laboratory, Physiology Departament, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
| | - Ana H. R. Paz
- Embriology and Cell Differentiation Laboratory, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
| | - Ana Alegretti
- Embriology and Cell Differentiation Laboratory, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
| | - Ludmila Miquelito
- Embriology and Cell Differentiation Laboratory, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
| | - Hugo Bock
- Post-Graduate Program of Biologic Sciences: Biochemistry, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
| | - Roberto Giugliani
- Medical Genetics Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
- Post-Graduate Program of Genetics and Molecular Biology, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
- Post-Graduate Program of Biologic Sciences: Biochemistry, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
- Biosciences Institute, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
| | - Nadine Clausell
- Cardiovascular Research Laboratory, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
- Post-Graduate Program of Cardiology and Cardiovascular Sciences, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
- Medical School, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
| | - Elizabeth Cirne-Lima
- Embriology and Cell Differentiation Laboratory, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
- Veterinary School, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
| | - Luis E. Rohde
- Cardiovascular Research Laboratory, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
- Post-Graduate Program of Cardiology and Cardiovascular Sciences, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
- Medical School, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
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Guarita-Souza LC, Francisco JC, Simeoni R, Faria-Neto JR, de Carvalho KAT. Benefit of stem cells and skeletal myoblast cells in dilated cardiomyopathies. World J Cardiol 2011; 3:93-7. [PMID: 21503169 PMCID: PMC3078487 DOI: 10.4330/wjc.v3.i3.93] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2011] [Revised: 03/02/2011] [Accepted: 03/09/2011] [Indexed: 02/06/2023] Open
Abstract
Although some authors suggest that there is mitotic division in the heart, most cardiomyocytes do not have the capacity to regenerate after myocardial infarction and when this occurs there is a deterioration of contractile function, and if the area of infarction is extensive ventricular remodeling may occur, leading to the development of heart failure. Cell transplantation into the myocardium with the goal of recovery of cardiac function has been extensively studied in recent years. The effects of cell therapy are based directly on the cell type used and the type of cardiac pathology. For myocardial ischemia in the hibernating myocardium, bone marrow cells have functional benefits, however these results in transmural fibrosis are not evident. In these cases there is a benefit of implantation with skeletal myoblasts, for treating the underlying cause of disease, the loss of cell contractility.
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Affiliation(s)
- Luiz César Guarita-Souza
- Luiz César Guarita-Souza, Júlio César Francisco, Rossana Simeoni, Jose Rocha Faria-Neto, Department of Post Graduation Surgery, Pontifical Catholic University of Parana, 81200-525 Curitiba Pr, Brazil
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28
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Fujimoto KL, Clause KC, Liu LJ, Tinney JP, Verma S, Wagner WR, Keller BB, Tobita K. Engineered fetal cardiac graft preserves its cardiomyocyte proliferation within postinfarcted myocardium and sustains cardiac function. Tissue Eng Part A 2011; 17:585-96. [PMID: 20868205 DOI: 10.1089/ten.tea.2010.0259] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
The goal of cellular cardiomyoplasty is to replace damaged myocardium by healthy myocardium achieved by host myocardial regeneration and/or transplantation of donor cardiomyocytes (CMs). In the case of CM transplantation, studies suggest that immature CMs may be the optimal cell type to survive and functionally integrate into damaged myocardium. In the present study, we tested the hypothesis that active proliferation of immature CMs contributes graft survival and functional recovery of recipient myocardium. We constructed engineered cardiac tissue from gestational day 14 rat fetal cardiac cells (EFCT) or day 3 neonatal cardiac cells (ENCT). Culture day 7 EFCTs or ENCTs were implanted onto the postinfarct adult left ventricle (LV). CM proliferation rate of EFCT was significantly higher than that of ENCT at 3 days and 8 weeks after the graft implantation, whereas CM apoptosis rate remained the same in both groups. Echocardiogram showed that ENCT implantation sustained LV contraction, whereas EFCT implantation significantly increased the LV contraction at 8 weeks versus sham group (p < 0.05, analysis of variance). These results suggest that active CM proliferation may play a critical role in immature donor CM survival and the functional recovery of damaged recipient myocardium.
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Affiliation(s)
- Kazuro L Fujimoto
- Department of Surgery, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15224, USA
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29
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Bone marrow stem cell derived paracrine factors for regenerative medicine: current perspectives and therapeutic potential. BONE MARROW RESEARCH 2010; 2011:207326. [PMID: 22046556 PMCID: PMC3195349 DOI: 10.1155/2011/207326] [Citation(s) in RCA: 107] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/31/2010] [Accepted: 10/12/2010] [Indexed: 12/11/2022]
Abstract
During the past several years, there has been intense research in the field of bone marrow-derived stem cell (BMSC) therapy to facilitate its translation into clinical setting. Although a lot has been accomplished, plenty of challenges lie ahead. Furthermore, there is a growing body of evidence showing that administration of BMSC-derived conditioned media (BMSC-CM) can recapitulate the beneficial effects observed after stem cell therapy. BMSCs produce a wide range of cytokines and chemokines that have, until now, shown extensive therapeutic potential. These paracrine mechanisms could be as diverse as stimulating receptor-mediated survival pathways, inducing stem cell homing and differentiation or regulating the anti-inflammatory effects in wounded areas. The current review reflects the rapid shift of interest from BMSC to BMSC-CM to alleviate many logistical and technical issues regarding cell therapy and evaluates its future potential as an effective regenerative therapy.
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Povsic TJ, O'Connor CM. Cell therapy for heart failure: the need for a new therapeutic strategy. Expert Rev Cardiovasc Ther 2010; 8:1107-26. [PMID: 20670189 DOI: 10.1586/erc.10.99] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Improvements in the treatment of ischemic heart disease have led to a significant growth in the numbers of patients with systolic heart failure secondary to myocardial injury. Current therapies fail to address the loss of contractile tissue due to myocardial injury. Cell therapy is singular in its promise of primarily treating this underlying issue through salvage of viable myocardium or generation of new contractile tissue. Multiple cell types have been used to target acute myocardial infarction, chronic ischemic heart disease and heart failure due to infarction. Bone marrow mononuclear cells have been used to increase myocardial salvage after acute infarction. Randomized trials of over 800 patients have demonstrated no safety issues, and meta-analyses have suggested an improvement in left ventricular function in treated patients with trends toward improvements in hard cardiac end points. Cell therapy for chronic ischemic heart disease with bone marrow angiogenic progenitors has shown similar safety and trends toward improvement in function. While these therapies have targeted patients with viable myocardium, myoblasts have been used to treat patients with left ventricular dysfunction secondary to transmural infarction. Cell types with cardiomyogenic potential, including induced pluripotent stem cells and cardiac progenitor cells, offer the promise of true myocardial regeneration. Future studies with these cells may open the door for true myocardial regeneration.
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Affiliation(s)
- Thomas J Povsic
- Division of Cardiology, Duke University Medical Center, Durham, NC 27710, USA.
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31
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Guo HD, Wang HJ, Tan YZ, Wu JH. Transplantation of marrow-derived cardiac stem cells carried in fibrin improves cardiac function after myocardial infarction. Tissue Eng Part A 2010; 17:45-58. [PMID: 20673001 DOI: 10.1089/ten.tea.2010.0124] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
The high death rate of the transplanted stem cells in the infarcted heart and the low efficiency of differentiation toward cardiomyocytes influence the outcome of stem cell transplantation for treatment of myocardial infarction (MI). Fibrin glue (FG) has been extensively used as a cell implantation matrix to increase cell survival. However, mechanisms of the effects of FG for stem cell transplantation to improve cardiac function are unclear. We have isolated c-kit+/Sca-1+ marrow-derived cardiac stem cells (MCSCs) from rat bone marrow; the cells expressed weakly early cardiac transcription factor Nkx2.5, GATA-4, Mef2C, and Tbx5. Effects of FG on survival, proliferation, and migration of MCSCs were examined in vitro. Cytoprotective effects of FG were assessed by exposure of MCSCs to anoxia. Efficacy of MCSC transplantation in FG was evaluated in the female rat MI model. The MCSCs survived well and proliferated in FG, and they may migrate out from the edge of FG in the wound and nature state. Acridine orange/ethidium bromide staining and lactate dehydrogenase analysis showed that MCSCs in FG were more resistant to anoxia as compared with MCSCs alone. In a rat MI model, cardiac function was improved and scar area was obviously reduced in group of MCSCs in FG compared with group of MCSCs and FG alone, respectively. Y chromosome fluorescence in situ hybridization showed that there were more survived MCSCs in group of MCSCs in FG than those in group of MCSCs alone, and most Y chromosome positive cells expressed cardiac troponin T (cTnT) and connexin-43 (Cx-43). Cx-43 was located between Y chromosome positive cells and recipient cardiomyocytes. Microvessel density in the peri-infarct regions and infarct regions significantly increased in group of MCSCs in FG. These results suggest that FG provide a suitable microenvironment for survival and proliferation of MCSCs and protect cells from apoptosis and necrosis caused by anoxia. MCSCs could differentiate into cardiomyocytes after being transplanted in the border of the infarcted myocardium and form connections with native cardiomyocytes. FG is helpful for MCSC transplantation to repair myocardium and improve cardiac function through promoting the survival, migration, and cardiomyogenic differentiation of MCSCs and inducing angiogenesis.
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Affiliation(s)
- Hai-Dong Guo
- Department of Anatomy and Histology and Embryology, Shanghai Medical School of Fudan University, Shanghai, People's Republic of China
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Khouzami L, Bourin MC, Christov C, Damy T, Escoubet B, Caramelle P, Perier M, Wahbi K, Meune C, Pavoine C, Pecker F. Delayed cardiomyopathy in dystrophin deficient mdx mice relies on intrinsic glutathione resource. THE AMERICAN JOURNAL OF PATHOLOGY 2010; 177:1356-64. [PMID: 20696779 DOI: 10.2353/ajpath.2010.090479] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Oxidative stress contributes to the pathogenesis of Duchenne muscular dystrophy (DMD). Although they have been a model for DMD, mdx mice exhibit slowly developing cardiomyopathy. We hypothesized that disease process was delayed owing to the development of an adaptive mechanism against oxidative stress, involving glutathione synthesis. At 15 to 20 weeks of age, mdx mice displayed a 33% increase in blood glutathione levels compared with age-matched C57BL/6 mice. In contrast, cardiac glutathione content was similar in mdx and C57BL/6 mice as a result of the balanced increased expression of glutamate cysteine ligase catalytic and regulatory subunits ensuring glutathione synthesis in the mdx mouse heart, as well as increased glutathione peroxidase-1 using glutathione. Oral administration from 10 weeks of age of the glutamate cysteine ligase inhibitor, l-buthionine(S,R)-sulfoximine (BSO, 5 mmol/L), led to a 33% and 50% drop in blood and cardiac glutathione, respectively, in 15- to 20-week-old mdx mice. Moreover, 20-week-old BSO-treated mdx mice displayed left ventricular hypertrophy associated with diastolic dysfunction, discontinuities in beta-dystroglycan expression, micronecrosis and microangiopathic injuries. Examination of the glutathione status in four DMD patients showed that three displayed systemic glutathione deficiency as well. In conclusion, low glutathione resource hastens the onset of cardiomyopathy linked to a defect in dystrophin in mdx mice. This is relevant to the glutathione deficiency that DMD patients may suffer.
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Affiliation(s)
- Lara Khouzami
- Institut National de la Santé et de la Recherche Médicale, Institut Mondor de Recherche Biomédicale, Créteil, France
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Guo HD, Cui GH, Wang HJ, Tan YZ. Transplantation of marrow-derived cardiac stem cells carried in designer self-assembling peptide nanofibers improves cardiac function after myocardial infarction. Biochem Biophys Res Commun 2010; 399:42-8. [DOI: 10.1016/j.bbrc.2010.07.031] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2010] [Accepted: 07/11/2010] [Indexed: 12/24/2022]
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Pinho-Ribeiro V, Maia ACV, Werneck-de-Castro JPS, Oliveira PF, Goldenberg RCS, Carvalho ACCD. Human umbilical cord blood cells in infarcted rats. Braz J Med Biol Res 2010; 43:290-296. [PMID: 20401437 DOI: 10.1590/s0100-879x2010007500007] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2009] [Accepted: 01/26/2010] [Indexed: 02/08/2023] Open
Abstract
Therapy with bone marrow-derived cells has been used in ischemic patients with reported success. The aim of this study was to determine the therapeutic efficacy of fresh and frozen human umbilical cord blood cells (hUCB) in Wistar rats submitted to permanent occlusion of the left coronary artery. Three hours after myocardial infarction, 2 x 10(7) hUCB cells or vehicle were administered by intramyocardial injection. The animals were divided into five groups: control (N = 10), sham operated (N = 10), infarcted that received vehicle (N = 9), infarcted treated with cryopreserved hUCB (N = 7), and infarcted treated with fresh hUCB (N = 5). Cardiac function was evaluated by electrocardiogram (ECG) and echocardiogram (ECHO) before cell therapy, and by ECG, ECHO, cardiopulmonary test, and left ventricular pressure measurements 3 weeks later. After 3 weeks, both groups treated with hUCB still had Q wave present in L1, âQRS >90 degrees and reduced shortening fraction (less than 50%). In addition, cardiac indexes of left ventricular contractility and relaxation were 5484 +/- 875 and -4032 +/- 643 mmHg (cryopreserved hUCB) and 4585 +/- 955 and -2862 +/- 590 mmHg (fresh hUCB), respectively. These values were not statistically different from those of saline-treated animals. Cardiopulmonary exercise test profile was typical of infarcted hearts; exercise time was about 14 min and maximal VO2 was 24.77 +/- 5.00 mL.kg-1.min-1. These data show that hUCB therapy did not improve the cardiac function of infarcted animals or prevent cardiac remodeling.
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Affiliation(s)
- V Pinho-Ribeiro
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Brasil
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35
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Shiba Y, Hauch KD, Laflamme MA. Cardiac applications for human pluripotent stem cells. Curr Pharm Des 2009; 15:2791-806. [PMID: 19689350 DOI: 10.2174/138161209788923804] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Human embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs) can self-renew indefinitely, while maintaining the capacity to differentiate into useful somatic cell types, including cardiomyocytes. As such, these stem cell types represent an essentially inexhaustible source of committed human cardiomyocytes of potential use in cell-based cardiac therapies, high-throughput screening and safety testing of new drugs, and modeling human heart development. These stem cell-derived cardiomyocytes have an unambiguous cardiac phenotype and proliferate robustly both in vitro and in vivo. Recent transplantation studies in preclinical models have provided exciting proof-of-principle for their use in infarct repair and in the formation of a "biological pacemaker". While these successes give reason for cautious optimism, major challenges remain to the successful application of hESCs (or hiPSCs) to cardiac repair, including the need for preparations of high cardiac purity, improved methods of delivery, and approaches to overcome immune rejection and other causes of graft cell death. In this review, we describe the phenotype of hESC- and hiPSC-derived cardiomyocytes, the state of preclinical transplantation studies with these cells, and potential approaches to overcome the aforementioned hurdles.
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Affiliation(s)
- Yuji Shiba
- Department of Pathology, University of Washington, Seattle, WA 98109, USA
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36
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Kim H, Kim SW, Nam D, Kim S, Yoon YS. Cell therapy with bone marrow cells for myocardial regeneration. Antioxid Redox Signal 2009; 11:1897-911. [PMID: 19203213 PMCID: PMC2788115 DOI: 10.1089/ars.2009.2486] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2009] [Revised: 02/01/2009] [Accepted: 02/07/2009] [Indexed: 01/07/2023]
Abstract
Cell therapy has tremendous potential for the damaged heart, which has limited self-renewing capability. Bone marrow (BM) cells are attractive for cell therapy, as they contain diverse stem and progenitor cell populations that can give rise to various cell types, including cardiomyocytes, endothelial cells, and smooth muscle cells. Studies have shown BM cells to be safe and efficacious in the treatment of myocardial infarction. Possible therapeutic mechanisms mediated by both host and transplanted cells include cardiomyogenesis, neovascularization, and attenuation of adverse remodeling. In this review, different stem and progenitor cells in the bone marrow and their application in cell therapy are reviewed, and evidence for their therapeutic mechanisms is discussed.
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Affiliation(s)
- Hyongbum Kim
- Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA
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37
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Zhou J, Liu L, Li X, Chen H, Zhang Q. Primary Study on Transplantation of Endothelialized Dermal Equivalents Into Normal Rats. ACTA ACUST UNITED AC 2009; 35:377-90. [PMID: 17701484 DOI: 10.1080/10731190701460242] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
This study was designed to determine the ability of human umbilical vein endothelial cells (HUVEC) in dermal equivalent (DE) to form microvessel-like tubes after transplantation into normal rats. A mixture of rat fibroblasts and HUVEC was inosculated into collagen-chitosan sponges to prepare endothelialized dermal equivalents (EDE). After culture in vitro for 24 hours, inosculated cells dispersed throughout the sponges and the equivalents were transplanted subcutaneously into the back of normal Lewis rats. Anti-human specific CD31 antibody was used for immunohistochemical localization of human endothelial cells in sections of EDE excised from rats after grafting. HUVEC in EDE organized into microvessel-like tubes at the end of the first week after transplantation, which still persisted after two weeks. The host microvessels began to pervade both DE and EDE during the second week after transplantation. These results demonstrated that HUVEC in EDE was able to persist and form microvessel-like tubes after transplantation into normal rats, and this is the first time to transplant DE containing HUVEC into normal rats.
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Affiliation(s)
- Juan Zhou
- Institute of Biomedical Engineering, Chinese Academy of Medical Science, Peking Union Medical College [corrected] Key Laboratory of Biomedical Material of Tianjin, Tianjin, PR China
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Soares MBP, Santos RRD. Current status and perspectives of cell therapy in Chagas disease. Mem Inst Oswaldo Cruz 2009; 104 Suppl 1:325-32. [DOI: 10.1590/s0074-02762009000900043] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2009] [Accepted: 05/28/2009] [Indexed: 02/08/2023] Open
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Schabort EJ, Myburgh KH, Wiehe JM, Torzewski J, Niesler CU. Potential Myogenic Stem Cell Populations: Sources, Plasticity, and Application for Cardiac Repair. Stem Cells Dev 2009; 18:813-30. [DOI: 10.1089/scd.2008.0387] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Affiliation(s)
- Elske J. Schabort
- Department of Physiological Sciences, University of Stellenbosch, Stellenbosch, South Africa
| | - Kathryn H. Myburgh
- Department of Physiological Sciences, University of Stellenbosch, Stellenbosch, South Africa
| | - Juliane M. Wiehe
- Department of Internal Medicine II, University of Ulm, Ulm, Germany
| | - Jan Torzewski
- Cardiovascular Unit, Oberallgäu Kliniken GmbH, Immenstadt, Germany
| | - Carola U. Niesler
- Department of Biochemistry, School of Biochemistry, Genetics, Microbiology, and Plant Pathology, University of KwaZulu-Natal, Pietermaritzburg, South Africa
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41
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Injection of bone marrow cell extract into infarcted hearts results in functional improvement comparable to intact cell therapy. Mol Ther 2009; 17:1250-6. [PMID: 19384293 DOI: 10.1038/mt.2009.85] [Citation(s) in RCA: 76] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
We compared therapeutic benefits of intramyocardial injection of unfractionated bone marrow cells (BMCs) versus BMC extract as treatments for myocardial infarction (MI), using closed-chest ultrasound-guided injection at a clinically relevant time post-MI. MI was induced in mice and the animals treated at day 3 with either: (i) BMCs from green fluorescent protein (GFP)-expressing mice (n = 14), (ii) BMC extract (n = 14), or (iii) saline control (n = 14). Six animals per group were used for histology at day 6 and the rest followed to day 28 for functional analysis. Ejection fraction was similarly improved in the BMC and extract groups versus control (40.6 +/- 3.4 and 39.1 +/- 2.9% versus 33.2 +/- 5.0%, P < 0.05) with smaller scar sizes. At day 6 but not day 28, both therapies led to significantly higher capillary area and number of arterioles versus control. At day 6, BMCs increased the number of cycling cardiomyocytes (CMs) versus control whereas extract therapy resulted in significant reduction in the number of apoptotic CMs at the border zone (BZ) versus control. Intracellular components within BMCs can enhance vascularity, reduce infarct size, improve cardiac function, and influence CM apoptosis and cycling early after therapy following MI. Intact cells are not necessary and death of implanted cells may be a major component of the benefit.
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McAllister TN, Dusserre N, Maruszewski M, L'heureux N. Cell-based therapeutics from an economic perspective: primed for a commercial success or a research sinkhole? Regen Med 2009; 3:925-37. [PMID: 18947313 DOI: 10.2217/17460751.3.6.925] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Despite widespread hype and significant investment through the late 1980s and 1990s, cell-based therapeutics have largely failed from both a clinical and financial perspective. While the early pioneers were able to create clinically efficacious products, small margins coupled with small initial indications made it impossible to produce a reasonable return on the huge initial investments that had been made to support widespread research activities. Even as US FDA clearance opened up larger markets, investor interest waned, and the crown jewels of cell-based therapeutics went bankrupt or were rescued by corporate bailout. Despite the hard lessons learned from these pioneering companies, many of today's regenerative medicine companies are supporting nearly identical strategies. It remains to be seen whether or not our proposed tenets for investment and commercialization strategy yield an economic success or whether the original model can produce a return on investment sufficient to justify the large up-front investments. Irrespective of which approach yields a success, it is critically important that more of the second-generation products establish profitability if the field is to enjoy continued investment from both public and private sectors.
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Affiliation(s)
- Todd N McAllister
- Cytograft Tissue Engineering, 3 Hamilton Landing, Ste. 220, Novato, CA 94949, USA.
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43
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Guarita-Souza LC, Teixeira de Carvalho KA, Francisco JC, Simeoni R, Faria-Neto JR. Cellular transplantation for the treatment of non-ischaemic dilated cardiomyopathies. Eur Heart J Suppl 2008. [DOI: 10.1093/eurheartj/sun045] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
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44
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Cheng AS, Yau TM. Paracrine effects of cell transplantation: strategies to augment the efficacy of cell therapies. Semin Thorac Cardiovasc Surg 2008; 20:94-101. [PMID: 18707640 DOI: 10.1053/j.semtcvs.2008.04.003] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/07/2008] [Indexed: 11/11/2022]
Abstract
Within the last few years, it has become evident that the beneficial effect of cell transplantation on ventricular function and myocardial perfusion is in large part mediated through paracrine effects on the host myocardium. Studies in which medium conditioned by cultured cells, usually mesenchymal stem cells, were injected into infarcted animal hearts have provided definitive evidence of this mechanism of action. Paracrine effects of the donor cells include but are not limited to angiogenesis, mobilization of both circulating and bone-marrow-derived stem cells, activation of cardiac-resident stem cells (CRSCs), and stabilization of the extracellular matrix (ECM). These paracrine effects can be augmented by transplantation of cells modified to express therapeutically useful transgenes, or by preconditioning through hypoxic or pharmacologic means. Strategies to enhance the paracrine effects of cell transplantation may thus be employed in the next generation of cell therapies, with greater functional benefit.
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Affiliation(s)
- Andrew S Cheng
- Division of Cardiovascular Surgery, Toronto General Hospital, Toronto, Ontario, Canada
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46
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Robey TE, Saiget MK, Reinecke H, Murry CE. Systems approaches to preventing transplanted cell death in cardiac repair. J Mol Cell Cardiol 2008; 45:567-81. [PMID: 18466917 PMCID: PMC2587485 DOI: 10.1016/j.yjmcc.2008.03.009] [Citation(s) in RCA: 312] [Impact Index Per Article: 18.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2008] [Revised: 02/20/2008] [Accepted: 03/06/2008] [Indexed: 12/26/2022]
Abstract
Stem cell transplantation may repair the injured heart, but tissue regeneration is limited by death of transplanted cells. Most cell death occurs in the first few days post-transplantation, likely from a combination of ischemia, anoikis and inflammation. Interventions known to enhance transplanted cell survival include heat shock, over-expressing anti-apoptotic proteins, free radical scavengers, anti-inflammatory therapy and co-delivery of extracellular matrix molecules. Combinatorial use of such interventions markedly enhances graft cell survival, but death still remains a significant problem. We review these challenges to cardiac cell transplantation and present an approach to systematically address them. Most anti-death studies use histology to assess engraftment, which is time- and labor-intensive. To increase throughput, we developed two biochemical approaches to follow graft viability in the mouse heart. The first relies on LacZ enzymatic activity to track genetically modified cells, and the second quantifies human genomic DNA content using repetitive Alu sequences. Both show linear relationships between input cell number and biochemical signal, but require correction for the time lag between cell death and loss of signal. Once optimized, they permit detection of as few as 1 graft cell in 40,000 host cells. Pro-survival effects measured biochemically at three days predict long-term histological engraftment benefits. These methods permitted identification of carbamylated erythropoietin (CEPO) as a pro-survival factor for human embryonic stem cell-derived cardiomyocyte grafts. CEPO's effects were additive to heat shock, implying independent survival pathways. This system should permit combinatorial approaches to enhance graft viability in a fraction of the time required for conventional histology.
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Affiliation(s)
- Thomas E. Robey
- Department of Bioengineering, University of Washington, Seattle, WA 98195
- Department of Pathology, Center for Cardiovascular Biology, Institute for Stem Cell andRegenerative Medicine, University of Washington, Seattle, WA 98109
| | - Mark K Saiget
- Department of Bioengineering, University of Washington, Seattle, WA 98195
- Department of Pathology, Center for Cardiovascular Biology, Institute for Stem Cell andRegenerative Medicine, University of Washington, Seattle, WA 98109
| | - Hans Reinecke
- Department of Pathology, Center for Cardiovascular Biology, Institute for Stem Cell andRegenerative Medicine, University of Washington, Seattle, WA 98109
| | - Charles E. Murry
- Department of Bioengineering, University of Washington, Seattle, WA 98195
- Department of Pathology, Center for Cardiovascular Biology, Institute for Stem Cell andRegenerative Medicine, University of Washington, Seattle, WA 98109
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Lyon AR, Harding SE, Peters NS. Cardiac stem cell therapy and arrhythmogenicity: prometheus and the arrows of Apollo and Artemis. J Cardiovasc Transl Res 2008; 1:207-16. [PMID: 20559921 DOI: 10.1007/s12265-008-9045-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2008] [Accepted: 06/18/2008] [Indexed: 01/02/2023]
Abstract
Cardiac cell therapy is an expanding scientific field which is yielding new insights into the pathogenesis of cardiac disease and offers new therapeutic strategies. Inherent to both these areas of research are the electrical properties of individual cells, the electrical interplay between cardiomyocytes, and their roles in arrhythmogenesis. This review discusses the potential mechanisms by which various candidate cells for cardiac therapy may modulate the ventricular arrhythmic substrate and highlights the data and lessons learnt from the clinical cardiac cell therapy trials published to date. Pro- and antiarrhythmic mechanistic factors are discussed, and the importance of their consideration in the design of any future clinical cell therapy trials.
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Affiliation(s)
- Alexander R Lyon
- National Heart and Lung Institute, Faculty of Medicine, Imperial College, London, UK
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Laflamme MA, Zbinden S, Epstein SE, Murry CE. Cell-based therapy for myocardial ischemia and infarction: pathophysiological mechanisms. ANNUAL REVIEW OF PATHOLOGY-MECHANISMS OF DISEASE 2008; 2:307-39. [PMID: 18039102 DOI: 10.1146/annurev.pathol.2.010506.092038] [Citation(s) in RCA: 124] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Cell-based cardiac repair has emerged as an attractive approach to preventing or reversing heart failure resulting from myocyte dysfunction-e.g., due to infarction-and to enhancing the development of collaterals in patients with symptoms of myocardial ischemia. These two problems involve both overlapping and differing mechanisms, and these differences must be considered in cell-based therapies. In terms of myocardial dysfunction due to infarction, only committed cardiomyocytes have been shown to form new myocardium that is electrically coupled with the host heart. Despite this, multiple cell populations appear to improve function of the infarcted heart, including many that are clearly nonmyogenic. In terms of myocardial ischemia, although cell-based strategies improve ischemia in animal models, clinical trials to date have not shown robustly beneficial results. We review the evidence for potential mechanisms underlying the benefits of cell transplantation in the heart and discuss the clinical contexts in which they may be relevant.
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Affiliation(s)
- Michael A Laflamme
- Department of Pathology, Center for Cardiovascular Biology, Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington 98109, USA.
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Bao C, Guo J, Lin G, Hu M, Hu Z. TNFR gene-modified mesenchymal stem cells attenuate inflammation and cardiac dysfunction following MI. SCAND CARDIOVASC J 2008; 42:56-62. [PMID: 17852784 DOI: 10.1080/14017430701543556] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
OBJECTIVES To investigate the protective effect of tumor necrosis factor receptor (TNFR) gene modified mesenchymal stem cells (MSCs) transplantation against inflammation and cardiac dysfunction following acute myocardial infarction (AMI). DESIGN MSCs were extracted from the tibias and femurs of rats and transfected with recombinant adeno-associated viral (rAAV) expressing EGFP (enhanced green fluorescent protein) or p75 (human 75 kilodalton) TNFR at multiplicity of infection of 10(5) particles/cell. Rats with AMI induced by occlusion of the left coronary artery were randomized to MSCs-TNFR transplantation group, MSCs-EGFP transplantation group and MI control group. RESULTS The effects of MSCs-TNFR transplantation on cardiac inflammation and left ventricular dysfunction were observed after 2 weeks of MI. We found that: 1) MSCs-TNFR transplantation attenuated protein production and gene expression of inflammatory cytokines TNF-, IL-1beta and IL-6; 2) MSCs-TNFR transplantation inhibited cardiomyocytes apoptosis and 3) MSCs-TNFR transplantation improved left ventricular function. CONCLUSIONS The experimental data show that transplantation with rAAV-TNFR transfected MSCs improves left ventricular function following MI through anti-apoptotic and anti-inflammatory mechanisms.
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MESH Headings
- Animals
- Apoptosis
- Cells, Cultured
- Dependovirus/genetics
- Disease Models, Animal
- Down-Regulation
- Genetic Therapy/methods
- Genetic Vectors
- Humans
- Inflammation Mediators/metabolism
- Interleukin-1beta/metabolism
- Interleukin-6/metabolism
- Male
- Mesenchymal Stem Cell Transplantation
- Mesenchymal Stem Cells/metabolism
- Myocardial Infarction/complications
- Myocardial Infarction/genetics
- Myocardial Infarction/metabolism
- Myocardial Infarction/surgery
- Myocardial Infarction/therapy
- Myocarditis/etiology
- Myocarditis/genetics
- Myocarditis/metabolism
- Myocarditis/prevention & control
- Myocytes, Cardiac/metabolism
- Myocytes, Cardiac/pathology
- Rats
- Rats, Sprague-Dawley
- Receptors, Tumor Necrosis Factor, Type II/genetics
- Receptors, Tumor Necrosis Factor, Type II/metabolism
- Time Factors
- Transfection
- Tumor Necrosis Factor-alpha/metabolism
- Ventricular Dysfunction, Left/etiology
- Ventricular Dysfunction, Left/genetics
- Ventricular Dysfunction, Left/metabolism
- Ventricular Dysfunction, Left/prevention & control
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Affiliation(s)
- Cuiyu Bao
- Cardiovascular Research Institute, Xianning College, and Department of Cardiology, Renmin Hospital, Hubei, PR China
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50
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Taheri SA, Yeh J, Batt RE, Fang Y, Ashraf H, Heffner R, Nemes B, Naughton J. Uterine myometrium as a cell patch as an alternative graft for transplantation to infarcted cardiac myocardium: a preliminary study. Int J Artif Organs 2008; 31:62-7. [PMID: 18286456 DOI: 10.1177/039139880803100109] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
PURPOSE Currently, only a small fraction of patients are able to receive reperfusion therapy for myocardial infarctions. We hypothesize that myometrial cell patch transplantation could be an alternative approach for the treatment of myocardial infarction. DESIGN We performed a preliminary study to determine the feasibility of this novel therapeutic approach in a rabbit model. PROCEDURES Six adult female New Zealand rabbits were used. Myocardial infarction was induced by left anterior descending artery ligation. A segment of uterus was removed via a laparotomy incision, and this uterine segment was transplanted as an autologous graft over the infarcted myocardium, which was then reinforced by greater omentum. Statistical methods and outcome measures: Hemodynamic measurements and histological studies. MAIN FINDINGS All uterine myometrial patches survived in the test animals. Fluoroscopic hemodynamic measurements were made for ejection fractions at 8 weeks after the application of the uterine patch. Histological study demonstrated well-healed myometrial-myocardium junctions with minimum scar tissue. Angiogenesis occurred in the transplanted myometrium. Connexin 43 expression was demonstrated in the transplanted patches. CONCLUSION Our noncontrolled preliminary rabbit experiments indicate that patches of uterine myometrium reinforced by greater omentum can be used as autologous transplant therapy for infracted myocardium. This is an innovative technique that could lead to future treatment for individuals who may suffer from an infarcted myocardium and may not be eligible for traditional reperfusion therapy.
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Affiliation(s)
- S A Taheri
- Department of Thoracic and Cardiovascular Surgery, University at Buffalo and Kaleida Health, Buffalo, New York - USA.
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