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Chen C, Zhong W, Zheng H, Zhao W, Wang Y, Shen B. Current state of heart failure treatment: are mesenchymal stem cells and their exosomes a future therapy? Front Cardiovasc Med 2025; 12:1518036. [PMID: 40357434 PMCID: PMC12066684 DOI: 10.3389/fcvm.2025.1518036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2024] [Accepted: 04/16/2025] [Indexed: 05/15/2025] Open
Abstract
Heart failure (HF) represents the terminal stage of cardiovascular disease and remains a leading cause of mortality. Epidemiological studies indicate a high prevalence and mortality rate of HF globally. Current treatment options primarily include pharmacological and non-pharmacological approaches. With the development of mesenchymal stem cell (MSC) transplantation technology, increasing research has shown that stem cell therapy and exosomes derived from these cells hold promise for repairing damaged myocardium and improving cardiac function, becoming a hot topic in clinical treatment for HF. However, this approach also presents certain limitations. This review summarizes the mechanisms of HF, current treatment strategies, and the latest progress in the application of MSCs and their exosomes in HF therapy.
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Affiliation(s)
- Chengqian Chen
- Department of Cardiology Center, The First Hospital of Jilin University, Changchun, China
| | - Wentao Zhong
- Department of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun, China
| | - Hao Zheng
- Department of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun, China
| | - Wei Zhao
- Department of Cardiology Center, The First Hospital of Jilin University, Changchun, China
| | - Yushi Wang
- Department of Cardiology Center, The First Hospital of Jilin University, Changchun, China
| | - Botao Shen
- Department of Cardiology Center, The First Hospital of Jilin University, Changchun, China
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2
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Guan A, Alibrandi L, Verma E, Sareen N, Guan Q, Lionetti V, Dhingra S. Clinical translation of mesenchymal stem cells in ischemic heart failure: Challenges and future perspectives. Vascul Pharmacol 2025; 159:107491. [PMID: 40112941 DOI: 10.1016/j.vph.2025.107491] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2024] [Revised: 03/12/2025] [Accepted: 03/17/2025] [Indexed: 03/22/2025]
Abstract
Myocardial infarction (MI) with resulting congestive heart failure is one of the leading causes of death worldwide. Current therapies for treating MI, such as devices, traditional medicine, and surgeries, come with many limitations as patients in their final stages of heart failure have little chances of experiencing any reversible changes. In recent decades, Mesenchymal stem cell (MSC) based therapy has become one of the most popular and rapidly developing fields in treating MI. Their supremacy for clinical applications is partially due to their unique properties and encouraging pre-clinical outcomes in various animal disease models. However, the majority of clinical trials registered for MSC therapy for diverse human diseases, including MI, have fallen short of expectations. This review intends to discuss the recent advances in the clinical application of using MSCs for cardiac repair and discuss challenges facing the clinical translation of MSCs for cardiac regeneration such as restoration of endothelial-cardiomyocyte crosstalk, immunomodulation and immune rejection, poor homing and migration, as well as low retention and survival. Furthermore, we will discuss recent strategies being investigated to help overcome some of these challenges.
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Affiliation(s)
- Anqi Guan
- Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Department of Physiology and Pathophysiology, Max Rady College of Medicine, Rady Faculty of Health Sciences, Biomedical Engineering Program, University of Manitoba, Winnipeg, Manitoba R2H 2A6, Canada
| | - Lisa Alibrandi
- TrancriLab, Laboratory of Basic and Applied Medical Sciences, Interdisciplinary Research Center "Health Science", Scuola Superiore Sant'Anna, Pisa, Italy
| | - Elika Verma
- Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Department of Physiology and Pathophysiology, Max Rady College of Medicine, Rady Faculty of Health Sciences, Biomedical Engineering Program, University of Manitoba, Winnipeg, Manitoba R2H 2A6, Canada
| | - Niketa Sareen
- Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Department of Physiology and Pathophysiology, Max Rady College of Medicine, Rady Faculty of Health Sciences, Biomedical Engineering Program, University of Manitoba, Winnipeg, Manitoba R2H 2A6, Canada
| | - Qingdong Guan
- Manitoba Blood and Marrow Transplant Program, CancerCare Manitoba; Department of Immunology and Internal Medicina, University of Manitoba, Winnipeg, Canada
| | - Vincenzo Lionetti
- TrancriLab, Laboratory of Basic and Applied Medical Sciences, Interdisciplinary Research Center "Health Science", Scuola Superiore Sant'Anna, Pisa, Italy.; UOSVD Anesthesiology and Intensive Care, Fondazione Toscana G. Monasterio, Pisa, Italy
| | - Sanjiv Dhingra
- Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Department of Physiology and Pathophysiology, Max Rady College of Medicine, Rady Faculty of Health Sciences, Biomedical Engineering Program, University of Manitoba, Winnipeg, Manitoba R2H 2A6, Canada.
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3
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Seow KS, Ling APK. Mesenchymal stem cells as future treatment for cardiovascular regeneration and its challenges. ANNALS OF TRANSLATIONAL MEDICINE 2024; 12:73. [PMID: 39118948 PMCID: PMC11304428 DOI: 10.21037/atm-23-1936] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Accepted: 12/04/2023] [Indexed: 08/10/2024]
Abstract
Cardiovascular diseases (CVDs), particularly stroke and myocardial infarction (MI) contributed to the leading cause of death annually among the chronic diseases globally. Despite the advancement of technology, the current available treatments mainly served as palliative care but not treating the diseases. However, the discovery of mesenchymal stem cells (MSCs) had gained a consideration to serve as promising strategy in treating CVDs. Recent evidence also showed that MSCs are the strong candidate to be used as stem cell therapy involving cardiovascular regeneration due to its cardiomyogenesis, anti-inflammatory and immunomodulatory properties, antifibrotic effects and neovascularization capacity. Besides, MSCs could be used for cellular cardiomyoplasty with its transdifferentiation of MSCs into cardiomyocytes, paracrine effects, microvesicles and exosomes as well as mitochondrial transfer. The safety and efficacy of utilizing MSCs have been described in well-established preclinical and clinical studies in which the accomplishment of MSCs transplantation resulted in further improvement of the cardiac function. Tissue engineering could enhance the desired properties and therapeutic effects of MSCs in cardiovascular regeneration by genome-editing, facilitating the cell delivery and retention, biomaterials-based scaffold, and three-dimensional (3D)-bioprinting. However, there are still obstacles in the use of MSCs due to the complexity and versatility of MSCs, low retention rate, route of administration and the ethical and safety issues of the use of MSCs. The aim of this review is to highlight the details of therapeutic properties of MSCs in treating CVDs, strategies to facilitate the therapeutic effects of MSCs through tissue engineering and the challenges faced using MSCs. A comprehensive review has been done through PubMed and National Center for Biotechnology Information (NCBI) from the year of 2010 to 2021 based on some specific key terms such as 'mesenchymal stem cells in cardiovascular disease', 'mesenchymal stem cells in cardiac regeneration', 'mesenchymal stem cells facilitate cardiac repairs', 'tissue engineering of MSCs' to include relevant literature in this review.
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Affiliation(s)
- Ke Sin Seow
- Division of Applied Biomedical Sciences and Biotechnology, School of Health Sciences, International Medical University, Kuala Lumpur, Malaysia
| | - Anna Pick Kiong Ling
- Division of Applied Biomedical Sciences and Biotechnology, School of Health Sciences, International Medical University, Kuala Lumpur, Malaysia
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Zhang J, Li J, Qu X, Liu Y, Sun L, Harada A, Hua Y, Sougawa N, Tabata A, Liu L, Miyagawa S. Development of composite functional tissue sheets using hiPSC-CMs and hADSCs to improve the cardiac function after myocardial infarction. Bioact Mater 2024; 37:533-548. [PMID: 38689657 PMCID: PMC11058078 DOI: 10.1016/j.bioactmat.2024.03.028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Revised: 02/28/2024] [Accepted: 03/21/2024] [Indexed: 05/02/2024] Open
Abstract
Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have been widely used in therapy of ischemic heart disease. However, there are still remaining issues that limit the therapeutic efficacy, such as immune rejection and low retention of hiPSC-CMs. Human adipose mesenchymal stromal cells (hADSCs) have been reported to be able to regulate the immune response, promote angiogenesis and promote the maturation of hiPSC-CMs. In this study, we co-cultured these two types of cells on fiber scaffold made of biodegradable poly (D,L-lactic-co-glycolic acid) (PLGA) polymer for several days to develop a composited 3D cardiac tissue sheet. As expected, the cells formed 231.00 ± 15.14 μm thickness tissue, with improved organization, alignment, ECM condition, contractile ability, and paracrine function compared to culture hiPSC-CMs only on PLGA fiber. Furthermore, the composited 3D cardiac tissue sheet significantly promoted the engraftment and survival after transplantation. The composited 3D cardiac tissue sheet also increased cardiac function, attenuated ventricular remodeling, decreased fibrosis, and enhanced angiogenesis in rat myocardial infarction model, indicating that this strategy wound be a promising therapeutic option in the clinical scenario.
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Affiliation(s)
- Jingbo Zhang
- Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Osaka, 565-0871, Japan
| | - Junjun Li
- Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Osaka, 565-0871, Japan
- Department of Applied Physics Osaka University, Osaka University, 2-2 Yamada-oka, Osaka, 565-0871, Japan
| | - Xiang Qu
- Frontier of Regenerative Medicine, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka, 565-0871, Japan
| | - Yuting Liu
- Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Osaka, 565-0871, Japan
| | - Lifu Sun
- Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Osaka, 565-0871, Japan
| | - Akima Harada
- Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Osaka, 565-0871, Japan
| | - Ying Hua
- Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Osaka, 565-0871, Japan
| | - Nagako Sougawa
- Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Osaka, 565-0871, Japan
- Department of Physiology, Osaka Dental University, 8-1 Kuzuha Hanazono-cho, Hirakata, 573-1121, Japan
| | - Akiko Tabata
- Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Osaka, 565-0871, Japan
| | - Li Liu
- Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Osaka, 565-0871, Japan
- Department of Applied Physics Osaka University, Osaka University, 2-2 Yamada-oka, Osaka, 565-0871, Japan
| | - Shigeru Miyagawa
- Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Osaka, 565-0871, Japan
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Fatehi Hassanabad A, Zarzycki AN, Fedak PWM. Cellular and molecular mechanisms driving cardiac tissue fibrosis: On the precipice of personalized and precision medicine. Cardiovasc Pathol 2024; 71:107635. [PMID: 38508436 DOI: 10.1016/j.carpath.2024.107635] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 03/13/2024] [Accepted: 03/15/2024] [Indexed: 03/22/2024] Open
Abstract
Cardiac fibrosis is a significant contributor to heart failure, a condition that continues to affect a growing number of patients worldwide. Various cardiovascular comorbidities can exacerbate cardiac fibrosis. While fibroblasts are believed to be the primary cell type underlying fibrosis, recent and emerging data suggest that other cell types can also potentiate or expedite fibrotic processes. Over the past few decades, clinicians have developed therapeutics that can blunt the development and progression of cardiac fibrosis. While these strategies have yielded positive results, overall clinical outcomes for patients suffering from heart failure continue to be dire. Herein, we overview the molecular and cellular mechanisms underlying cardiac tissue fibrosis. To do so, we establish the known mechanisms that drive fibrosis in the heart, outline the diagnostic tools available, and summarize the treatment options used in contemporary clinical practice. Finally, we underscore the critical role the immune microenvironment plays in the pathogenesis of cardiac fibrosis.
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Affiliation(s)
- Ali Fatehi Hassanabad
- Section of Cardiac Surgery, Department of Cardiac Science, Libin Cardiovascular Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Anna N Zarzycki
- Section of Cardiac Surgery, Department of Cardiac Science, Libin Cardiovascular Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Paul W M Fedak
- Section of Cardiac Surgery, Department of Cardiac Science, Libin Cardiovascular Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
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Barrère-Lemaire S, Vincent A, Jorgensen C, Piot C, Nargeot J, Djouad F. Mesenchymal stromal cells for improvement of cardiac function following acute myocardial infarction: a matter of timing. Physiol Rev 2024; 104:659-725. [PMID: 37589393 DOI: 10.1152/physrev.00009.2023] [Citation(s) in RCA: 31] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 07/05/2023] [Accepted: 08/16/2023] [Indexed: 08/18/2023] Open
Abstract
Acute myocardial infarction (AMI) is the leading cause of cardiovascular death and remains the most common cause of heart failure. Reopening of the occluded artery, i.e., reperfusion, is the only way to save the myocardium. However, the expected benefits of reducing infarct size are disappointing due to the reperfusion paradox, which also induces specific cell death. These ischemia-reperfusion (I/R) lesions can account for up to 50% of final infarct size, a major determinant for both mortality and the risk of heart failure (morbidity). In this review, we provide a detailed description of the cell death and inflammation mechanisms as features of I/R injury and cardioprotective strategies such as ischemic postconditioning as well as their underlying mechanisms. Due to their biological properties, the use of mesenchymal stromal/stem cells (MSCs) has been considered a potential therapeutic approach in AMI. Despite promising results and evidence of safety in preclinical studies using MSCs, the effects reported in clinical trials are not conclusive and even inconsistent. These discrepancies were attributed to many parameters such as donor age, in vitro culture, and storage time as well as injection time window after AMI, which alter MSC therapeutic properties. In the context of AMI, future directions will be to generate MSCs with enhanced properties to limit cell death in myocardial tissue and thereby reduce infarct size and improve the healing phase to increase postinfarct myocardial performance.
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Affiliation(s)
- Stéphanie Barrère-Lemaire
- Institut de Génomique Fonctionnelle, Université de Montpellier, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Montpellier, France
- LabEx Ion Channel Science and Therapeutics, Université de Nice, Nice, France
| | - Anne Vincent
- Institut de Génomique Fonctionnelle, Université de Montpellier, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Montpellier, France
- LabEx Ion Channel Science and Therapeutics, Université de Nice, Nice, France
| | - Christian Jorgensen
- Institute of Regenerative Medicine and Biotherapies, Université de Montpellier, Institut National de la Santé et de la Recherche Médicale, Montpellier, France
- Centre Hospitalier Universitaire Montpellier, Montpellier, France
| | - Christophe Piot
- Département de Cardiologie Interventionnelle, Clinique du Millénaire, Montpellier, France
| | - Joël Nargeot
- Institut de Génomique Fonctionnelle, Université de Montpellier, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Montpellier, France
- LabEx Ion Channel Science and Therapeutics, Université de Nice, Nice, France
| | - Farida Djouad
- Institute of Regenerative Medicine and Biotherapies, Université de Montpellier, Institut National de la Santé et de la Recherche Médicale, Montpellier, France
- Centre Hospitalier Universitaire Montpellier, Montpellier, France
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7
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Hassanzadeh A, Shomali N, Kamrani A, Nasiri H, Ahmadian Heris J, Pashaiasl M, Sadeghi M, Sadeghvand S, Valedkarimi Z, Akbari M. Detailed role of mesenchymal stem cell (MSC)-derived exosome therapy in cardiac diseases. EXCLI JOURNAL 2024; 23:401-420. [PMID: 38741729 PMCID: PMC11089093 DOI: 10.17179/excli2023-6538] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Accepted: 01/05/2024] [Indexed: 05/16/2024]
Abstract
Coronary heart disease (CHD) continues to be the leading cause of morbidity and mortality. There are numerous therapeutic reperfusion methods, including thrombolytic therapy, primary percutaneous coronary intervention, and anti-remodeling drugs like angiotensin-converting enzyme inhibitors and beta-blockers. Despite this, there is no pharmacological treatment that can effectively stop cardiomyocyte death brought on by myocardial ischemia/reperfusion (I/R) injury. For the purpose of regenerating cardiac tissue, mesenchymal stem cell (MSC) therapy has recently gained more attention. The pleiotropic effects of MSCs are instead arbitrated by the secretion of soluble paracrine factors and are unrelated to their capacity for differentiation. One of these paracrine mediators is the extracellular vesicle known as an exosome. Exosomes deliver useful cargo to recipient cells from MSCs, including peptides, proteins, cytokines, lipids, miRNA, and mRNA molecules. Exosomes take part in intercellular communication processes and help tissues and organs that have been injured or are ill heal. Exosomes alone were found to be the cause of MSCs' therapeutic effects in a variety of animal models, according to studies. Here, we have focused on the recent development in the therapeutic capabilities of exosomal MSCs in cardiac diseases.
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Affiliation(s)
- Ali Hassanzadeh
- Department of Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Navid Shomali
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amin Kamrani
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hadi Nasiri
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Javad Ahmadian Heris
- Department of Allergy and Clinical Immunology, Pediatric Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Maryam Pashaiasl
- Department of Anatomical Sciences, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
- Women’s Reproductive Health Research Center, Tabriz University of Medical Sciences, P.O. Box 51376563833, Tabriz, Iran
| | - Mohammadreza Sadeghi
- Department of Molecular Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Shahram Sadeghvand
- Pediatrics Health Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Zahra Valedkarimi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Morteza Akbari
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
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Gill JK, Rehsia SK, Verma E, Sareen N, Dhingra S. Stem cell therapy for cardiac regeneration: past, present, and future. Can J Physiol Pharmacol 2024; 102:161-179. [PMID: 38226807 DOI: 10.1139/cjpp-2023-0202] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2024]
Abstract
Cardiac disorders remain the leading cause of mortality worldwide. Current clinical strategies, including drug therapy, surgical interventions, and organ transplantation offer limited benefits to patients without regenerating the damaged myocardium. Over the past decade, stem cell therapy has generated a keen interest owing to its unique self-renewal and immune privileged characteristics. Furthermore, the ability of stem cells to differentiate into specialized cell types, has made them a popular therapeutic tool against various diseases. This comprehensive review provides an overview of therapeutic potential of different types of stem cells in reference to cardiovascular diseases. Furthermore, it sheds light on the advantages and limitations associated with each cell type. An in-depth analysis of the challenges associated with stem cell research and the hurdles for its clinical translation and their possible solutions have also been elaborated upon. It examines the controversies surrounding embryonic stem cells and the emergence of alternative approaches, such as the use of induced pluripotent stem cells for cardiac therapeutic applications. Overall, this review serves as a valuable resource for researchers, clinicians, and policymakers involved in the field of regenerative medicine, guiding the development of safe and effective stem cell-based therapies to revolutionize patient care.
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Affiliation(s)
- Jaideep Kaur Gill
- Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre Regenerative Medicine Program, Department of Physiology and Pathophysiology, Rady Faculty of Health Sciences, Biomedical Engineering Program, University of Manitoba, Winnipeg MB, R2H2A6, Canada
| | - Sargun Kaur Rehsia
- Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre Regenerative Medicine Program, Department of Physiology and Pathophysiology, Rady Faculty of Health Sciences, Biomedical Engineering Program, University of Manitoba, Winnipeg MB, R2H2A6, Canada
| | - Elika Verma
- Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre Regenerative Medicine Program, Department of Physiology and Pathophysiology, Rady Faculty of Health Sciences, Biomedical Engineering Program, University of Manitoba, Winnipeg MB, R2H2A6, Canada
| | - Niketa Sareen
- Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre Regenerative Medicine Program, Department of Physiology and Pathophysiology, Rady Faculty of Health Sciences, Biomedical Engineering Program, University of Manitoba, Winnipeg MB, R2H2A6, Canada
| | - Sanjiv Dhingra
- Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre Regenerative Medicine Program, Department of Physiology and Pathophysiology, Rady Faculty of Health Sciences, Biomedical Engineering Program, University of Manitoba, Winnipeg MB, R2H2A6, Canada
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Yang GD, Ma DS, Ma CY, Bai Y. Research Progress on Cardiac Tissue Construction of Mesenchymal Stem Cells for Myocardial Infarction. Curr Stem Cell Res Ther 2024; 19:942-958. [PMID: 37612870 DOI: 10.2174/1574888x18666230823091017] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 07/13/2023] [Accepted: 07/26/2023] [Indexed: 08/25/2023]
Abstract
Heart failure is still the main complication affecting the prognosis of acute myocardial infarction (AMI), and mesenchymal stem cells (MSCs) are an effective treatment to replace necrotic myocardium and improve cardiac functioning. However, the transplant survival rate of MSCs still presents challenges. In this review, the biological characteristics of MSCs, the progress of mechanism research in the treatment of myocardial infarction, and the advances in improving the transplant survival rate of MSCs in the replacement of necrotic myocardial infarction are systematically described. From a basic to advanced clinical research, MSC transplants have evolved from a pure injection, an exosome injection, the genetic modification of MSCs prior to injection to the cardiac tissue engineering of MSC patch grafting. This study shows that MSCs have wide clinical applications in the treatment of AMI, suggesting improved myocardial tissue creation. A broader clinical application prospect will be explored and developed to improve the survival rate of MSC transplants and myocardial vascularization.
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Affiliation(s)
- Guo-Dong Yang
- Department of Cardiac Surgery, The First Hospital of Jilin University, Changchun, 130021, China
| | - Da-Shi Ma
- Department of Cardiac Surgery, The First Hospital of Jilin University, Changchun, 130021, China
| | - Chun-Ye Ma
- Department of Cardiac Surgery, The First Hospital of Jilin University, Changchun, 130021, China
| | - Yang Bai
- Department of Cardiac Surgery, The First Hospital of Jilin University, Changchun, 130021, China
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10
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Chepeleva EV. Cell Therapy in the Treatment of Coronary Heart Disease. Int J Mol Sci 2023; 24:16844. [PMID: 38069167 PMCID: PMC10706847 DOI: 10.3390/ijms242316844] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 11/24/2023] [Accepted: 11/27/2023] [Indexed: 12/18/2023] Open
Abstract
Heart failure is a leading cause of death in patients who have suffered a myocardial infarction. Despite the timely use of modern reperfusion therapies such as thrombolysis, surgical revascularization and balloon angioplasty, they are sometimes unable to prevent the development of significant areas of myocardial damage and subsequent heart failure. Research efforts have focused on developing strategies to improve the functional status of myocardial injury areas. Consequently, the restoration of cardiac function using cell therapy is an exciting prospect. This review describes the characteristics of various cell types relevant to cellular cardiomyoplasty and presents findings from experimental and clinical studies investigating cell therapy for coronary heart disease. Cell delivery methods, optimal dosage and potential treatment mechanisms are discussed.
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Affiliation(s)
- Elena V. Chepeleva
- Federal State Budgetary Institution National Medical Research Center Named after Academician E.N. Meshalkin of the Ministry of Health of the Russian Federation, 15, Rechkunovskaya Str., 630055 Novosibirsk, Russia;
- Research Institute of Clinical and Experimental Lymphology—Branch of the Institute of Cytology and Genetics Siberian Branch of Russian Academy of Sciences, 2, Timakova Str., 630060 Novosibirsk, Russia
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11
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Seok J, Park H, Lee DH, You JH, Kim GJ. The Dose-Related Efficacy of Human Placenta-Derived Mesenchymal Stem Cell Transplantation on Antioxidant Effects in a Rat Model with Ovariectomy. Antioxidants (Basel) 2023; 12:1575. [PMID: 37627570 PMCID: PMC10451747 DOI: 10.3390/antiox12081575] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Revised: 07/26/2023] [Accepted: 08/03/2023] [Indexed: 08/27/2023] Open
Abstract
Oxidative stress initiates various degenerative diseases, and it is caused by excessive reactive oxygen species (ROS) production. Oxidative stress is a key factor that causes infertility by inducing ovarian dysfunction, characterized by irregular hormone levels, lower quality of mature follicles, and loss of follicles. Hence, stem cell therapy has been actively studied as an approach to overcome the side effects of hormone replacement therapy (HRT) on ovarian dysfunction. However, there is a lack of evidence about the appropriate number of cells required for stem cell therapy. Therefore, based on the antioxidant effects investigated in this study, we focused on determining the appropriate dose of stem cells for transplantation in an animal model with ovarian dysfunction. One week after half-ovariectomy, placenta-derived mesenchymal stem cells (PD-MSCs, 1 × 105 cells, 5 × 105 cells, or 2.5 × 106 cells) were injected intravenously into the Tx groups through the tail vein. As a result, the mRNA expression of hAlu gradually increased as the transplanted cell concentration increased. Compared with no transplantation (NTx), the transplantation of PD-MSCs improved folliculogenesis, including the levels of secreted hormones and numbers of follicles, by exerting antioxidant effects. Also, the levels of oxidized glutathione in the serum of animal models after transplantation were significantly increased (* p < 0.05). These results indicated that PD-MSC transplantation improved ovarian function in half-ovariectomized rats by exerting antioxidant effects. According to our data, increasing the number of transplanted cells did not proportionally increase the effectiveness of the treatment. We suggest that low-dose PD-MSC transplantation has the same therapeutic effect as described in previous studies. These findings provide new insights for further understanding reproductive systems and provide evidence for related clinical trials.
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Affiliation(s)
- Jin Seok
- Department of Bioinspired Science, CHA University, Seongnam-si 13488, Republic of Korea; (J.S.); (H.P.); (D.-H.L.); (J.H.Y.)
| | - Hyeri Park
- Department of Bioinspired Science, CHA University, Seongnam-si 13488, Republic of Korea; (J.S.); (H.P.); (D.-H.L.); (J.H.Y.)
- PLABiologics, Co., Ltd., Seongnam-si 13522, Republic of Korea
| | - Dae-Hyun Lee
- Department of Bioinspired Science, CHA University, Seongnam-si 13488, Republic of Korea; (J.S.); (H.P.); (D.-H.L.); (J.H.Y.)
- PLABiologics, Co., Ltd., Seongnam-si 13522, Republic of Korea
| | - Jun Hyeong You
- Department of Bioinspired Science, CHA University, Seongnam-si 13488, Republic of Korea; (J.S.); (H.P.); (D.-H.L.); (J.H.Y.)
| | - Gi Jin Kim
- Department of Bioinspired Science, CHA University, Seongnam-si 13488, Republic of Korea; (J.S.); (H.P.); (D.-H.L.); (J.H.Y.)
- PLABiologics, Co., Ltd., Seongnam-si 13522, Republic of Korea
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12
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Alhejailan RS, Garoffolo G, Raveendran VV, Pesce M. Cells and Materials for Cardiac Repair and Regeneration. J Clin Med 2023; 12:jcm12103398. [PMID: 37240504 DOI: 10.3390/jcm12103398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Revised: 05/05/2023] [Accepted: 05/09/2023] [Indexed: 05/28/2023] Open
Abstract
After more than 20 years following the introduction of regenerative medicine to address the problem of cardiac diseases, still questions arise as to the best cell types and materials to use to obtain effective clinical translation. Now that it is definitively clear that the heart does not have a consistent reservoir of stem cells that could give rise to new myocytes, and that there are cells that could contribute, at most, with their pro-angiogenic or immunomodulatory potential, there is fierce debate on what will emerge as the winning strategy. In this regard, new developments in somatic cells' reprogramming, material science and cell biophysics may be of help, not only for protecting the heart from the deleterious consequences of aging, ischemia and metabolic disorders, but also to boost an endogenous regeneration potential that seems to be lost in the adulthood of the human heart.
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Affiliation(s)
- Reem Saud Alhejailan
- Cell Biology Department, King's Faisal Specialist Hospital & Research Center, Riyadh 11564, Saudi Arabia
| | - Gloria Garoffolo
- Unità di Ingegneria Tissutale Cardiovascolare, Centro Cardiologico Monzino, IRCCS, 20138 Milan, Italy
| | - Vineesh Vimala Raveendran
- Cell Biology Department, King's Faisal Specialist Hospital & Research Center, Riyadh 11564, Saudi Arabia
| | - Maurizio Pesce
- Unità di Ingegneria Tissutale Cardiovascolare, Centro Cardiologico Monzino, IRCCS, 20138 Milan, Italy
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13
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Ramnaraign DJ, Godbout C, Hali K, Hegner C, Bates BD, Desjardins S, Peck J, Schemitsch EH, Nauth A. Endothelial Progenitor Cell Therapy for Fracture Healing: A Dose-Response Study in a Rat Femoral Defect Model. J Tissue Eng Regen Med 2023; 2023:8105599. [PMID: 40226398 PMCID: PMC11918885 DOI: 10.1155/2023/8105599] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 02/17/2023] [Accepted: 02/20/2023] [Indexed: 04/15/2025]
Abstract
Endothelial progenitor cell (EPC) therapy has been successfully used in orthopaedic preclinical models to heal bone defects. However, no previous studies have investigated the dose-response relationship between EPC therapy and bone healing. This study aimed to assess the effect of different EPC doses on bone healing in a rat model to define an optimal dose. Five-millimeter segmental defects were created in the right femora of Fischer 344 rats, followed by stabilization with a miniplate and screws. Rats were assigned to one of six groups (control, 0.1 M, 0.5 M, 1.0 M, 2.0 M, and 4.0 M; n = 6), receiving 0, 1 × 105, 5 × 105, 1 × 106, 2 × 106, and 4 × 106 EPCs, respectively, delivered into the defect on a gelatin scaffold. Radiographs were taken every two weeks until the animals were euthanized 10 weeks after surgery. The operated femora were then evaluated using micro-computed tomography and biomechanical testing. Overall, the groups that received higher doses of EPCs (0.5 M, 1.0 M, 2.0 M, and 4.0 M) reached better outcomes. At 10 weeks, full radiographic union was observed in 67% of animals in the 0.5 M group, 83% of animals in the 1.0 M group, and 100% of the animals in the 2.0 M and 4.0 M groups, but none in the control and 0.1 M groups. The 2.0 M group also displayed the strongest biomechanical properties, which significantly improved relative to the control and 0.1 M groups. In summary, this study defined a dose-response relationship between EPC therapy and bone healing, with 2 × 106 EPCs being the optimal dose in this model. Our findings emphasize the importance of dosing considerations in the application of cell therapies aimed at tissue regeneration and will help guide future investigations and clinical translation of EPC therapy.
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Affiliation(s)
- David J. Ramnaraign
- Keenan Research Centre for Biomedical Science, Unity Health Toronto (St. Michael's Hospital), University of Toronto, Toronto, Ontario, Canada
| | - Charles Godbout
- Keenan Research Centre for Biomedical Science, Unity Health Toronto (St. Michael's Hospital), University of Toronto, Toronto, Ontario, Canada
| | - Kalter Hali
- Keenan Research Centre for Biomedical Science, Unity Health Toronto (St. Michael's Hospital), University of Toronto, Toronto, Ontario, Canada
| | - Christian Hegner
- Keenan Research Centre for Biomedical Science, Unity Health Toronto (St. Michael's Hospital), University of Toronto, Toronto, Ontario, Canada
| | - Brent D. Bates
- Keenan Research Centre for Biomedical Science, Unity Health Toronto (St. Michael's Hospital), University of Toronto, Toronto, Ontario, Canada
| | - Sarah Desjardins
- Keenan Research Centre for Biomedical Science, Unity Health Toronto (St. Michael's Hospital), University of Toronto, Toronto, Ontario, Canada
| | - Jonathan Peck
- Division of Orthopaedic Surgery, Department of Surgery, Unity Health Toronto (St. Michael's Hospital), University of Toronto, Toronto, Ontario, Canada
| | | | - Aaron Nauth
- Keenan Research Centre for Biomedical Science, Unity Health Toronto (St. Michael's Hospital), University of Toronto, Toronto, Ontario, Canada
- Division of Orthopaedic Surgery, Department of Surgery, Unity Health Toronto (St. Michael's Hospital), University of Toronto, Toronto, Ontario, Canada
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14
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Szydlak R. Mesenchymal stem cells in ischemic tissue regeneration. World J Stem Cells 2023; 15:16-30. [PMID: 36909782 PMCID: PMC9993139 DOI: 10.4252/wjsc.v15.i2.16] [Citation(s) in RCA: 4] [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: 10/14/2022] [Revised: 11/10/2022] [Accepted: 01/19/2023] [Indexed: 02/21/2023] Open
Abstract
Diseases caused by ischemia are one of the leading causes of death in the world. Current therapies for treating acute myocardial infarction, ischemic stroke, and critical limb ischemia do not complete recovery. Regenerative therapies opens new therapeutic strategy in the treatment of ischemic disorders. Mesenchymal stem cells (MSCs) are the most promising option in the field of cell-based therapies, due to their secretory and immunomodulatory abilities, that contribute to ease inflammation and promote the regeneration of damaged tissues. This review presents the current knowledge of the mechanisms of action of MSCs and their therapeutic effects in the treatment of ischemic diseases, described on the basis of data from in vitro experiments and preclinical animal studies, and also summarize the effects of using these cells in clinical trial settings. Since the obtained therapeutic benefits are not always satisfactory, approaches aimed at enhancing the effect of MSCs in regenerative therapies are presented at the end.
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Affiliation(s)
- Renata Szydlak
- Chair of Medical Biochemistry, Faculty of Medicine, Jagiellonian University Medical College, Kraków 31-034, Poland
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15
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Liao R, Li Z, Wang Q, Lin H, Sun H. Revascularization of chronic total occlusion coronary artery and cardiac regeneration. Front Cardiovasc Med 2022; 9:940808. [PMID: 36093131 PMCID: PMC9455703 DOI: 10.3389/fcvm.2022.940808] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Accepted: 08/05/2022] [Indexed: 11/13/2022] Open
Abstract
Coronary chronic total occlusion (CTO) contributes to the progression of heart failure in patients with ischemic cardiomyopathy. Randomized controlled trials demonstrated that percutaneous coronary intervention (PCI) for CTO significantly improves angina symptoms and quality of life but fails to reduce clinical events compared with optimal medical therapy. Even so, intervening physicians strongly support CTO-PCI. Cardiac regeneration therapy after CTO-PCI should be a promising approach to improving the prognosis of ischemic cardiomyopathy. However, the relationship between CTO revascularization and cardiac regeneration has rarely been studied, and experimental studies on cardiac regeneration usually employ rodent models with permanent ligation of the coronary artery rather than reopening of the occlusive artery. Limited early-stage clinical trials demonstrated that cell therapy for cardiac regeneration in ischemic cardiomyopathy reduces scar size, reverses cardiac remodeling, and promotes angiogenesis. This review focuses on the status quo of CTO-PCI in ischemic cardiomyopathy and the clinical prospect of cardiac regeneration in this setting.
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Affiliation(s)
- Ruoxi Liao
- Department of Clinical Medicine, Dalian Medical University, Dalian, China
| | - Zhihong Li
- State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Qiancheng Wang
- State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Hairuo Lin
- State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China
- *Correspondence: Hairuo Lin, ,
| | - Huijun Sun
- Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China
- Huijun Sun,
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16
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Ahmad B, Skorska A, Wolfien M, Sadraddin H, Lemcke H, Vasudevan P, Wolkenhauer O, Steinhoff G, David R, Gaebel R. The Effects of Hypoxic Preconditioned Murine Mesenchymal Stem Cells on Post-Infarct Arrhythmias in the Mouse Model. Int J Mol Sci 2022; 23:ijms23168843. [PMID: 36012110 PMCID: PMC9408396 DOI: 10.3390/ijms23168843] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Revised: 08/04/2022] [Accepted: 08/05/2022] [Indexed: 11/16/2022] Open
Abstract
Ventricular arrhythmias associated with myocardial infarction (MI) have a significant impact on mortality in patients following heart attack. Therefore, targeted reduction of arrhythmia represents a therapeutic approach for the prevention and treatment of severe events after infarction. Recent research transplanting mesenchymal stem cells (MSC) showed their potential in MI therapy. Our study aimed to investigate the effects of MSC injection on post-infarction arrhythmia. We used our murine double infarction model, which we previously established, to more closely mimic the clinical situation and intramyocardially injected hypoxic pre-conditioned murine MSC to the infarction border. Thereafter, various types of arrhythmias were recorded and analyzed. We observed a homogenous distribution of all types of arrhythmias after the first infarction, without any significant differences between the groups. Yet, MSC therapy after double infarction led to a highly significant reduction in simple and complex arrhythmias. Moreover, RNA-sequencing of samples from stem cell treated mice after re-infarction demonstrated a significant decline in most arrhythmias with reduced inflammatory pathways. Additionally, following stem-cell therapy we found numerous highly expressed genes to be either linked to lowering the risk of heart failure, cardiomyopathy or sudden cardiac death. Moreover, genes known to be associated with arrhythmogenesis and key mutations underlying arrhythmias were downregulated. In summary, our stem-cell therapy led to a reduction in cardiac arrhythmias after MI and showed a downregulation of already established inflammatory pathways. Furthermore, our study reveals gene regulation pathways that have a potentially direct influence on arrhythmogenesis after myocardial infarction.
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Affiliation(s)
- Beschan Ahmad
- Department of Cardiac Surgery, Rostock University Medical Center, 18057 Rostock, Germany
- Department of Life, Light & Matter, Interdisciplinary Faculty, Rostock University, 18059 Rostock, Germany
| | - Anna Skorska
- Department of Cardiac Surgery, Rostock University Medical Center, 18057 Rostock, Germany
- Department of Life, Light & Matter, Interdisciplinary Faculty, Rostock University, 18059 Rostock, Germany
| | - Markus Wolfien
- Department of Systems Biology and Bioinformatics, University of Rostock, 18051 Rostock, Germany
- Institute for Medical Informatics and Biometry, Faculty of Medicine Carl Gustav Carus, Technical University Dresden, 01307 Dresden, Germany
| | - Haval Sadraddin
- Department of Cardiac Surgery, Rostock University Medical Center, 18057 Rostock, Germany
- Department of Life, Light & Matter, Interdisciplinary Faculty, Rostock University, 18059 Rostock, Germany
| | - Heiko Lemcke
- Department of Cardiac Surgery, Rostock University Medical Center, 18057 Rostock, Germany
- Department of Life, Light & Matter, Interdisciplinary Faculty, Rostock University, 18059 Rostock, Germany
| | - Praveen Vasudevan
- Department of Cardiac Surgery, Rostock University Medical Center, 18057 Rostock, Germany
- Department of Life, Light & Matter, Interdisciplinary Faculty, Rostock University, 18059 Rostock, Germany
| | - Olaf Wolkenhauer
- Department of Systems Biology and Bioinformatics, University of Rostock, 18051 Rostock, Germany
| | - Gustav Steinhoff
- Department of Cardiac Surgery, Rostock University Medical Center, 18057 Rostock, Germany
- Department of Life, Light & Matter, Interdisciplinary Faculty, Rostock University, 18059 Rostock, Germany
| | - Robert David
- Department of Cardiac Surgery, Rostock University Medical Center, 18057 Rostock, Germany
- Department of Life, Light & Matter, Interdisciplinary Faculty, Rostock University, 18059 Rostock, Germany
- Correspondence: ; Tel.: +49-381-4988973; Fax: +49-381-4988970
| | - Ralf Gaebel
- Department of Cardiac Surgery, Rostock University Medical Center, 18057 Rostock, Germany
- Department of Life, Light & Matter, Interdisciplinary Faculty, Rostock University, 18059 Rostock, Germany
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17
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Munderere R, Kim SH, Kim C, Park SH. The Progress of Stem Cell Therapy in Myocardial-Infarcted Heart Regeneration: Cell Sheet Technology. Tissue Eng Regen Med 2022; 19:969-986. [PMID: 35857259 DOI: 10.1007/s13770-022-00467-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Revised: 05/18/2022] [Accepted: 05/19/2022] [Indexed: 11/30/2022] Open
Abstract
Various tissues, including the heart, cornea, bone, esophagus, bladder and liver, have been vascularized using the cell sheet technique. It overcomes the limitations of existing techniques by allowing small layers of the cell sheet to generate capillaries on their own, and it can also be used to vascularize tissue-engineered transplants. Cell sheets eliminate the need for traditional tissue engineering procedures such as isolated cell injections and scaffold-based technologies, which have limited applicability. While cell sheet engineering can eliminate many of the drawbacks, there are still a few challenges that need to be addressed. The number of cell sheets that can be layered without triggering core ischemia or hypoxia is limited. Even when scaffold-based technologies are disregarded, strategies to tackle this problem remain a substantial impediment to the efficient regeneration of thick, living three-dimensional cell sheets. In this review, we summarize the cell sheet technology in myocardial infarcted tissue regeneration.
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Affiliation(s)
- Raissa Munderere
- Industry 4.0 Convergence Bionics Engineering, Pukyong National University, Busan, Republic of Korea.,The Center for Marine Integrated Biomedical Technology (BK21 PLUS), Pukyong National University, Busan, Republic of Korea
| | - Seon-Hwa Kim
- Industry 4.0 Convergence Bionics Engineering, Pukyong National University, Busan, Republic of Korea.,The Center for Marine Integrated Biomedical Technology (BK21 PLUS), Pukyong National University, Busan, Republic of Korea
| | - Changsu Kim
- Department of Orthopedics Surgery, Kosin University Gospel Hospital, Busan, Republic of Korea
| | - Sang-Hyug Park
- Industry 4.0 Convergence Bionics Engineering, Pukyong National University, Busan, Republic of Korea. .,The Center for Marine Integrated Biomedical Technology (BK21 PLUS), Pukyong National University, Busan, Republic of Korea. .,Major of Biomedical Engineering, Division of Smart Healthcare, College of Information Technology and Convergence, Pukyong National University, 45 Yongso-ro, Nam-gu, Busan, 48513, Republic of Korea.
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18
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Shazly T, Smith A, Uline MJ, Spinale FG. Therapeutic payload delivery to the myocardium: Evolving strategies and obstacles. JTCVS OPEN 2022; 10:185-194. [PMID: 36004211 PMCID: PMC9390211 DOI: 10.1016/j.xjon.2022.04.043] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Revised: 04/19/2022] [Accepted: 04/27/2022] [Indexed: 06/15/2023]
Key Words
- BMC, bone marrow cell
- HF, heart failure
- ID, intracoronary delivery
- IMD, intramyocardial delivery
- IPD, intrapericardial delivery
- LV, left ventricle
- MI, myocardial infarct
- MSC, mesenchymal stem cell
- TED, transendocardial delivery
- bFGF, basic fibroblast growth factor
- biomaterial
- cardiac
- injection
- local delivery
- myocardium
- payload
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Affiliation(s)
- Tarek Shazly
- College of Engineering and Computing, School of Medicine, University of South Carolina, Columbia, SC
| | - Arianna Smith
- College of Arts and Sciences, Florida Gulf Coast University, Fort Myers, Fla
| | - Mark J. Uline
- College of Engineering and Computing, School of Medicine, University of South Carolina, Columbia, SC
| | - Francis G. Spinale
- College of Engineering and Computing, School of Medicine, University of South Carolina, Columbia, SC
- Cardiovascular Translational Research Center, School of Medicine, University of South Carolina, Columbia, SC
- Columbia VA Health Care System, Columbia, SC
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19
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Tracy EP, Stielberg V, Rowe G, Benson D, Nunes SS, Hoying JB, Murfee WL, LeBlanc AJ. State of the field: cellular and exosomal therapeutic approaches in vascular regeneration. Am J Physiol Heart Circ Physiol 2022; 322:H647-H680. [PMID: 35179976 PMCID: PMC8957327 DOI: 10.1152/ajpheart.00674.2021] [Citation(s) in RCA: 15] [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: 12/14/2021] [Revised: 02/07/2022] [Accepted: 02/09/2022] [Indexed: 01/19/2023]
Abstract
Pathologies of the vasculature including the microvasculature are often complex in nature, leading to loss of physiological homeostatic regulation of patency and adequate perfusion to match tissue metabolic demands. Microvascular dysfunction is a key underlying element in the majority of pathologies of failing organs and tissues. Contributing pathological factors to this dysfunction include oxidative stress, mitochondrial dysfunction, endoplasmic reticular (ER) stress, endothelial dysfunction, loss of angiogenic potential and vascular density, and greater senescence and apoptosis. In many clinical settings, current pharmacologic strategies use a single or narrow targeted approach to address symptoms of pathology rather than a comprehensive and multifaceted approach to address their root cause. To address this, efforts have been heavily focused on cellular therapies and cell-free therapies (e.g., exosomes) that can tackle the multifaceted etiology of vascular and microvascular dysfunction. In this review, we discuss 1) the state of the field in terms of common therapeutic cell population isolation techniques, their unique characteristics, and their advantages and disadvantages, 2) common molecular mechanisms of cell therapies to restore vascularization and/or vascular function, 3) arguments for and against allogeneic versus autologous applications of cell therapies, 4) emerging strategies to optimize and enhance cell therapies through priming and preconditioning, and, finally, 5) emerging strategies to bolster therapeutic effect. Relevant and recent clinical and animal studies using cellular therapies to restore vascular function or pathologic tissue health by way of improved vascularization are highlighted throughout these sections.
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Affiliation(s)
- Evan Paul Tracy
- Cardiovascular Innovation Institute and the Department of Physiology, University of Louisville, Louisville, Kentucky
| | - Virginia Stielberg
- Cardiovascular Innovation Institute and the Department of Physiology, University of Louisville, Louisville, Kentucky
| | - Gabrielle Rowe
- Cardiovascular Innovation Institute and the Department of Physiology, University of Louisville, Louisville, Kentucky
| | - Daniel Benson
- Cardiovascular Innovation Institute and the Department of Physiology, University of Louisville, Louisville, Kentucky
- Department of Bioengineering, University of Louisville, Louisville, Kentucky
| | - Sara S Nunes
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
- Institute of Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada
- Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
- Heart & Stroke/Richard Lewar Centre of Excellence, University of Toronto, Toronto, Ontario, Canada
| | - James B Hoying
- Advanced Solutions Life Sciences, Manchester, New Hampshire
| | - Walter Lee Murfee
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, Florida
| | - Amanda Jo LeBlanc
- Cardiovascular Innovation Institute and the Department of Physiology, University of Louisville, Louisville, Kentucky
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20
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Frljak S, Poglajen G, Vrtovec B. Cell Therapy in Heart Failure with Preserved Ejection Fraction. Card Fail Rev 2022; 8:e08. [PMID: 35399548 PMCID: PMC8977993 DOI: 10.15420/cfr.2021.21] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Accepted: 11/19/2021] [Indexed: 12/27/2022] Open
Abstract
Heart failure with preserved ejection fraction (HFpEF) is the most common cause of hospitalisation for heart failure. However, only limited effective treatments are available. Recent evidence suggests that HFpEF may result from a systemic proinflammatory state, microvascular endothelial inflammation and microvascular rarefaction. Formation of new microvasculature in ischaemic tissues is dependent on CD34+ cells, which incorporate into the newly developing vasculature and produce pro-angiogenic cytokines. In HFpEF patients, worsening of diastolic function appears to correlate with decreased numbers of CD34+ cells. Therefore, it is plausible that increasing the myocardial numbers of CD34+ cells could theoretically lead to improved microvascular function and improved diastolic parameters in HFpEF. In accordance with this hypothesis, recent pilot clinical data suggest that CD34+ cell therapy may indeed be associated with improved diastolic function and better functional capacity in HFpEF patients and could thus represent a promising novel therapeutic modality for this patient population.
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Affiliation(s)
- Sabina Frljak
- Advanced Heart Failure and Transplantation Center, UMC Ljubljana, Slovenia
| | - Gregor Poglajen
- Advanced Heart Failure and Transplantation Center, UMC Ljubljana, Slovenia
| | - Bojan Vrtovec
- Advanced Heart Failure and Transplantation Center, UMC Ljubljana, Slovenia
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21
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Tang XL, Wysoczynski M, Gumpert AM, Li Y, Wu WJ, Li H, Stowers H, Bolli R. Effect of intravenous cell therapy in rats with old myocardial infarction. Mol Cell Biochem 2022; 477:431-444. [PMID: 34783963 PMCID: PMC8896398 DOI: 10.1007/s11010-021-04283-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2021] [Accepted: 10/21/2021] [Indexed: 10/19/2022]
Abstract
Mounting evidence shows that cell therapy provides therapeutic benefits in experimental and clinical settings of chronic heart failure. However, direct cardiac delivery of cells via transendocardial injection is logistically complex, expensive, entails risks, and is not amenable to multiple dosing. Intravenous administration would be a more convenient and clinically applicable route for cell therapy. Thus, we determined whether intravenous infusion of three widely used cell types improves left ventricular (LV) function and structure and compared their efficacy. Rats with a 30-day-old myocardial infarction (MI) received intravenous infusion of vehicle (PBS) or 1 of 3 types of cells: bone marrow mesenchymal stromal cells (MSCs), cardiac mesenchymal cells (CMCs), and c-kit-positive cardiac cells (CPCs), at a dose of 12 × 106 cells. Rats were followed for 35 days after treatment to determine LV functional status by serial echocardiography and hemodynamic studies. Blood samples were collected for Hemavet analysis to determine inflammatory cell profile. LV ejection fraction (EF) dropped ≥ 20 points in all hearts at 30 days after MI and deteriorated further at 35-day follow-up in the vehicle-treated group. In contrast, deterioration of EF was halted in rats that received MSCs and attenuated in those that received CMCs or CPCs. None of the 3 types of cells significantly altered scar size, myocardial content of collagen or CD45-positive cells, or Hemavet profile. This study demonstrates that a single intravenous administration of 3 types of cells in rats with chronic ischemic cardiomyopathy is effective in attenuating the progressive deterioration in LV function. The extent of LV functional improvement was greatest with CPCs, intermediate with CMCs, and least with MSCs.
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Affiliation(s)
- Xian-Liang Tang
- Institute of Molecular Cardiology, University of Louisville, 550 S Jackson Street, ACB Bldg, 3rd Floor, Louisville, KY, 40202, USA
| | - Marcin Wysoczynski
- Institute of Molecular Cardiology, University of Louisville, 550 S Jackson Street, ACB Bldg, 3rd Floor, Louisville, KY, 40202, USA
| | - Anna M Gumpert
- Institute of Molecular Cardiology, University of Louisville, 550 S Jackson Street, ACB Bldg, 3rd Floor, Louisville, KY, 40202, USA
| | - Yan Li
- Institute of Molecular Cardiology, University of Louisville, 550 S Jackson Street, ACB Bldg, 3rd Floor, Louisville, KY, 40202, USA
| | - Wen-Jian Wu
- Institute of Molecular Cardiology, University of Louisville, 550 S Jackson Street, ACB Bldg, 3rd Floor, Louisville, KY, 40202, USA
| | - Hong Li
- Institute of Molecular Cardiology, University of Louisville, 550 S Jackson Street, ACB Bldg, 3rd Floor, Louisville, KY, 40202, USA
| | - Heather Stowers
- Institute of Molecular Cardiology, University of Louisville, 550 S Jackson Street, ACB Bldg, 3rd Floor, Louisville, KY, 40202, USA
| | - Roberto Bolli
- Institute of Molecular Cardiology, University of Louisville, 550 S Jackson Street, ACB Bldg, 3rd Floor, Louisville, KY, 40202, USA.
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22
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Neef K, Drey F, Lepperhof V, Wahlers T, Hescheler J, Choi YH, Šarić T. Co-transplantation of Mesenchymal Stromal Cells and Induced Pluripotent Stem Cell-Derived Cardiomyocytes Improves Cardiac Function After Myocardial Damage. Front Cardiovasc Med 2022; 8:794690. [PMID: 35071360 PMCID: PMC8770928 DOI: 10.3389/fcvm.2021.794690] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Accepted: 11/22/2021] [Indexed: 01/01/2023] Open
Abstract
Induced pluripotent stem cell-derived cardiomyocytes (iPS-CMs) represent an attractive resource for cardiac regeneration. However, survival and functional integration of transplanted iPS-CM is poor and remains a major challenge for the development of effective therapies. We hypothesized that paracrine effects of co-transplanted mesenchymal stromal cells (MSCs) augment the retention and therapeutic efficacy of iPS-CM in a mouse model of myocardial infarction (MI). To test this, either iPS-CM, MSC, or both cell types were transplanted into the cryoinfarction border zone of syngeneic mice immediately after injury. Bioluminescence imaging (BLI) of iPS-CM did not confirm enhanced retention by co-application of MSC during the 28-day follow-up period. However, histological analyses of hearts 28 days after cell transplantation showed that MSC increased the fraction of animals with detectable iPS-CM by 2-fold. Cardiac MRI analyses showed that from day 14 after transplantation on, the animals that have received cells had a significantly higher left ventricular ejection fraction (LVEF) compared to the placebo group. There was no statistically significant difference in LVEF between animals transplanted only with iPS-CM or only with MSC. However, combined iPS-CM and MSC transplantation resulted in higher LVEF compared to transplantation of single-cell populations during the whole observation period. Histological analyses revealed that MSC increased the capillarization in the myocardium when transplanted alone or with iPS-CM and decreased the infarct scar area only when transplanted in combination with iPS-CM. These results indicate that co-transplantation of iPS-CM and MSC improves cardiac regeneration after cardiac damage, demonstrating the potential of combining multiple cell types for increasing the efficacy of future cardiac cell therapies.
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Affiliation(s)
- Klaus Neef
- Department of Cardiac and Thoracic Surgery, Heart Center, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
| | - Florian Drey
- Department of Cardiac and Thoracic Surgery, Heart Center, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
| | - Vera Lepperhof
- Institute for Neurophysiology, Center for Physiology and Pathophysiology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
| | - Thorsten Wahlers
- Department of Cardiac and Thoracic Surgery, Heart Center, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
| | - Jürgen Hescheler
- Institute for Neurophysiology, Center for Physiology and Pathophysiology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
| | - Yeong-Hoon Choi
- Department of Cardiac and Thoracic Surgery, Heart Center, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
- Clinic for Cardiac Surgery and Surgical Intensive Care Medicine, Kerckhoff Clinic Bad Nauheim, Kerckhoff Campus, Justus Liebig University Giessen, Giessen, Germany
| | - Tomo Šarić
- Institute for Neurophysiology, Center for Physiology and Pathophysiology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
- *Correspondence: Tomo Šarić
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23
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ZENG L, DING T, CHEN X, XIA Y, YANG N, XIAN W. Therapeutic value of bone marrow mesenchymal stem cell transplantation incorporated with milrinone on restoring cardiac function. FOOD SCIENCE AND TECHNOLOGY 2022. [DOI: 10.1590/fst.15322] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Affiliation(s)
| | | | - Xi CHEN
- Qiqihar Medical College, China
| | | | - Na YANG
- Qiqihar Medical College, China
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24
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Hopes and Hurdles of Employing Mesenchymal Stromal Cells in the Treatment of Cardiac Fibrosis. Int J Mol Sci 2021; 22:ijms222313000. [PMID: 34884805 PMCID: PMC8657815 DOI: 10.3390/ijms222313000] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 11/25/2021] [Accepted: 11/29/2021] [Indexed: 12/04/2022] Open
Abstract
Excessive cardiac fibrosis plays a crucial role in almost all types of heart disease. Generally, cardiac fibrosis is a scarring process triggered in response to stress, injury, or aging and is characterized by the accumulation of activated myofibroblasts that deposit high levels of extracellular matrix proteins in the myocardium. While it is beneficial for cardiac repair in the short term, it can also result in pathological remodeling, tissue stiffening, and cardiac dysfunction, contributing to the progression of heart failure, arrhythmia, and sudden cardiac death. Despite its high prevalence, there is a lack of effective and safe therapies that specifically target myofibroblasts to inhibit or even reverse pathological cardiac fibrosis. In the past few decades, cell therapy has been under continuous evaluation as a potential treatment strategy, and several studies have shown that transplantation of mesenchymal stromal cells (MSCs) can reduce cardiac fibrosis and improve heart function. Mechanistically, it is believed that the heart benefits from MSC therapy by stimulating innate anti-fibrotic and regenerative reactions. The mechanisms of action include paracrine signaling and cell-to-cell interactions. In this review, we provide an overview of the anti-fibrotic properties of MSCs and approaches to enhance them and discuss future directions of MSCs for the treatment of cardiac fibrosis.
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25
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Zhuang WZ, Lin YH, Su LJ, Wu MS, Jeng HY, Chang HC, Huang YH, Ling TY. Mesenchymal stem/stromal cell-based therapy: mechanism, systemic safety and biodistribution for precision clinical applications. J Biomed Sci 2021; 28:28. [PMID: 33849537 PMCID: PMC8043779 DOI: 10.1186/s12929-021-00725-7] [Citation(s) in RCA: 155] [Impact Index Per Article: 38.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2020] [Accepted: 04/07/2021] [Indexed: 12/13/2022] Open
Abstract
Mesenchymal stem/stromal cells (MSCs) are a promising resource for cell-based therapy because of their high immunomodulation ability, tropism towards inflamed and injured tissues, and their easy access and isolation. Currently, there are more than 1200 registered MSC clinical trials globally. However, a lack of standardized methods to characterize cell safety, efficacy, and biodistribution dramatically hinders the progress of MSC utility in clinical practice. In this review, we summarize the current state of MSC-based cell therapy, focusing on the systemic safety and biodistribution of MSCs. MSC-associated risks of tumor initiation and promotion and the underlying mechanisms of these risks are discussed. In addition, MSC biodistribution methodology and the pharmacokinetics and pharmacodynamics of cell therapies are addressed. Better understanding of the systemic safety and biodistribution of MSCs will facilitate future clinical applications of precision medicine using stem cells.
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Affiliation(s)
- Wei-Zhan Zhuang
- Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan.,Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan.,TMU Research Center of Cell Therapy and Regeneration Medicine, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan
| | - Yi-Heng Lin
- Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan.,Department of Obstetrics and Gynecology, College of Medicine, National Taiwan University, Taipei, 10041, Taiwan.,Department of Obstetrics and Gynecology, National Taiwan University Hospital Yunlin Branch, Yunlin, 64041, Taiwan
| | - Long-Jyun Su
- Institute of Atomic and Molecular Sciences, Academia Sinica, Taipei, 106, Taiwan
| | - Meng-Shiue Wu
- Department and Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, 10617, Taiwan
| | - Han-Yin Jeng
- Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan.,TMU Research Center of Cell Therapy and Regeneration Medicine, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan
| | - Huan-Cheng Chang
- Institute of Atomic and Molecular Sciences, Academia Sinica, Taipei, 106, Taiwan.,Department of Chemical Engineering, National Taiwan University of Science and Technology, Taipei, 106, Taiwan
| | - Yen-Hua Huang
- Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan. .,Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan. .,TMU Research Center of Cell Therapy and Regeneration Medicine, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan. .,International PhD Program for Cell Therapy and Regeneration Medicine, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan. .,Center for Reproductive Medicine, Taipei Medical University Hospital, Taipei Medical University, Taipei, 11031, Taiwan. .,Comprehensive Cancer Center of Taipei Medical University, Taipei, 11031, Taiwan. .,The PhD Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, 11031, Taiwan.
| | - Thai-Yen Ling
- Department and Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, 10617, Taiwan. .,Research Center for Developmental Biology and Regenerative Medicine, National Taiwan University, Taipei, 100, Taiwan.
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26
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Bolli R, Mitrani RD, Hare JM, Pepine CJ, Perin EC, Willerson JT, Traverse JH, Henry TD, Yang PC, Murphy MP, March KL, Schulman IH, Ikram S, Lee DP, O’Brien C, Lima JA, Ostovaneh MR, Ambale-Venkatesh B, Lewis G, Khan A, Bacallao K, Valasaki K, Longsomboon B, Gee AP, Richman S, Taylor DA, Lai D, Sayre SL, Bettencourt J, Vojvodic RW, Cohen ML, Simpson L, Aguilar D, Loghin C, Moyé L, Ebert RF, Davis BR, Simari RD, Cardiovascular Cell Therapy Research Network (CCTRN). A Phase II study of autologous mesenchymal stromal cells and c-kit positive cardiac cells, alone or in combination, in patients with ischaemic heart failure: the CCTRN CONCERT-HF trial. Eur J Heart Fail 2021; 23:661-674. [PMID: 33811444 PMCID: PMC8357352 DOI: 10.1002/ejhf.2178] [Citation(s) in RCA: 95] [Impact Index Per Article: 23.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Revised: 03/19/2021] [Accepted: 03/23/2021] [Indexed: 12/21/2022] Open
Abstract
AIMS CONCERT-HF is an NHLBI-sponsored, double-blind, placebo-controlled, Phase II trial designed to determine whether treatment with autologous bone marrow-derived mesenchymal stromal cells (MSCs) and c-kit positive cardiac cells (CPCs), given alone or in combination, is feasible, safe, and beneficial in patients with heart failure (HF) caused by ischaemic cardiomyopathy. METHODS AND RESULTS Patients were randomized (1:1:1:1) to transendocardial injection of MSCs combined with CPCs, MSCs alone, CPCs alone, or placebo, and followed for 12 months. Seven centres enrolled 125 participants with left ventricular ejection fraction of 28.6 ± 6.1% and scar size 19.4 ± 5.8%, in New York Heart Association class II or III. The proportion of major adverse cardiac events (MACE) was significantly decreased by CPCs alone (-22% vs. placebo, P = 0.043). Quality of life (Minnesota Living with Heart Failure Questionnaire score) was significantly improved by MSCs alone (P = 0.050) and MSCs + CPCs (P = 0.023) vs. placebo. Left ventricular ejection fraction, left ventricular volumes, scar size, 6-min walking distance, and peak oxygen consumption did not differ significantly among groups. CONCLUSIONS This is the first multicentre trial assessing CPCs and a combination of two cell types from different tissues in HF patients. The results show that treatment is safe and feasible. Even with maximal guideline-directed therapy, both CPCs and MSCs were associated with improved clinical outcomes (MACE and quality of life, respectively) in ischaemic HF without affecting left ventricular function or structure, suggesting possible systemic or paracrine cellular mechanisms. Combining MSCs with CPCs was associated with improvement in both these outcomes. These results suggest potential important beneficial effects of CPCs and MSCs and support further investigation in HF patients.
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Affiliation(s)
- Roberto Bolli
- University of Louisville, School of Medicine, Louisville, KY, USA
| | - Raul D. Mitrani
- University of Miami, Miller School of Medicine, Miami, FL, USA
| | - Joshua M. Hare
- University of Miami, Miller School of Medicine, Miami, FL, USA
| | - Carl J. Pepine
- University of Florida College of Medicine, Gainesville, FL, USA
| | - Emerson C. Perin
- Texas Heart Institute, CHI St. Luke’s Health Baylor College of Medicine Medical Center, Houston, TX, USA
| | - James T. Willerson
- Texas Heart Institute, CHI St. Luke’s Health Baylor College of Medicine Medical Center, Houston, TX, USA
| | - Jay H. Traverse
- Minneapolis Heart Institute Foundation at Abbott Northwestern Hospital, and University of Minnesota School of Medicine, Minneapolis, MN, USA
| | - Timothy D. Henry
- The Carl and Edyth Lindner Center for Research and Education, The Christ Hospital, Cincinnati, OH, USA
| | | | | | - Keith L. March
- University of Florida College of Medicine, Gainesville, FL, USA
| | | | - Sohail Ikram
- University of Louisville, School of Medicine, Louisville, KY, USA
| | - David P. Lee
- Stanford University School of Medicine, Stanford, CA, USA
| | - Connor O’Brien
- Stanford University School of Medicine, Stanford, CA, USA
| | - Joao A. Lima
- Johns Hopkins University, Cardiovascular Imaging, Baltimore, MD, USA
| | | | | | - Gregory Lewis
- Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Aisha Khan
- University of Miami, Miller School of Medicine, Interdisciplinary Stem Cell Institute, Miami, FL, USA
| | - Ketty Bacallao
- University of Miami, Miller School of Medicine, Interdisciplinary Stem Cell Institute, Miami, FL, USA
| | - Krystalenia Valasaki
- University of Miami, Miller School of Medicine, Interdisciplinary Stem Cell Institute, Miami, FL, USA
| | - Bangon Longsomboon
- University of Miami, Miller School of Medicine, Interdisciplinary Stem Cell Institute, Miami, FL, USA
| | - Adrian P. Gee
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA
| | - Sara Richman
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA
| | - Doris A. Taylor
- Texas Heart Institute, CHI St. Luke’s Health Baylor College of Medicine Medical Center, Houston, TX, USA
| | - Dejian Lai
- UTHealth University of Texas Health Science Center at Houston School of Public Health, Houston, TX, USA
| | - Shelly L. Sayre
- UTHealth University of Texas Health Science Center at Houston School of Public Health, Houston, TX, USA
| | - Judy Bettencourt
- UTHealth University of Texas Health Science Center at Houston School of Public Health, Houston, TX, USA
| | - Rachel W. Vojvodic
- UTHealth University of Texas Health Science Center at Houston School of Public Health, Houston, TX, USA
| | - Michelle L. Cohen
- UTHealth University of Texas Health Science Center at Houston School of Public Health, Houston, TX, USA
| | - Lara Simpson
- UTHealth University of Texas Health Science Center at Houston School of Public Health, Houston, TX, USA
| | - David Aguilar
- UTHealth University of Texas Health Science Center at Houston School of Public Health, Houston, TX, USA
- UTHealth University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX, USA
| | - Catalin Loghin
- UTHealth University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX, USA
| | - Lem Moyé
- UTHealth University of Texas Health Science Center at Houston School of Public Health, Houston, TX, USA
| | - Ray F. Ebert
- NIH, National Heart, Lung and Blood Institute, Bethesda, MD, USA
| | - Barry R. Davis
- UTHealth University of Texas Health Science Center at Houston School of Public Health, Houston, TX, USA
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27
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Cruz-Samperio R, Jordan M, Perriman A. Cell augmentation strategies for cardiac stem cell therapies. Stem Cells Transl Med 2021; 10:855-866. [PMID: 33660953 PMCID: PMC8133336 DOI: 10.1002/sctm.20-0489] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Revised: 01/06/2021] [Accepted: 01/12/2021] [Indexed: 12/12/2022] Open
Abstract
Myocardial infarction (MI) has been the primary cause of death in developed countries, resulting in a major psychological and financial burden for society. Current treatments for acute MI are directed toward rapid restoration of perfusion to limit damage to the myocardium, rather than promoting tissue regeneration and subsequent contractile function recovery. Regenerative cell therapies (CTs), in particular those using multipotent stem cells (SCs), are in the spotlight for treatment post‐MI. Unfortunately, the efficacy of CTs is somewhat limited by their poor long‐term viability, homing, and engraftment to the myocardium. In response, a range of novel SC‐based technologies are in development to provide additional cellular modalities, bringing CTs a step closer to the clinic. In this review, the current landscape of emerging CTs and their augmentation strategies for the treatment post‐MI are discussed. In doing so, we highlight recent advances in cell membrane reengineering via genetic modifications, recombinant protein immobilization, and the utilization of soft biomimetic scaffold interfaces.
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Affiliation(s)
| | - Millie Jordan
- School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK
| | - Adam Perriman
- School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK
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28
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Tadevosyan K, Iglesias-García O, Mazo MM, Prósper F, Raya A. Engineering and Assessing Cardiac Tissue Complexity. Int J Mol Sci 2021; 22:ijms22031479. [PMID: 33540699 PMCID: PMC7867236 DOI: 10.3390/ijms22031479] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 01/28/2021] [Accepted: 01/28/2021] [Indexed: 01/14/2023] Open
Abstract
Cardiac tissue engineering is very much in a current focus of regenerative medicine research as it represents a promising strategy for cardiac disease modelling, cardiotoxicity testing and cardiovascular repair. Advances in this field over the last two decades have enabled the generation of human engineered cardiac tissue constructs with progressively increased functional capabilities. However, reproducing tissue-like properties is still a pending issue, as constructs generated to date remain immature relative to native adult heart. Moreover, there is a high degree of heterogeneity in the methodologies used to assess the functionality and cardiac maturation state of engineered cardiac tissue constructs, which further complicates the comparison of constructs generated in different ways. Here, we present an overview of the general approaches developed to generate functional cardiac tissues, discussing the different cell sources, biomaterials, and types of engineering strategies utilized to date. Moreover, we discuss the main functional assays used to evaluate the cardiac maturation state of the constructs, both at the cellular and the tissue levels. We trust that researchers interested in developing engineered cardiac tissue constructs will find the information reviewed here useful. Furthermore, we believe that providing a unified framework for comparison will further the development of human engineered cardiac tissue constructs displaying the specific properties best suited for each particular application.
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Affiliation(s)
- Karine Tadevosyan
- Regenerative Medicine Program, Bellvitge Institute for Biomedical Research (IDIBELL) and Program for Clinical Translation of Regenerative Medicine in Catalonia (P-CMRC), 08908 L’Hospitalet del Llobregat, Spain;
- Center for Networked Biomedical Research on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), 28029 Madrid, Spain
| | - Olalla Iglesias-García
- Regenerative Medicine Program, Bellvitge Institute for Biomedical Research (IDIBELL) and Program for Clinical Translation of Regenerative Medicine in Catalonia (P-CMRC), 08908 L’Hospitalet del Llobregat, Spain;
- Center for Networked Biomedical Research on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), 28029 Madrid, Spain
- Regenerative Medicine Program, Cima Universidad de Navarra, Foundation for Applied Medical Research, 31008 Pamplona, Spain; (M.M.M.); (F.P.)
- IdiSNA, Navarra Institute for Health Research, 31008 Pamplona, Spain
- Correspondence: (O.I.-G.); (A.R.)
| | - Manuel M. Mazo
- Regenerative Medicine Program, Cima Universidad de Navarra, Foundation for Applied Medical Research, 31008 Pamplona, Spain; (M.M.M.); (F.P.)
- IdiSNA, Navarra Institute for Health Research, 31008 Pamplona, Spain
- Hematology and Cell Therapy Area, Clínica Universidad de Navarra, 31008 Pamplona, Spain
| | - Felipe Prósper
- Regenerative Medicine Program, Cima Universidad de Navarra, Foundation for Applied Medical Research, 31008 Pamplona, Spain; (M.M.M.); (F.P.)
- IdiSNA, Navarra Institute for Health Research, 31008 Pamplona, Spain
- Hematology and Cell Therapy Area, Clínica Universidad de Navarra, 31008 Pamplona, Spain
- Center for Networked Biomedical Research on Cancer (CIBERONC), 28029 Madrid, Spain
| | - Angel Raya
- Regenerative Medicine Program, Bellvitge Institute for Biomedical Research (IDIBELL) and Program for Clinical Translation of Regenerative Medicine in Catalonia (P-CMRC), 08908 L’Hospitalet del Llobregat, Spain;
- Center for Networked Biomedical Research on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), 28029 Madrid, Spain
- Catalan Institution for Research and Advanced Studies (ICREA), 08010 Barcelona, Spain
- Correspondence: (O.I.-G.); (A.R.)
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29
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Evolution of Stem Cells in Cardio-Regenerative Therapy. Stem Cells 2021. [DOI: 10.1007/978-3-030-77052-5_7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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30
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Mesenchymal Stem/Progenitor Cells: The Prospect of Human Clinical Translation. Stem Cells Int 2020; 2020:8837654. [PMID: 33953753 PMCID: PMC8063852 DOI: 10.1155/2020/8837654] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Revised: 06/19/2020] [Accepted: 07/20/2020] [Indexed: 12/13/2022] Open
Abstract
Mesenchymal stem/progenitor cells (MSCs) are key players in regenerative medicine, relying principally on their differentiation/regeneration potential, immunomodulatory properties, paracrine effects, and potent homing ability with minimal if any ethical concerns. Even though multiple preclinical and clinical studies have demonstrated remarkable properties for MSCs, the clinical applicability of MSC-based therapies is still questionable. Several challenges exist that critically hinder a successful clinical translation of MSC-based therapies, including but not limited to heterogeneity of their populations, variability in their quality and quantity, donor-related factors, discrepancies in protocols for isolation, in vitro expansion and premodification, and variability in methods of cell delivery, dosing, and cell homing. Alterations of MSC viability, proliferation, properties, and/or function are also affected by various drugs and chemicals. Moreover, significant safety concerns exist due to possible teratogenic/neoplastic potential and transmission of infectious diseases. Through the current review, we aim to highlight the major challenges facing MSCs' human clinical translation and shed light on the undergoing strategies to overcome them.
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31
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Wu X, Jiang J, Gu Z, Zhang J, Chen Y, Liu X. Mesenchymal stromal cell therapies: immunomodulatory properties and clinical progress. Stem Cell Res Ther 2020; 11:345. [PMID: 32771052 PMCID: PMC7414268 DOI: 10.1186/s13287-020-01855-9] [Citation(s) in RCA: 189] [Impact Index Per Article: 37.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Revised: 07/09/2020] [Accepted: 07/27/2020] [Indexed: 02/08/2023] Open
Abstract
Mesenchymal stromal cells (MSCs) are a subset of heterogeneous non-hematopoietic fibroblast-like cells that can differentiate into cells of multiple lineages, such as chondrocytes, osteoblasts, adipocytes, myoblasts, and others. These multipotent MSCs can be found in nearly all tissues but mostly located in perivascular niches, playing a significant role in tissue repair and regeneration. Additionally, MSCs interact with immune cells both in innate and adaptive immune systems, modulating immune responses and enabling immunosuppression and tolerance induction. Understanding the biology of MSCs and their roles in clinical treatment is crucial for developing MSC-based cellular therapy for a variety of pathological conditions. Here, we review the progress in the study on the mechanisms underlying the immunomodulatory and regenerative effects of MSCs; update the medical translation of MSCs, focusing on the registration trials leading to regulatory approvals; and discuss how to improve therapeutic efficacy and safety of MSC applications for future.
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Affiliation(s)
- Xiaomo Wu
- Dermatology Institute of Fuzhou, Dermatology Hospital of Fuzhou, Xihong Road 243, Fuzhou, 350025, China
- Department of Biomedicine, University of Basel, Klingelbergstr 70, CH-4056, Basel, Switzerland
| | - Ju Jiang
- Dermatology Institute of Fuzhou, Dermatology Hospital of Fuzhou, Xihong Road 243, Fuzhou, 350025, China
| | - Zhongkai Gu
- The Institute of Biomedical Sciences, Fudan University, Mingdao Building, Dongan Road 131, Shanghai, 200032, China
| | - Jinyan Zhang
- Dermatology Institute of Fuzhou, Dermatology Hospital of Fuzhou, Xihong Road 243, Fuzhou, 350025, China
| | - Yang Chen
- Dermatology Institute of Fuzhou, Dermatology Hospital of Fuzhou, Xihong Road 243, Fuzhou, 350025, China.
| | - Xiaolong Liu
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Xihong Road 312, Fuzhou, 350025, China.
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32
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Nazari-Shafti TZ, Neuber S, Garcia Duran A, Xu Z, Beltsios E, Seifert M, Falk V, Stamm C. Human mesenchymal stromal cells and derived extracellular vesicles: Translational strategies to increase their proangiogenic potential for the treatment of cardiovascular disease. Stem Cells Transl Med 2020; 9:1558-1569. [PMID: 32761804 PMCID: PMC7695640 DOI: 10.1002/sctm.19-0432] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Revised: 05/14/2020] [Accepted: 05/18/2020] [Indexed: 12/15/2022] Open
Abstract
Mesenchymal stromal cells (MSCs) offer great potential for the treatment of cardiovascular diseases (CVDs) such as myocardial infarction and heart failure. Studies have revealed that the efficacy of MSCs is mainly attributed to their capacity to secrete numerous trophic factors that promote angiogenesis, inhibit apoptosis, and modulate the immune response. There is growing evidence that MSC‐derived extracellular vesicles (EVs) containing a cargo of lipids, proteins, metabolites, and RNAs play a key role in this paracrine mechanism. In particular, encapsulated microRNAs have been identified as important positive regulators of angiogenesis in pathological settings of insufficient blood supply to the heart, thus opening a new path for the treatment of CVD. In the present review, we discuss the current knowledge related to the proangiogenic potential of MSCs and MSC‐derived EVs as well as methods to enhance their biological activities for improved cardiac tissue repair. Increasing our understanding of mechanisms supporting angiogenesis will help optimize future approaches to CVD intervention.
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Affiliation(s)
- Timo Z Nazari-Shafti
- Department of Cardiothoracic and Vascular Surgery, German Heart Center Berlin, Berlin, Germany.,German Centre for Cardiovascular Research, Partner Site Berlin, Berlin, Germany.,Berlin Institute of Health Center for Regenerative Therapies, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Sebastian Neuber
- Department of Cardiothoracic and Vascular Surgery, German Heart Center Berlin, Berlin, Germany.,German Centre for Cardiovascular Research, Partner Site Berlin, Berlin, Germany.,Berlin Institute of Health Center for Regenerative Therapies, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Ana Garcia Duran
- Department of Cardiothoracic and Vascular Surgery, German Heart Center Berlin, Berlin, Germany.,Berlin Institute of Health Center for Regenerative Therapies, Charité - Universitätsmedizin Berlin, Berlin, Germany.,Berlin-Brandenburg School for Regenerative Therapies, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Zhiyi Xu
- Berlin Institute of Health Center for Regenerative Therapies, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Eleftherios Beltsios
- Berlin Institute of Health Center for Regenerative Therapies, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Martina Seifert
- Berlin Institute of Health Center for Regenerative Therapies, Charité - Universitätsmedizin Berlin, Berlin, Germany.,Institute of Medical Immunology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt- Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Volkmar Falk
- Department of Cardiothoracic and Vascular Surgery, German Heart Center Berlin, Berlin, Germany.,German Centre for Cardiovascular Research, Partner Site Berlin, Berlin, Germany.,Berlin Institute of Health Center for Regenerative Therapies, Charité - Universitätsmedizin Berlin, Berlin, Germany.,Division of Cardiovascular Surgery, University of Zurich, Zurich, Switzerland
| | - Christof Stamm
- Department of Cardiothoracic and Vascular Surgery, German Heart Center Berlin, Berlin, Germany.,German Centre for Cardiovascular Research, Partner Site Berlin, Berlin, Germany.,Berlin Institute of Health Center for Regenerative Therapies, Charité - Universitätsmedizin Berlin, Berlin, Germany
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33
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Hotham WE, Henson FMD. The use of large animals to facilitate the process of MSC going from laboratory to patient-'bench to bedside'. Cell Biol Toxicol 2020; 36:103-114. [PMID: 32206986 PMCID: PMC7196082 DOI: 10.1007/s10565-020-09521-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2019] [Accepted: 03/03/2020] [Indexed: 12/20/2022]
Abstract
Large animal models have been widely used to facilitate the translation of mesenchymal stem cells (MSC) from the laboratory to patient. MSC, with their multi-potent capacity, have been proposed to have therapeutic benefits in a number of pathological conditions. Laboratory studies allow the investigation of cellular and molecular interactions, while small animal models allow initial 'proof of concept' experiments. Large animals (dogs, pigs, sheep, goats and horses) are more similar physiologically and structurally to man. These models have allowed clinically relevant assessments of safety, efficacy and dosing of different MSC sources prior to clinical trials. In this review, we recapitulate the use of large animal models to facilitate the use of MSC to treat myocardial infarction-an example of one large animal model being considered the 'gold standard' for research and osteoarthritis-an example of the complexities of using different large animal models in a multifactorial disease. These examples show how large animals can provide a research platform that can be used to evaluate the value of cell-based therapies and facilitate the process of 'bench to bedside'.
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Affiliation(s)
- W E Hotham
- Division of Trauma and Orthopaedic Surgery, Cambridge University, Cambridge, UK.
| | - F M D Henson
- Division of Trauma and Orthopaedic Surgery, Cambridge University, Cambridge, UK
- Animal Health Trust, Newmarket, UK
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34
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Khoei SG, Dermani FK, Malih S, Fayazi N, Sheykhhasan M. The Use of Mesenchymal Stem Cells and their Derived Extracellular Vesicles in Cardiovascular Disease Treatment. Curr Stem Cell Res Ther 2020; 15:623-638. [PMID: 32357818 DOI: 10.2174/1574888x15666200501235201] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2019] [Revised: 03/03/2020] [Accepted: 04/07/2020] [Indexed: 02/08/2023]
Abstract
BACKGROUND Cardiovascular disease (CVD), including disorders of cardiac muscle and vascular, is the major cause of death globally. Many unsuccessful attempts have been made to intervene in the disease's pathogenesis and treatment. Stem cell-based therapies, as a regeneration strategy, cast a new hope for CVD treatment. One of the most well-known stem cells is mesenchymal stem cells (MSCs), classified as one of the adult stem cells and can be obtained from different tissues. These cells have superior properties, such as proliferation and highly specialized differentiation. On the other hand, they have the potential to modulate the immune system and anti-inflammatory activity. One of their most important features is the secreting the extracellular vesicles (EVs) like exosomes (EXOs) as an intercellular communication system mediating the different physiological and pathophysiological affairs. METHODS In this review study, the importance of MSC and its secretory exosomes for the treatment of heart disease has been together and specifically addressed and the use of these promising natural and accessible agents is predicted to replace the current treatment modalities even faster than we imagine. RESULTS MSC derived EXOs by providing a pro-regenerative condition allowing innate stem cells to repair damaged tissues successfully. As a result, MSCs are considered as the appropriate cellular source in regenerative medicine. In the plethora of experiments, MSCs and MSC-EXOs have been used for the treatment and regeneration of heart diseases and myocardial lesions. CONCLUSION Administration of MSCs has been provided a replacement therapeutic option for heart regeneration, obtaining great attention among the basic researcher and the medical doctors.
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Affiliation(s)
- Saeideh Gholamzadeh Khoei
- Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Hamadan University of Medical Sciences, Hamadan, Iran
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Fateme Karimi Dermani
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Sara Malih
- Department of Medical Biotechnology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Nashmin Fayazi
- Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Hamadan University of Medical Sciences, Hamadan, Iran
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Mohsen Sheykhhasan
- Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Hamadan University of Medical Sciences, Hamadan, Iran
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
- Department of Mesenchymal Stem Cell, the Academic Center for Education, Culture and Research, Qom, Iran
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35
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Affiliation(s)
- Benjamin P Woodall
- From the Skaggs School of Pharmacy and Pharmaceutical Sciences, Department of Pharmacology, University of California San Diego, La Jolla
| | - Åsa B Gustafsson
- From the Skaggs School of Pharmacy and Pharmaceutical Sciences, Department of Pharmacology, University of California San Diego, La Jolla
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36
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Oliva AA, McClain-Moss L, Pena A, Drouillard A, Hare JM. Allogeneic mesenchymal stem cell therapy: A regenerative medicine approach to geroscience. Aging Med (Milton) 2019; 2:142-146. [PMID: 31667462 PMCID: PMC6820701 DOI: 10.1002/agm2.12079] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Extraordinary advances in medicine and public health have contributed to increasing life expectancy worldwide. However, health span-"healthy aging"-has paradoxically lagged to parallel this increase. Consequently, aging-associated illnesses, such as Alzheimer's disease and aging frailty, are having a growing impact on patients, their families, and entire health-care systems. Typically, such disorders have been treated as isolated disease entities. However, the inextricable links between aging-associated disorders and the aging process itself have become increasingly recognized, leading to formation of the field of geroscience. The geroscience concept is that treating the aging process itself should lead to treatment and prevention of aging-related disorders. However, the aging process is complex, dictated by highly interrelated pleiotropic processes. As such, therapeutics with pleiotropic mechanisms of action (either alone, or as part of combinatorial strategies) will be required for preventing and treating both aging and related disorders. Mesenchymal stem cells (MSCs) have multiple mechanisms of action that make these highly promising geroscience therapeutic candidates. These cells have a high safety profile for clinical use, are amenable to allogeneic use since tissue-type matching is not required, and can have sustained activity after transplantation. Herein, we review preclinical and clinical data supporting the utility of allogeneic MSCs as a geroscience therapeutic candidate.
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Affiliation(s)
| | | | | | | | - Joshua M Hare
- Longeveron LLC, Miami, FL, USA.,Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA
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37
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Tompkins BA, Balkan W, Winkler J, Gyöngyösi M, Goliasch G, Fernández-Avilés F, Hare JM. Preclinical Studies of Stem Cell Therapy for Heart Disease. Circ Res 2019; 122:1006-1020. [PMID: 29599277 DOI: 10.1161/circresaha.117.312486] [Citation(s) in RCA: 108] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
As part of the TACTICS (Transnational Alliance for Regenerative Therapies in Cardiovascular Syndromes) series to enhance regenerative medicine, here, we discuss the role of preclinical studies designed to advance stem cell therapies for cardiovascular disease. The quality of this research has improved over the past 10 to 15 years and overall indicates that cell therapy promotes cardiac repair. However, many issues remain, including inability to provide complete cardiac recovery. Recent studies question the need for intact cells suggesting that harnessing what the cells release is the solution. Our contribution describes important breakthroughs and current directions in a cell-based approach to alleviating cardiovascular disease.
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Affiliation(s)
- Bryon A Tompkins
- From the Interdisciplinary Stem Cell Institute (B.A.T., W.B., J.M.H.), Department of Surgery (B.A.T.), and Department of Medicine (W.B., J.M.H.), University of Miami Miller School of Medicine, FL; Department of Cardiology, Medical University of Vienna, Austria (J.W., M.G., G.G.); Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Complutense, Madrid, Spain (F.F.-A.); and CIBERCV, ISCIII, Madrid, Spain (F.F.-A.)
| | - Wayne Balkan
- From the Interdisciplinary Stem Cell Institute (B.A.T., W.B., J.M.H.), Department of Surgery (B.A.T.), and Department of Medicine (W.B., J.M.H.), University of Miami Miller School of Medicine, FL; Department of Cardiology, Medical University of Vienna, Austria (J.W., M.G., G.G.); Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Complutense, Madrid, Spain (F.F.-A.); and CIBERCV, ISCIII, Madrid, Spain (F.F.-A.)
| | - Johannes Winkler
- From the Interdisciplinary Stem Cell Institute (B.A.T., W.B., J.M.H.), Department of Surgery (B.A.T.), and Department of Medicine (W.B., J.M.H.), University of Miami Miller School of Medicine, FL; Department of Cardiology, Medical University of Vienna, Austria (J.W., M.G., G.G.); Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Complutense, Madrid, Spain (F.F.-A.); and CIBERCV, ISCIII, Madrid, Spain (F.F.-A.)
| | - Mariann Gyöngyösi
- From the Interdisciplinary Stem Cell Institute (B.A.T., W.B., J.M.H.), Department of Surgery (B.A.T.), and Department of Medicine (W.B., J.M.H.), University of Miami Miller School of Medicine, FL; Department of Cardiology, Medical University of Vienna, Austria (J.W., M.G., G.G.); Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Complutense, Madrid, Spain (F.F.-A.); and CIBERCV, ISCIII, Madrid, Spain (F.F.-A.)
| | - Georg Goliasch
- From the Interdisciplinary Stem Cell Institute (B.A.T., W.B., J.M.H.), Department of Surgery (B.A.T.), and Department of Medicine (W.B., J.M.H.), University of Miami Miller School of Medicine, FL; Department of Cardiology, Medical University of Vienna, Austria (J.W., M.G., G.G.); Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Complutense, Madrid, Spain (F.F.-A.); and CIBERCV, ISCIII, Madrid, Spain (F.F.-A.)
| | - Francisco Fernández-Avilés
- From the Interdisciplinary Stem Cell Institute (B.A.T., W.B., J.M.H.), Department of Surgery (B.A.T.), and Department of Medicine (W.B., J.M.H.), University of Miami Miller School of Medicine, FL; Department of Cardiology, Medical University of Vienna, Austria (J.W., M.G., G.G.); Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Complutense, Madrid, Spain (F.F.-A.); and CIBERCV, ISCIII, Madrid, Spain (F.F.-A.)
| | - Joshua M Hare
- From the Interdisciplinary Stem Cell Institute (B.A.T., W.B., J.M.H.), Department of Surgery (B.A.T.), and Department of Medicine (W.B., J.M.H.), University of Miami Miller School of Medicine, FL; Department of Cardiology, Medical University of Vienna, Austria (J.W., M.G., G.G.); Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Complutense, Madrid, Spain (F.F.-A.); and CIBERCV, ISCIII, Madrid, Spain (F.F.-A.).
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38
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van Klarenbosch BR, Chamuleau SA, Teske AJ. Deformation imaging to assess global and regional effects of cardiac regenerative therapy in ischaemic heart disease: A systematic review. J Tissue Eng Regen Med 2019; 13:1872-1882. [PMID: 31314949 PMCID: PMC6852417 DOI: 10.1002/term.2937] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2019] [Revised: 06/14/2019] [Accepted: 07/11/2019] [Indexed: 01/19/2023]
Abstract
Currently, left ventricular ejection fraction (LVEF) is the most common endpoint in cardiovascular stem cell therapy research. However, this global measure of cardiac function might not be suitable to detect the regional effects sorted by this therapy and is hampered by high operator variability and loading dependency. Deformation imaging might be more accurate in detecting potential regional functional improvements by cardiac regenerative therapy. The aim of this systematic review is to provide a comprehensive overview of current literature on the value of deformation imaging in cardiac regenerative therapy. A systematic review of current literature available on PubMed, Embase, and Cochrane databases was performed regarding both animal and patient studies in which deformation imaging was used to study cardiac cell therapy. After critical appraisal, outcomes regarding study design, type of cell therapy, procedural characteristics, outcome measure, method for measuring strain, and efficacy on both LVEF and deformation parameters were depicted. A total of 30 studies, 15 preclinical and 15 clinical, were included for analysis. Deformation outcomes improved significantly in 14 out of 15 preclinical studies and in 10 out of 15 clinical studies, whereas LVEF improved in 12 and 4 articles, respectively. Study designs and used deformation outcomes varied significantly among the included papers. Six studies found a positive effect on deformation outcomes without LVEF improvement. Hence, deformation imaging seems at least equal, and perhaps superior, to LVEF measurement in the assessment of cardiac regenerative therapy. However, strategies varied substantially and call for a standardized approach.
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Affiliation(s)
| | | | - Arco J. Teske
- Department of CardiologyUniversity Medical Center UtrechtUtrechtThe Netherlands
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Suzuki G, Weil BR, Young RF, Fallavollita JA, Canty JM. Nonocclusive multivessel intracoronary infusion of allogeneic cardiosphere-derived cells early after reperfusion prevents remote zone myocyte loss and improves global left ventricular function in swine with myocardial infarction. Am J Physiol Heart Circ Physiol 2019; 317:H345-H356. [PMID: 31125261 DOI: 10.1152/ajpheart.00124.2019] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Intracoronary cardiosphere-derived cells (icCDCs) infused into the infarct-related artery reduce scar volume but do not improve left ventricular (LV) ejection fraction (LVEF). We tested the hypothesis that this reflects the inability of regional delivery to prevent myocyte death or promote myocyte proliferation in viable myocardium remote from the infarct. Swine (n = 23) pretreated with oral cyclosporine (200 mg/day) underwent a 1-h left anterior descending coronary artery (LAD) occlusion, which reduced LVEF from 61.6 ± 1.0 to 45.3 ± 1.5% 30 min after reperfusion. At that time, animals received global infusion of allogeneic icCDCs (n = 8), regional infusion of icCDCs restricted to the LAD using the stop-flow technique (n = 8), or vehicle (n = 7). After 1 mo, global icCDCs increased LVEF from 44.8 ± 1.9 to 60.8 ± 3.8% (P < 0.05) with no significant change after LAD stop-flow icCDCs (44.8 ± 3.6 to 50.9 ± 3.1%) or vehicle (46.5 ± 2.5 to 47.7 ± 2.6%). In contrast, global icCDCs did not alter infarct volume (%LV mass) assessed at 2 days (11.2 ± 2.3 vs. 12.6 ± 2.3%), whereas it was reduced after LAD stop-flow icCDCs (7.1 ± 1.1%, P < 0.05). Histopathological analysis of remote myocardium after global icCDCs demonstrated a significant increase in myocyte proliferation (147 ± 32 vs. 14 ± 10 nuclei/106 myocytes, P < 0.05) and a reduction in myocyte apoptosis (15 ± 9 vs. 46 ± 10 nuclei/106 myocytes, P < 0.05) that increased myocyte nuclear density (1,264 ± 39 vs. 1,157 ± 33 nuclei/mm2, P < 0.05) and decreased myocyte diameter (13.2 ± 0.2 vs. 14.5 ± 0.3 μm, P < 0.05) compared with vehicle-treated controls. In contrast, remote zone changes after regional LAD icCDCs were no different from vehicle. These data indicate that changes in global LVEF after icCDCs are dependent upon preventing myocyte loss and hypertrophy in myocardium remote from the infarct. These arise from stimulating myocyte proliferation and reducing myocyte apoptosis indicating the importance of directing cell therapy to viable remote regions.NEW & NOTEWORTHY Administration of allogeneic cardiosphere-derived cells to the entire heart via global intracoronary infusion shortly after myocardial infarction favorably influenced left ventricular ejection fraction by preventing myocyte death and promoting myocyte proliferation in remote, noninfarcted myocardium in swine. In contrast, regional intracoronary cell infusion did not significantly affect remote zone myocyte remodeling. Global cell administration targeting viable myocardium remote from the infarct may be an effective approach to prevent adverse ventricular remodeling after myocardial infarction.
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Affiliation(s)
- Gen Suzuki
- Department of Medicine, University at Buffalo, Buffalo, New York.,Clinical and Translational Research Institute, University at Buffalo, Buffalo, New York
| | - Brian R Weil
- Physiology and Biophysics, University at Buffalo, Buffalo, New York.,Clinical and Translational Research Institute, University at Buffalo, Buffalo, New York
| | - Rebeccah F Young
- Department of Medicine, University at Buffalo, Buffalo, New York.,Clinical and Translational Research Institute, University at Buffalo, Buffalo, New York
| | - James A Fallavollita
- Veterans Affairs Western New York Health Care System, Buffalo, New York.,Department of Medicine, University at Buffalo, Buffalo, New York.,Clinical and Translational Research Institute, University at Buffalo, Buffalo, New York
| | - John M Canty
- Veterans Affairs Western New York Health Care System, Buffalo, New York.,Department of Medicine, University at Buffalo, Buffalo, New York.,Physiology and Biophysics, University at Buffalo, Buffalo, New York.,Biomedical Engineering, University at Buffalo, Buffalo, New York.,Clinical and Translational Research Institute, University at Buffalo, Buffalo, New York
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Abstract
IMPACT STATEMENT Over the past several decades, ex vivo perfusion has emerged as a promising technology for the assessment, preservation, and recovery of donor organs. Many exciting pre-clinical findings have now been translated to clinical use, and successful transplantation following ex vivo perfusion has been achieved for heart, lung, and liver. While machine perfusion provides distinct advantages over traditional cold preservation, many challenges remain, including that of long-term (multi-day) ex vivo support. Here, we provide an overview of the current status of ex vivo machine perfusion in the pre-clinical and clinical setting and share our perspective on the future direction of the field.
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Affiliation(s)
- Meghan Pinezich
- Department of Biomedical Engineering, Columbia University, New York, NY 10032, USA
| | - Gordana Vunjak-Novakovic
- Department of Biomedical Engineering, Columbia University, New York, NY 10032, USA
- Department of Medicine, Columbia University, New York NY 10032, USA
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41
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Ju X, Xue D, Wang T, Ge B, Zhang Y, Li Z. Catalpol Promotes the Survival and VEGF Secretion of Bone Marrow-Derived Stem Cells and Their Role in Myocardial Repair After Myocardial Infarction in Rats. Cardiovasc Toxicol 2019; 18:471-481. [PMID: 29752623 DOI: 10.1007/s12012-018-9460-4] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Bone mesenchymal stem cells (BMSCs) transplantation has been recognized as an effective method for the treatment of myocardial infarction (MI). However, its efficacy is always restricted by the low survival of transplanted BMSCs in the ischemic myocardium. The aim of this study was to investigate the effect of catalpol pre-treatment on the survival and vascular endothelial growth factor (VEGF) secretion of BMSCs under oxygen glucose deprivation (OGD) condition and their role in myocardial repair in a rat model of MI. According to our results, pre-treatment with catalpol enhanced VEGF secretion and survival of OGD-treated BMSCs. Moreover, the apoptosis of BMSCs induced by OGD was restrained by catalpol as evidenced by increased level of B-cell lymphoma-2 (Bcl-2) and decreased levels of BCL2-associated X (Bax) and cleaved caspase-3. In vivo study suggested that the survival of transplanted BMSCs was improved by catalpol pre-treatment. The myocardial fibrosis and apoptosis was further inhibited in catalpol pre-treated BMSCs group. Cardiac function detected by echocardiography was obviously improved by catalpol pre-treated BMSCs transplantation. Finally, angiogenesis and VEGF expression in the ischemic myocardium were significantly promoted in catalpol pre-treated BMSCs group. In conclusion, catalpol pre-treatment may facilitate the survival and VEGF secretion of BMSCs and improve their therapeutic effect on MI.
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Affiliation(s)
- Xing'ai Ju
- Department of Cardiology, Shengjing Hospital of China Medical University, 36 Sanhao Street, Shenyang, 110004, Liaoning, People's Republic of China.,Department of Emergency Medicine, The People's Hospital of Liaoning Province, Shenyang, 110016, Liaoning, People's Republic of China
| | - Degang Xue
- Comprehensive Circulation Ward, The General Hospital of Fushun Mining Affairs Bureau, Fushun, 113008, Liaoning, People's Republic of China
| | - Tongyi Wang
- Department of Emergency Medicine, The People's Hospital of Liaoning Province, Shenyang, 110016, Liaoning, People's Republic of China
| | - Baiping Ge
- Department of Emergency Medicine, The People's Hospital of Liaoning Province, Shenyang, 110016, Liaoning, People's Republic of China
| | - Yu Zhang
- Department of Emergency Medicine, The People's Hospital of Liaoning Province, Shenyang, 110016, Liaoning, People's Republic of China
| | - Zhanquan Li
- Department of Cardiology, Shengjing Hospital of China Medical University, 36 Sanhao Street, Shenyang, 110004, Liaoning, People's Republic of China.
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42
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Poglajen G, Gregoric ID, Radovancevic R, Vrtovec B. Stem Cell and Left Ventricular Assist Device Combination Therapy. Circ Heart Fail 2019; 12:e005454. [PMID: 30759999 DOI: 10.1161/circheartfailure.118.005454] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Ventricular assist device (VAD) technology has evolved significantly over the past decades and currently represents one of the most important treatment strategies for patients with advanced chronic heart failure. There is increasing evidence that in selected patients undergoing long-term VAD support, improvement of myocardial structure and function may occur. However, there seems to be a significant discrepancy between structural and functional recovery of the failing myocardium, as only a small fraction of VAD-supported patients demonstrate reverse structural remodeling and eventually reach clinically significant and stable, functional improvement. More recently, cell therapy has gained a growing interest in the heart failure community because of its potential to augment reverse remodeling of the failing myocardium. Although theoretically the combination of long-term VAD support and cell therapy may offer significant advantages over using these therapeutic modalities separately, it remains largely unexplored. This review aims to summarize the current state of the art of the effects of VAD support and cell therapy on the reverse remodeling of the failing myocardium and to discuss the rationale for using a combined treatment strategy to further promote myocardial recovery in patients with advanced chronic heart failure.
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Affiliation(s)
- Gregor Poglajen
- Advanced Heart Failure and Transplantation Center, University Medical Center Ljubljana, Slovenia (G.P., B.V.).,Department of Advanced Cardiopulmonary Therapies and Transplantation, Center for Advanced Heart Failure, University of Texas Health Science Center at Houston (G.P., I.D.G., R.R.)
| | - Igor D Gregoric
- Department of Advanced Cardiopulmonary Therapies and Transplantation, Center for Advanced Heart Failure, University of Texas Health Science Center at Houston (G.P., I.D.G., R.R.)
| | - Rajko Radovancevic
- Department of Advanced Cardiopulmonary Therapies and Transplantation, Center for Advanced Heart Failure, University of Texas Health Science Center at Houston (G.P., I.D.G., R.R.)
| | - Bojan Vrtovec
- Advanced Heart Failure and Transplantation Center, University Medical Center Ljubljana, Slovenia (G.P., B.V.)
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43
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Cellular Therapy for Ischemic Heart Disease: An Update. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1201:195-213. [PMID: 31898788 DOI: 10.1007/978-3-030-31206-0_10] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Ischemic heart disease (IHD), which includes heart failure (HF) induced by heart attack (myocardial infarction, MI), is a significant cause of morbidity and mortality worldwide (Benjamin, et al. Circulation 139:e56-e66, 2019). MI occurs at an alarmingly high rate in the United States (approx. One case every 40 seconds), and the failure to repair damaged myocardium is the leading cause of recurrent heart attacks, heart failure (HF), and death within 5 years of MI (Benjamin, et al. Circulation 139:e56-e66, 2019). At present, HF represents an unmet need with no approved clinical therapies to replace the damaged myocardium. As the population ages, the number of heart failure patients is projected to increase, doubling the annual cost by 2030 (Benjamin, et al. Circulation 139:e56-e66, 2019). In the past decades, stem cell therapy has become a promising strategy for cardiac regeneration. However, stem cell-based therapy yielded modest success in human clinical trials. This chapter examines the types of cells examined in cardiac therapy in the setting of IHD, with a brief introduction to ongoing research aiming at enhancing the therapeutic potential of transplanted cells.
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Enhancement of the efficacy of mesenchymal stem cells in the treatment of ischemic diseases. Biomed Pharmacother 2018; 109:2022-2034. [PMID: 30551458 DOI: 10.1016/j.biopha.2018.11.068] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2018] [Revised: 11/17/2018] [Accepted: 11/19/2018] [Indexed: 02/05/2023] Open
Abstract
Ischemic diseases refer to a wide range of diseases caused by reduced blood flow and a subsequently deficient oxygen and nutrient supply. The pathogenesis of ischemia is multifaceted and primarily involves inflammation, oxidative stress and an apoptotic response. Over the last decade, mesenchymal stem cells (MSCs) have been widely studied as potential cell therapy agents for ischemic diseases due to their multiple favourable functions. However, the low homing and survival rates of transplanted cells have been concerns limiting for their clinical application. Recently, increasing studies have attempted to enhance the efficacy of MSCs by various strategies including genetic modification, pretreatment, combined application and biomaterial application. The purpose of this review is to summarize these creative strategies and the progress in basic and preclinical studies.
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45
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Haider KH. Bone marrow cell therapy and cardiac reparability: better cell characterization will enhance clinical success. Regen Med 2018; 13:457-475. [PMID: 29985118 DOI: 10.2217/rme-2017-0134] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Nearly two decades of experimental and clinical research with bone marrow cells have paved the way for Phase III pivotal trials in larger groups of heart patients. Despite immense advancements, a multitude of factors are hampering the acceptance of bone marrow cell-based therapy for routine clinical use. These include uncertainties regarding purification and characterization of the cell preparation, delivery protocols, mechanistic understanding and study end points and their methods of assessment. Clinical data show mediocre outcomes in terms of sustained cardiac pump function. This review reasons that the modest outcomes observed in trials thus far are based on quality of the cell preparation with a focus on the chronological aging of cells when autologous cells are used for transplantation in elderly patients.
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Affiliation(s)
- Khawaja H Haider
- Department of Basic Sciences, Sulaiman AlRajhi Medical School, Al Qassim, Al Bukayria, 51941, Kingdom of Saudi Arabia
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46
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Pan J, Alimujiang M, Chen Q, Shi H, Luo X. Exosomes derived from miR‐146a‐modified adipose‐derived stem cells attenuate acute myocardial infarction−induced myocardial damage via downregulation of early growth response factor 1. J Cell Biochem 2018; 120:4433-4443. [PMID: 30362610 DOI: 10.1002/jcb.27731] [Citation(s) in RCA: 121] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2018] [Accepted: 08/30/2018] [Indexed: 12/19/2022]
Affiliation(s)
- Junjie Pan
- Department of Cardiovascular Medicine Huashan Hospital Affiliated to Fudan University Shanghai China
| | - Maimaitijiang Alimujiang
- Department of Cardiovascular Medicine Huashan Hospital Affiliated to Fudan University Shanghai China
| | - Qiying Chen
- Department of Cardiovascular Medicine Huashan Hospital Affiliated to Fudan University Shanghai China
| | - Haiming Shi
- Department of Cardiovascular Medicine Huashan Hospital Affiliated to Fudan University Shanghai China
| | - Xinping Luo
- Department of Cardiovascular Medicine Huashan Hospital Affiliated to Fudan University Shanghai China
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47
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Allogeneic Mesenchymal Stem Cells and Biomaterials: The Perfect Match for Cardiac Repair? Int J Mol Sci 2018; 19:ijms19103236. [PMID: 30347686 PMCID: PMC6213975 DOI: 10.3390/ijms19103236] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2018] [Revised: 10/16/2018] [Accepted: 10/17/2018] [Indexed: 12/11/2022] Open
Abstract
Coronary heart disease is the leading cause of death worldwide with huge socio-economic consequences. Cell therapy, and particularly mesenchymal stem cells (MSC), are considered a promising option to treat this disorder, due to their robust trophic and immunomodulatory properties. However, limitations such as their low rate of engraftment and poor survival after administration into the heart have precluded their large-scale clinical use. Nevertheless, the combination of MSC with polymer-made scaffolds or hydrogels has proven to enhance their retention and, therefore, their efficacy. Additionally, their allogeneic use could permit the creation of ready-to-use cell patches able to improve their feasibility and promote their application in clinical settings. In this review, the experimental and clinical results derived from the use of MSC in cardiac pathology, as well as advances in the bioengineering field to improve the potential of therapeutic cells, are extensively discussed. Additionally, the current understanding of the heart response to the allogeneic MSC transplants is addressed.
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48
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Dolati S, Yousefi M, Mahdipour M, Afrasiabi Rad A, Pishgahi A, Nouri M, Jodati AR. Mesenchymal stem cell and bone marrow mononuclear cell therapy for cardiomyopathy: From bench to bedside. J Cell Biochem 2018; 120:45-55. [DOI: 10.1002/jcb.27531] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Accepted: 08/01/2018] [Indexed: 12/19/2022]
Affiliation(s)
- Sanam Dolati
- Aging Research Institute, Tabriz University of Medical Sciences Tabriz Iran
- Drug Applied Research Center, Tabriz University of Medical Sciences Tabriz Iran
- Student’s Research Committee, Tabriz University of Medical Sciences Tabriz Iran
| | - Mehdi Yousefi
- Drug Applied Research Center, Tabriz University of Medical Sciences Tabriz Iran
- Stem Cell Research Center, Tabriz University of Medical Sciences Tabriz Iran
- Department of Immunology Tabriz University of Medical Sciences Tabriz Iran
| | - Mahdi Mahdipour
- Stem Cell Research Center, Tabriz University of Medical Sciences Tabriz Iran
- Department of Reproductive Biology Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences Tabriz Iran
| | - Abbas Afrasiabi Rad
- Cardiovascular Research Center, Tabriz University of Medical Sciences Tabriz Iran
- Department of Cardiac Surgery Tabriz University of Medical Tabriz Iran
| | - Alireza Pishgahi
- Department of Physical Medicine and Rehabilitation Physical Medicine and Rehabilitation Research Center, Tabriz University of Medical Science Tabriz Iran
| | - Mohammad Nouri
- Stem Cell Research Center, Tabriz University of Medical Sciences Tabriz Iran
- Department of Reproductive Biology Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences Tabriz Iran
| | - Ahmad Reza Jodati
- Cardiovascular Research Center, Tabriz University of Medical Sciences Tabriz Iran
- Department of Cardiac Surgery Tabriz University of Medical Tabriz Iran
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Wang X, Chen Y, Zhao Z, Meng Q, Yu Y, Sun J, Yang Z, Chen Y, Li J, Ma T, Liu H, Li Z, Yang J, Shen Z. Engineered Exosomes With Ischemic Myocardium-Targeting Peptide for Targeted Therapy in Myocardial Infarction. J Am Heart Assoc 2018; 7:e008737. [PMID: 30371236 PMCID: PMC6201471 DOI: 10.1161/jaha.118.008737] [Citation(s) in RCA: 270] [Impact Index Per Article: 38.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2018] [Accepted: 06/27/2018] [Indexed: 12/29/2022]
Abstract
Background Exosomes are membranous vesicles generated by almost all cells. Recent studies demonstrated that mesenchymal stem cell-derived exosomes possessed many effects, including antiapoptosis, anti-inflammatory effects, stimulation of angiogenesis, anticardiac remodeling, and recovery of cardiac function on cardiovascular diseases. However, targeting of exosomes to recipient cells precisely in vivo still remains a problem. Ligand fragments or homing peptides discovered by phage display and in vivo biopanning methods fused to the enriched molecules on the external part of exosomes have been exploited to improve the ability of exosomes to target specific tissues or organs carrying cognate receptors. Herein, we briefly elucidated how to improve targeting ability of exosomes to ischemic myocardium. Methods and Results We used technology of molecular cloning and lentivirus packaging to engineer exosomal enriched membrane protein (Lamp2b) fused with ischemic myocardium-targeting peptide CSTSMLKAC (IMTP). In vitro results showed that IMTP-exosomes could be internalized by hypoxia-injured H9C2 cells more efficiently than blank-exosomes. Compared with blank-exosomes, IMTP-exosomes were observed to be increasingly accumulated in ischemic heart area ( P<0.05). Meanwhile, attenuated inflammation and apoptosis, reduced fibrosis, enhanced vasculogenesis, and cardiac function were detected by mesenchymal stem cell-derived IMTP-exosome treatment in ischemic heart area. Conclusions Our research concludes that exosomes engineered by IMTP can specially target ischemic myocardium, and mesenchymal stem cell-derived IMTP-exosomes exert enhanced therapeutic effects on acute myocardial infarction.
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Affiliation(s)
- Xu Wang
- Department of Cardiovascular Surgery of the First Affiliated Hospital and Institute for Cardiovascular ScienceSoochow UniversitySuzhouChina
| | - Yihuan Chen
- Department of Cardiovascular Surgery of the First Affiliated Hospital and Institute for Cardiovascular ScienceSoochow UniversitySuzhouChina
| | - Zhenao Zhao
- Department of Cardiovascular Surgery of the First Affiliated Hospital and Institute for Cardiovascular ScienceSoochow UniversitySuzhouChina
| | - Qingyou Meng
- Department of Cardiovascular Surgery of the First Affiliated Hospital and Institute for Cardiovascular ScienceSoochow UniversitySuzhouChina
| | - You Yu
- Department of Cardiovascular Surgery of the First Affiliated Hospital and Institute for Cardiovascular ScienceSoochow UniversitySuzhouChina
| | - Jiacheng Sun
- Department of Cardiovascular Surgery of the First Affiliated Hospital and Institute for Cardiovascular ScienceSoochow UniversitySuzhouChina
| | - Ziying Yang
- Department of Cardiovascular Surgery of the First Affiliated Hospital and Institute for Cardiovascular ScienceSoochow UniversitySuzhouChina
| | - Yueqiu Chen
- Department of Cardiovascular Surgery of the First Affiliated Hospital and Institute for Cardiovascular ScienceSoochow UniversitySuzhouChina
| | - Jingjing Li
- Department of Cardiovascular Surgery of the First Affiliated Hospital and Institute for Cardiovascular ScienceSoochow UniversitySuzhouChina
| | - Teng Ma
- Department of Cardiovascular Surgery of the First Affiliated Hospital and Institute for Cardiovascular ScienceSoochow UniversitySuzhouChina
| | - Hanghang Liu
- Center for Molecular Imaging and Nuclear MedicineSchool for Radiological and Interdisciplinary SciencesSoochow UniversitySuzhouChina
| | - Zhen Li
- Center for Molecular Imaging and Nuclear MedicineSchool for Radiological and Interdisciplinary SciencesSoochow UniversitySuzhouChina
| | - Junjie Yang
- Department of Cardiovascular Surgery of the First Affiliated Hospital and Institute for Cardiovascular ScienceSoochow UniversitySuzhouChina
- Department of Biomedical EngineeringMolecular Cardiology Program, School of Medicine and School of EngineeringUniversity of Alabama at BirminghamBirminghamAlabama
| | - Zhenya Shen
- Department of Cardiovascular Surgery of the First Affiliated Hospital and Institute for Cardiovascular ScienceSoochow UniversitySuzhouChina
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50
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Shi C, Zhao Y, Yang Y, Chen C, Hou X, Shao J, Yao H, Li Q, Xia Y, Dai J. Collagen-binding VEGF targeting the cardiac extracellular matrix promotes recovery in porcine chronic myocardial infarction. Biomater Sci 2018; 6:356-363. [PMID: 29266144 DOI: 10.1039/c7bm00891k] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
An effective therapy for chronic myocardial infarction (MI) has yet to be developed. Vascular endothelial growth factor (VEGF) promotes angiogenesis and improves cardiac function after MI. However, non-targeted delivery of VEGF decreases its therapeutic efficacy. In this study, for targeting the cardiac extracellular matrix, a collagen-binding domain (CBD) VEGF was used to bind specifically to the collagen-rich cardiac extracellular matrix. When intramyocardially injected into the peri-infarct region of a chronically infarcted porcine heart, CBD-VEGF attenuated the remodeling of the left ventricle with a decreased infarct size and promoted cardiomyocyte survival and angiogenesis 3 months after injection. In the 12-month trial, mature vessel networks and myocardium-like tissues were observed in the infarct region after CBD-VEGF injection. Also these beneficial effects might derive from CBD-VEGF significantly protecting cardiomyocytes from apoptosis and recruiting cardiac progenitor cells to the infarcted region. These results demonstrated that CBD-VEGF could be a promising therapeutic strategy for chronic MI.
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Affiliation(s)
- Chunying Shi
- Department of Human Anatomy, Histology and Embryology, School of Basic Medicine, Qingdao University, Qingdao, 266021, China.
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