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1
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Verde PE, Rosner GL. A Bias-Corrected Bayesian Nonparametric Model for Combining Studies With Varying Quality in Meta-Analysis. Biom J 2025; 67:e70034. [PMID: 39917836 PMCID: PMC11803498 DOI: 10.1002/bimj.70034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Revised: 11/14/2024] [Accepted: 11/18/2024] [Indexed: 02/11/2025]
Abstract
Bayesian nonparametric (BNP) approaches for meta-analysis have been developed to relax distributional assumptions and handle the heterogeneity of random effects distributions. These models account for possible clustering and multimodality of the random effects distribution. However, when we combine studies of varying quality, the resulting posterior is not only a combination of the results of interest but also factors threatening the integrity of the studies' results. We refer to these factors as the studies' internal validity biases (e.g., reporting bias, data quality, and patient selection bias). In this paper, we introduce a new meta-analysis model called the bias-corrected Bayesian nonparametric (BC-BNP) model, which aims to automatically correct for internal validity bias in meta-analysis by only using the reported effects and their standard errors. The BC-BNP model is based on a mixture of a parametric random effects distribution, which represents the model of interest, and a BNP model for the bias component. This model relaxes the parametric assumptions of the bias distribution of the model introduced by Verde. Using simulated data sets, we evaluate the BC-BNP model and illustrate its applications with two real case studies. Our results show several potential advantages of the BC-BNP model: (1) It can detect bias when present while producing results similar to a simple normal-normal random effects model when bias is absent. (2) Relaxing the parametric assumptions of the bias component does not affect the model of interest and yields consistent results with the model of Verde. (3) In some applications, a BNP model of bias offers a better understanding of the studies' biases by clustering studies with similar biases. We implemented the BC-BNP model in the R package jarbes, facilitating its practical application.
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Affiliation(s)
- Pablo Emilio Verde
- Coordination Center for Clinical TrialsUniversity Hospital Dusseldorf Heinrich Heine University of DusseldorfDusseldorfGermany
| | - Gary L. Rosner
- Division of Quantitative SciencesJohns Hopkins UniversityBaltimoreMarylandUSA
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2
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Wu Y, Li J, Feng K, Tan A, Gao Y, Chen W, Jia W, Guo X, Kang J. N-CADHERIN +/CD168 - subpopulation determines therapeutic variations of UC-MSCs for cardiac repair after myocardial infarction. Stem Cell Res Ther 2024; 15:423. [PMID: 39533355 PMCID: PMC11559175 DOI: 10.1186/s13287-024-04032-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Accepted: 10/30/2024] [Indexed: 11/16/2024] Open
Abstract
BACKGROUND The efficiency of mesenchymal stem cells (MSCs) in treating myocardial infarction (MI) remains inconsistent, which limits their therapeutic applications. Therefore, exploring the mechanism for the inconsistent efficacy of MSCs and identification the criteria for screening MSCs are important for improving the efficiency of MSCs. METHODS Mouse model after MI was utilized to test the role of MSCs from different donors and the functional subpopulation in improving cardiac function. Heterogeneity of MSCs was identified using single-cell RNA sequencing (scRNA-seq) of MSC-GY. GSEA and Scissor analyses were used to find the functional subpopulations of MSCs that promote angiogenesis. The role of functional subpopulations in promoting angiogenesis was verified by detecting the secretory proteins, the ratio of N-CADHERIN+/CD168- subpopulations in MSCs, and the tube formation, migration, and proliferation of HUVECs after treatment with conditional medium (CM) derived from different MSCs. RESULTS We found that umbilical cord-derived MSCs (UC-MSCs) from different donors have varied therapeutic efficacy in MI mice and UC-MSCs with higher therapeutic effectiveness exhibited the most potent pro-angiogenic effects by secreting elevated levels of angiogenesis-related proteins, such as MYDGF, VEGFA, and FGF2. ScRNA-seq of 10,463 UC-MSCs revealed that the N-CADHERIN+/CD168- subpopulation was closely associated with pro-angiogenic effects, and the ratio of this cell subpopulation was positively correlated with the angiogenic potential of MSCs. We also found that the N-CADHERIN+/CD168- subpopulation was the functional subpopulation of MSCs in improving cardiac function of MI mice. CONCLUSIONS Our study identified that the N-CADHERIN+/CD168- subpopulation was the functional subpopulation of MSCs in treating MI, which was essential for the development and utilization of MSCs in MI treatment.
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Affiliation(s)
- Yukang Wu
- Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, National Stem Cell Translational Resource Center, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Jianguo Li
- Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, National Stem Cell Translational Resource Center, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Ke Feng
- Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, National Stem Cell Translational Resource Center, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Ailing Tan
- Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, National Stem Cell Translational Resource Center, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Yingying Gao
- Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, National Stem Cell Translational Resource Center, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Wen Chen
- Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, National Stem Cell Translational Resource Center, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Wenwen Jia
- Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, National Stem Cell Translational Resource Center, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Xudong Guo
- Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, National Stem Cell Translational Resource Center, School of Life Sciences and Technology, Tongji University, Shanghai, China.
| | - Jiuhong Kang
- Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, National Stem Cell Translational Resource Center, School of Life Sciences and Technology, Tongji University, Shanghai, China.
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3
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McCracken IR, Smart N. Control of coronary vascular cell fate in development and regeneration. Semin Cell Dev Biol 2024; 155:50-61. [PMID: 37714806 DOI: 10.1016/j.semcdb.2023.08.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Revised: 08/25/2023] [Accepted: 08/28/2023] [Indexed: 09/17/2023]
Abstract
The coronary vasculature consists of a complex hierarchal network of arteries, veins, and capillaries which collectively function to perfuse the myocardium. However, the pathways controlling the temporally and spatially restricted mechanisms underlying the formation of this vascular network remain poorly understood. In recent years, the increasing use and refinement of transgenic mouse models has played an instrumental role in offering new insights into the cellular origins of the coronary vasculature, as well as identifying a continuum of transitioning cell states preceding the full maturation of the coronary vasculature. Coupled with the emergence of single cell RNA sequencing platforms, these technologies have begun to uncover the key regulatory factors mediating the convergence of distinct cellular origins to ensure the formation of a collectively functional, yet phenotypically diverse, vascular network. Furthermore, improved understanding of the key regulatory factors governing coronary vessel formation in the embryo may provide crucial clues into future therapeutic strategies to reactivate these developmentally functional mechanisms to drive the revascularisation of the ischaemic adult heart.
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Affiliation(s)
- Ian R McCracken
- Institute of Developmental and Regenerative Medicine, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX3 7TY, United Kingdom
| | - Nicola Smart
- Institute of Developmental and Regenerative Medicine, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX3 7TY, United Kingdom.
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4
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Abstract
Endothelial colony-forming cells (ECFCs) are progenitor cells that can give rise to colonies of highly proliferative vascular endothelial cells (ECs) with clonal expansion and in vivo blood vessel-forming potential. More than two decades ago, the identification of ECFCs in human peripheral blood created tremendous opportunities as having a clinically accessible source of autologous ECs could facilitate meaningful therapies with the potential to impact multiple vascular diseases. Nevertheless, until recently, the field of endothelial progenitor cells has been plagued with ambiguities and controversies, and reaching a consensus on the definition of ECFCs has not been straightforward. Moreover, although the basic phenotypical and functional characteristics of cultured ECFCs are now well established, some fundamental questions such as the origin of ECFCs and their physiological roles in health and disease remain incompletely understood. Here, I highlight some critical studies that have shaped our current understanding of ECFCs in humans. Insights into the biological attributes of ECFCs are essential for facilitating the clinical translation of their therapeutic potential.
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Affiliation(s)
- Juan M Melero-Martin
- Department of Cardiac Surgery, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
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5
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Bouten CVC, Cheng C, Vermue IM, Gawlitta D, Passier R. Cardiovascular tissue engineering and regeneration: A plead for further knowledge convergence. Tissue Eng Part A 2022; 28:525-541. [PMID: 35382591 DOI: 10.1089/ten.tea.2021.0231] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Cardiovascular tissue engineering and regeneration strive to provide long-term, effective solutions for a growing group of patients in need of myocardial repair, vascular (access) grafts, heart valves, and regeneration of organ microcirculation. In the past two decades, ongoing convergence of disciplines and multidisciplinary collaborations between cardiothoracic surgeons, cardiologists, bioengineers, material scientists, and cell biologists have resulted in better understanding of the problems at hand and novel regenerative approaches. As a side effect, however, the field has become strongly organized and differentiated around topical areas at risk of reinvention of technologies and repetition of approaches and across the areas. A better integration of knowledge and technologies from the individual topical areas and regenerative approaches and technologies may pave the way towards faster and more effective treatments to cure the cardiovascular system. This review summarizes the evolution of research and regenerative approaches in the areas of myocardial regeneration, heart valve and vascular tissue engineering, and regeneration of microcirculations and discusses previous and potential future integration of these individual areas and developed technologies for improved clinical impact. Finally, it provides a perspective on the further integration of research organization, knowledge implementation, and valorization as a contributor to advancing cardiovascular tissue engineering and regenerative medicine.
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Affiliation(s)
- Carlijn V C Bouten
- Soft Tissue Engineering and Mechanobiology, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands
- Institute for Complex Molecular Systems (ICMS), Eindhoven, The Netherlands
| | - Caroline Cheng
- Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands
- Experimental Cardiology, Department of Cardiology, Thoraxcenter Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Ijsbrand M Vermue
- Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Debby Gawlitta
- Department of Oral and Maxillofacial Surgery, Prosthodontics and Special Dental Care, University Medical Center, Utrecht, The Netherlands
| | - Robert Passier
- Department of Applied Stem Cell Technologies, Faculty of Science and Technology, University of Twente, Enschede, The Netherlands
- Department of Anatomy and Embryology, Leiden University Medical Center, Leiden, The Netherlands
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6
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Xu Z, Neuber S, Nazari-Shafti T, Liu Z, Dong F, Stamm C. Impact of procedural variability and study design quality on the efficacy of cell-based therapies for heart failure - a meta-analysis. PLoS One 2022; 17:e0261462. [PMID: 34986181 PMCID: PMC8730409 DOI: 10.1371/journal.pone.0261462] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Accepted: 12/02/2021] [Indexed: 11/28/2022] Open
Abstract
BACKGROUND Cell-based therapy has long been considered a promising strategy for the treatment of heart failure (HF). However, its effectiveness in the clinical setting is now doubted. Because previous meta-analyses provided conflicting results, we sought to review all available data focusing on cell type and trial design. METHODS AND FINDINGS The electronic databases PubMed, Cochrane library, ClinicalTrials.gov, and EudraCT were searched for randomized controlled trials (RCTs) utilizing cell therapy for HF patients from January 1, 2000 to December 31, 2020. Forty-three RCTs with 2855 participants were identified. The quality of the reported study design was assessed by evaluating the risk-of-bias (ROB). Primary outcomes were defined as mortality rate and left ventricular ejection fraction (LVEF) change from baseline. Secondary outcomes included both heart function data and clinical symptoms/events. Between-study heterogeneity was assessed using the I2 index. Subgroup analysis was performed based on HF type, cell source, cell origin, cell type, cell processing, type of surgical intervention, cell delivery routes, cell dose, and follow-up duration. Only 10 of the 43 studies had a low ROB for all method- and outcome parameters. A higher ROB was associated with a greater increase in LVEF. Overall, there was no impact on mortality for up to 12 months follow-up, and a clinically irrelevant average LVEF increase by LVEF (2.4%, 95% CI = 0.75-4.05, p = 0.004). Freshly isolated, primary cells tended to produce better outcomes than cultured cell products, but there was no clear impact of the cell source tissue, bone marrow cell phenotype or cell chricdose (raw or normalized for CD34+ cells). A meaningful increase in LVEF was only observed when cell therapy was combined with myocardial revascularization. CONCLUSIONS The published results suggest a small increase in LVEF following cell therapy for heart failure, but publication bias and methodologic shortcomings need to be taken into account. Given that cardiac cell therapy has now been pursued for 20 years without real progress, further efforts should not be made. STUDY REGISTRY NUMBER This meta-analysis is registered at the international prospective register of systematic reviews, number CRD42019118872.
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Affiliation(s)
- Zhiyi Xu
- Berlin Institute of Health Center for Regenerative Therapies, Charité–Universitätsmedizin Berlin, Berlin, Germany
| | - Sebastian Neuber
- Berlin Institute of Health Center for Regenerative Therapies, Charité–Universitätsmedizin Berlin, Berlin, Germany
- Department of Cardiothoracic and Vascular Surgery, German Heart Center Berlin, Berlin, Germany
- German Centre for Cardiovascular Research, Partner Site Berlin, Berlin, Germany
| | - Timo Nazari-Shafti
- Berlin Institute of Health Center for Regenerative Therapies, Charité–Universitätsmedizin Berlin, Berlin, Germany
- 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 at Charité, Universitätsmedizin Berlin, Berlin, Germany
| | - Zihou Liu
- Berlin Institute of Health Center for Regenerative Therapies, Charité–Universitätsmedizin Berlin, Berlin, Germany
| | - Fengquan Dong
- Department of Cardiology, Shenzhen University General Hospital, Shenzhen, Guangdong, China
| | - Christof Stamm
- Berlin Institute of Health Center for Regenerative Therapies, Charité–Universitätsmedizin Berlin, Berlin, Germany
- Department of Cardiothoracic and Vascular Surgery, German Heart Center Berlin, Berlin, Germany
- German Centre for Cardiovascular Research, Partner Site Berlin, Berlin, Germany
- Helmholtz Zentrum Geesthacht, Institut für Aktive Polymere, Teltow, Germany
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7
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Stamm C. [Cardiac cell therapy-Lost in translation?]. ZEITSCHRIFT FUR HERZ THORAX UND GEFASSCHIRURGIE 2022; 36:107-114. [PMID: 35013648 PMCID: PMC8730298 DOI: 10.1007/s00398-021-00476-5] [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] [Accepted: 12/02/2021] [Indexed: 11/24/2022]
Abstract
Cardiac cell therapy covers more than two decades of tumultuous history. In this period of time, the perception of the heart as an organ consisting of a fixed number of terminally differentiated cardiomyocytes fundamentally changed. Suddenly, the myocardium was (or is) considered to be regenerative by intrinsic progenitor cells, inducible proliferation, and in particular by exogenic transplanted cells. While the clinical translation of real cardiomyocytes obtained by cellular reprogramming has progressed only slowly, a multitude of clinical studies were carried out with cell products of somatic origin. This was mostly based on assumptions and experimentally acquired data with respect to the plasticity of adult precursor cells that, in retrospect, lacked validity. Accordingly, on closer inspection the results of the clinical studies were not convincing but they were nevertheless often presented and viewed in a very optimistic light. Today, cardiac cell therapy with cells of a somatic origin is considered to have failed. Recapitulating the stages of this era can help recognize and avoid such undesirable developments in the future.
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Affiliation(s)
- Christof Stamm
- Deutsches Herzzentrum Berlin, Augustenburger Platz 1, 13353 Berlin, Deutschland
- Charité Universitätsmedizin, Berlin, Deutschland
- BIH Center for Regenerative Therapies, Berlin, Deutschland
- Deutsches Zentrum für Herz-Kreislaufforschung, Standort Berlin, Berlin, Deutschland
- Institut für Aktive Polymere, Helmholtz Zentrum Geesthacht, Teltow, Deutschland
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8
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Mazine A, Rushani D, Yau TM. Clinical mesenchymal stem cell therapy in ischemic cardiomyopathy. JTCVS OPEN 2021; 8:135-141. [PMID: 36004185 PMCID: PMC9390513 DOI: 10.1016/j.xjon.2021.06.030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Accepted: 06/08/2021] [Indexed: 11/19/2022]
Affiliation(s)
| | | | - Terrence M. Yau
- Address for reprints: Terrence M. Yau, MD, MSc, Division of Cardiovascular Surgery, Peter Munk Cardiac Center, Toronto General Hospital, University Health Network, University of Toronto, 200 Elizabeth St, 4N-470, Toronto, Ontario M5G 2C4, Canada.
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9
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Kasai-Brunswick TH, Carvalho AB, Campos de Carvalho AC. Stem cell therapies in cardiac diseases: Current status and future possibilities. World J Stem Cells 2021; 13:1231-1247. [PMID: 34630860 PMCID: PMC8474720 DOI: 10.4252/wjsc.v13.i9.1231] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 07/26/2021] [Accepted: 08/10/2021] [Indexed: 02/06/2023] Open
Abstract
Cardiovascular diseases represent the world's leading cause of death. In this heterogeneous group of diseases, ischemic cardiomyopathies are the most devastating and prevalent, estimated to cause 17.9 million deaths per year. Despite all biomedical efforts, there are no effective treatments that can replace the myocytes lost during an ischemic event or progression of the disease to heart failure. In this context, cell therapy is an emerging therapeutic alternative to treat cardiovascular diseases by cell administration, aimed at cardiac regeneration and repair. In this review, we will cover more than 30 years of cell therapy in cardiology, presenting the main milestones and drawbacks in the field and signaling future challenges and perspectives. The outcomes of cardiac cell therapies are discussed in three distinct aspects: The search for remuscularization by replacement of lost cells by exogenous adult cells, the endogenous stem cell era, which pursued the isolation of a progenitor with the ability to induce heart repair, and the utilization of pluripotent stem cells as a rich and reliable source of cardiomyocytes. Acellular therapies using cell derivatives, such as microvesicles and exosomes, are presented as a promising cell-free therapeutic alternative.
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Affiliation(s)
- Tais Hanae Kasai-Brunswick
- National Center of Structural Biology and Bioimaging, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
- National Institute of Science and Technology in Regenerative Medicine, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
| | - Adriana Bastos Carvalho
- National Institute of Science and Technology in Regenerative Medicine, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
- Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
| | - Antonio Carlos Campos de Carvalho
- National Center of Structural Biology and Bioimaging, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
- National Institute of Science and Technology in Regenerative Medicine, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
- Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil.
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Dight J, Zhao J, Styke C, Khosrotehrani K, Patel J. Resident vascular endothelial progenitor definition and function: the age of reckoning. Angiogenesis 2021; 25:15-33. [PMID: 34499264 PMCID: PMC8813834 DOI: 10.1007/s10456-021-09817-2] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 09/05/2021] [Indexed: 02/07/2023]
Abstract
The cardiovascular system is composed around the central function of the endothelium that lines the inner surfaces of its vessels. In recent years, the existence of a progenitor population within the endothelium has been validated through the study of endothelial colony-forming cells (ECFCs) in human peripheral blood and certain vascular beds. However, our knowledge on endothelial populations in vivo that can give rise to ECFCs in culture has been limited. In this review we report and analyse recent attempts at describing progenitor populations in vivo from murine studies that reflect the self-renewal and stemness capacity observed in ECFCs. We pinpoint seminal discoveries within the field, which have phenotypically defined, and functionally scrutinised these endothelial progenitors. Furthermore, we review recent publications utilising single-cell sequencing technologies to better understand the endothelium in homeostasis and pathology.
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Affiliation(s)
- James Dight
- The University of Queensland Diamantina Institute, 37 Kent Street, Woolloongabba, Brisbane, 4102, Australia
| | - Jilai Zhao
- The University of Queensland Diamantina Institute, 37 Kent Street, Woolloongabba, Brisbane, 4102, Australia
| | - Cassandra Styke
- The University of Queensland Diamantina Institute, 37 Kent Street, Woolloongabba, Brisbane, 4102, Australia
| | - Kiarash Khosrotehrani
- The University of Queensland Diamantina Institute, 37 Kent Street, Woolloongabba, Brisbane, 4102, Australia.
| | - Jatin Patel
- The University of Queensland Diamantina Institute, 37 Kent Street, Woolloongabba, Brisbane, 4102, Australia. .,Cancer and Ageing Research Program, School of Biomedical Sciences, Queensland University of Technology, 37 Kent Street, Woolloongabba, Brisbane, 4102, Australia.
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11
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Bioactive Scaffolds in Stem Cell-Based Therapies for Myocardial Infarction: a Systematic Review and Meta-Analysis of Preclinical Trials. Stem Cell Rev Rep 2021; 18:2104-2136. [PMID: 34463903 DOI: 10.1007/s12015-021-10186-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/12/2021] [Indexed: 10/20/2022]
Abstract
The use of bioactive scaffolds in conjunction with stem cell therapies for cardiac repair after a myocardial infarction shows significant promise for clinical translation. We performed a systematic review and meta-analysis of preclinical trials that investigated the use of bioactive scaffolds to support stem cell-aided cardiac regeneration, in comparison to stem cell treatment alone. Cochrane Library, Medline, Embase, PubMed, Scopus, Web of Science, and grey literature were searched through April 23, 2020 and 60 articles were included in the final analysis. The overall effect size observed in scaffold and stem cell-treated small animals compared to stem cell-treated controls for ejection fraction (EF) was 7.98 [95% confidence interval (CI): 6.36, 9.59] and for fractional shortening (FS) was 5.50 [95% CI: 4.35, 6.65] in small animal models. The largest improvements in EF and FS were observed when hydrogels were used (MD = 8.45 [95% CI: 6.46, 10.45] and MD = 5.76 [95% CI: 4.46, 7.05], respectively). Subgroup analysis revealed that cardiac progenitor cells had the largest effect size for FS, and was significant from pluripotent, mesenchymal and endothelial stem cell types. In large animal studies, the overall improvement of EF favoured the use of stem cell-embedded scaffolds compared to direct injection of cells (MD = 10.49 [95% CI: 6.30, 14.67]). Significant publication bias was present in the small animal trials for EF and FS. This study supports the use of bioactive scaffolds to aid in stem cell-based cardiac regeneration. Hydrogels should be further investigated in larger animal models for clinical translation.
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12
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Thébaud B, Lalu M, Renesme L, van Katwyk S, Presseau J, Thavorn K, Cobey KD, Hutton B, Moher D, Soll RF, Fergusson D. Benefits and obstacles to cell therapy in neonates: The INCuBAToR (Innovative Neonatal Cellular Therapy for Bronchopulmonary Dysplasia: Accelerating Translation of Research). Stem Cells Transl Med 2021; 10:968-975. [PMID: 33570257 PMCID: PMC8235145 DOI: 10.1002/sctm.20-0508] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Revised: 01/06/2021] [Accepted: 01/12/2021] [Indexed: 12/13/2022] Open
Abstract
Cell-based therapies hold promise to substantially curb complications from extreme preterm birth, the main cause of death in children below the age of 5 years. Exciting preclinical studies in experimental neonatal lung injury have provided the impetus for the initiation of early phase clinical trials in extreme preterm infants at risk of developing bronchopulmonary dysplasia. Clinical translation of promising therapies, however, is slow and often fails. In the adult population, results of clinical trials so far have not matched the enticing preclinical data. The neonatal field has experienced many hard-earned lessons with the implementation of oxygen therapy or postnatal steroids. Here we briefly summarize the preclinical data that have permitted the initiation of early phase clinical trials of cell-based therapies in extreme preterm infants and describe the INCuBAToR concept (Innovative Neonatal Cellular Therapy for Bronchopulmonary Dysplasia: Accelerating Translation of Research), an evidence-based approach to mitigate the risk of translating advanced therapies into this vulnerable patient population. The INCuBAToR addresses several of the shortcomings at the preclinical and the clinical stage that usually contribute to the failure of clinical translation through (a) systematic reviews of preclinical and clinical studies, (b) integrated knowledge transfer through engaging important stakeholders early on, (c) early economic evaluation to determine if a novel therapy is viable, and (d) retrospective and prospective studies to define and test ideal eligibility criteria to optimize clinical trial design. The INCuBAToR concept can be applied to any novel therapy in order to enhance the likelihood of success of clinical translation in a timely, transparent, rigorous, and evidence-based fashion.
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Affiliation(s)
- Bernard Thébaud
- Regenerative Medicine ProgramThe Ottawa Hospital Research Institute (OHRI)OttawaOntarioCanada
- Neonatology, Department of PediatricsChildren's Hospital of Eastern Ontario (CHEO) and CHEO Research InstituteOttawaOntarioCanada
- Department of Cellular and Molecular MedicineUniversity of OttawaOttawaOntarioCanada
| | - Manoj Lalu
- Regenerative Medicine ProgramThe Ottawa Hospital Research Institute (OHRI)OttawaOntarioCanada
- Department of Cellular and Molecular MedicineUniversity of OttawaOttawaOntarioCanada
- Department of Anesthesiology and Pain MedicineUniversity of OttawaOttawaOntarioCanada
- Clinical Epidemiology ProgramThe Ottawa Hospital Research Institute (OHRI)OttawaOntarioCanada
| | - Laurent Renesme
- Neonatology, Department of PediatricsChildren's Hospital of Eastern Ontario (CHEO) and CHEO Research InstituteOttawaOntarioCanada
| | - Sasha van Katwyk
- Clinical Epidemiology ProgramThe Ottawa Hospital Research Institute (OHRI)OttawaOntarioCanada
| | - Justin Presseau
- Clinical Epidemiology ProgramThe Ottawa Hospital Research Institute (OHRI)OttawaOntarioCanada
- School of Public Health and Preventive MedicineUniversity of OttawaOttawaOntarioCanada
| | - Kednapa Thavorn
- Clinical Epidemiology ProgramThe Ottawa Hospital Research Institute (OHRI)OttawaOntarioCanada
- School of Public Health and Preventive MedicineUniversity of OttawaOttawaOntarioCanada
| | - Kelly D. Cobey
- Clinical Epidemiology ProgramThe Ottawa Hospital Research Institute (OHRI)OttawaOntarioCanada
- Centre for JournalologyThe Ottawa Hospital Research Institute (OHRI)OttawaOntarioCanada
| | - Brian Hutton
- Clinical Epidemiology ProgramThe Ottawa Hospital Research Institute (OHRI)OttawaOntarioCanada
| | - David Moher
- Clinical Epidemiology ProgramThe Ottawa Hospital Research Institute (OHRI)OttawaOntarioCanada
| | - Roger F. Soll
- Department of Pediatrics, Larner College of MedicineUniversity of VermontBurlingtonVermontUSA
| | - Dean Fergusson
- Clinical Epidemiology ProgramThe Ottawa Hospital Research Institute (OHRI)OttawaOntarioCanada
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13
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Demurtas J, Fanelli GN, Romano SL, Solari M, Yang L, Soysal P, López Sánchez GF, Grabovac I, Smith L, Zorzi A, Luchini C, Veronese N. Stem cells for treatment of cardiovascular diseases: An umbrella review of randomized controlled trials. Ageing Res Rev 2021; 67:101257. [PMID: 33434684 DOI: 10.1016/j.arr.2021.101257] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2020] [Revised: 01/01/2021] [Accepted: 01/05/2021] [Indexed: 12/12/2022]
Abstract
AIMS Stem cells are a promising therapy for various medical conditions. The literature regarding their adoption for the clinical care of cardiovascular diseases (CVD) is still conflicting. Therefore, our aim is to assess the strength and credibility of the evidence on clinical outcomes and application of stem cells derived from systematic reviews and meta-analyses of intervention studies in CVD. METHODS AND RESULTS Umbrella review of systematic reviews with meta-analyses of randomized controlled trials (RCTs) using placebo/no intervention as control group. For meta-analyses of RCTs, outcomes with a random-effect p-value <0.05, the GRADE (Grading of Recommendations Assessment, Development and Evaluation) assessment was used, classifying the evidence from very low to high. From 184 abstracts initially identified, 11 meta-analyses (for a total of 34 outcomes) were included. Half of the outcomes were statistically significant (p < 0.05), indicating that stem cells are more useful than placebo. High certainty of evidence supports the associations of the use of stem cells with a better left ventricular end systolic volume and left ventricular ejection fraction (LVEF) in acute myocardial infarction; improved exercise time in refractory angina; a significant lower risk of amputation rate in critical limb ischemia; a higher successful rate in complete healing in case of lower extremities ulcer; and better values of LVEF in systolic heart failure, as compared to placebo. CONCLUSION AND RELEVANCE The adoption of stem cells in clinical practice is supported by a high certainty of strength in different CVD, with the highest strength in acute myocardial infarction and refractory angina.
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Affiliation(s)
- Jacopo Demurtas
- Primary Care Department, USL Toscana Sud Est-Grosseto, Grosseto, Italy; Clinical and Experimental Medicine PhD Program, University of Modena and Reggio Emilia, Modena, Italy
| | - Giuseppe Nicolò Fanelli
- Division of Pathology, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Italy
| | - Simone Lorenzo Romano
- Immunohaematology and Transfusion Medicine Service, USL Toscana Nord Ovest, San Luca Hospital, Lucca, Italy
| | - Marco Solari
- Cardiology Unit, USL Toscana Sus Est Grosseto, Grosseto, Italy
| | - Lin Yang
- Department of Cancer Epidemiology and Prevention Research, Alberta Health Services, Calgary, Canada; Departments of Oncology and Community Health Sciences, University of Calgary, Calgary, Canada
| | - Pinar Soysal
- Department of Geriatric Medicine, Bezmialem Vakif University, Faculty of Medicine, Istanbul, Turkey
| | - Guillermo F López Sánchez
- Vision and Eye Research Institute, School of Medicine, Faculty of Health, Education, Medicine and Social Care, Anglia Ruskin University-Cambridge Campus, Cambridge, United Kingdom
| | - Igor Grabovac
- Department of Social and Preventive Medicine, Centre for Public Health, Medical University of Vienna, Austria
| | - Lee Smith
- The Cambridge Centre for Sport and Exercise Sciences, Anglia Ruskin University, Cambridge, United Kingdom.
| | - Alessandro Zorzi
- Department of Cardiac, Thoracic and Vascular Sciences and Public Health, University of Padova, Padova, Italy
| | - Claudio Luchini
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
| | - Nicola Veronese
- Geriatric Unit, Department of Internal Medicine and Geriatrics, University of Palermo, Palermo, Italy
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14
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Therapeutic Applications of Stem Cells and Extracellular Vesicles in Emergency Care: Futuristic Perspectives. Stem Cell Rev Rep 2021; 17:390-410. [PMID: 32839921 PMCID: PMC7444453 DOI: 10.1007/s12015-020-10029-2] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Regenerative medicine (RM) is an interdisciplinary field that aims to repair, replace or regenerate damaged or missing tissue or organs to function as close as possible to its physiological architecture and functions. Stem cells, which are undifferentiated cells retaining self-renewal potential, excessive proliferation and differentiation capacity into offspring or daughter cells that form different lineage cells of an organism, are considered as an important part of the RM approaches. They have been widely investigated in preclinical and clinical studies for therapeutic purposes. Extracellular vesicles (EVs) are the vital mediators that regulate the therapeutic effects of stem cells. Besides, they carry various types of cargo between cells which make them a significant contributor of intercellular communication. Given their role in physiological and pathological conditions in living cells, EVs are considered as a new therapeutic alternative solution for a variety of diseases in which there is a high unmet clinical need. This review aims to summarize and identify therapeutic potential of stem cells and EVs in diseases requiring acute emergency care such as trauma, heart diseases, stroke, acute respiratory distress syndrome and burn injury. Diseases that affect militaries or societies including acute radiation syndrome, sepsis and viral pandemics such as novel coronavirus disease 2019 are also discussed. Additionally, featuring and problematic issues that hamper clinical translation of stem cells and EVs are debated in a comparative manner with a futuristic perspective. Graphical Abstract.
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15
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Madeddu P. Cell therapy for the treatment of heart disease: Renovation work on the broken heart is still in progress. Free Radic Biol Med 2021; 164:206-222. [PMID: 33421587 DOI: 10.1016/j.freeradbiomed.2020.12.444] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Revised: 11/26/2020] [Accepted: 12/29/2020] [Indexed: 12/20/2022]
Abstract
Cardiovascular disease (CVD) continues to be the number one killer in the aging population. Heart failure (HF) is also an important cause of morbidity and mortality in patients with congenital heart disease (CHD). Novel therapeutic approaches that could restore stable heart function are much needed in both paediatric and adult patients. Regenerative medicine holds promises to provide definitive solutions for correction of congenital and acquired cardiac defects. In this review article, we recap some important aspects of cardiovascular cell therapy. First, we report quantifiable data regarding the scientific advancements in the field and how this has been translated into tangible outcomes according clinical studies and related meta-analyses. We then comment on emerging trends and technologies, such as the use of second-generation cell products, including pericyte-like vascular progenitors, and reprogramming of cells by different approaches including modulation of oxidative stress. The more affordable and feasible strategy of repurposing clinically available drugs to awaken the intrinsic healing potential of the heart will be discussed in the light of current social, financial, and ethical context. Cell therapy remains a work in progress field. Uncertainty in the ability of the experts and policy makers to solve urgent medical problems is growing in a world that is significantly influenced by them. This is particularly true in the field of regenerative medicine, due to great public expectations, polarization of leadership and funding, and insufficient translational vision. Cardiovascular regenerative medicine should be contextualized in a holistic program with defined priorities to allow a complete realization. Reshaping the notion of medical expertise is fundamental to fill the current gap in translation.
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Affiliation(s)
- Paolo Madeddu
- Bristol Medical School, Translational Health Sciences, University of Bristol, Bristol Royal Infirmary, Upper Maudlin Street, BS28HW, Bristol, United Kingdom.
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16
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Verde PE. A bias‐corrected meta‐analysis model for combining, studies of different types and quality. Biom J 2020; 63:406-422. [DOI: 10.1002/bimj.201900376] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2019] [Revised: 09/02/2020] [Accepted: 09/02/2020] [Indexed: 01/17/2023]
Affiliation(s)
- Pablo Emilio Verde
- Coordination Center for Clinical Trials Düsseldorf University Hospital Düsseldorf Germany
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17
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Que WC, Qiu HQ, Chen HY, Wang SZ, Cheng Y, Liao LM. Systematic evaluation of therapeutic effects of stem cell transplantation trials for heart diseases in China. Clin Transplant 2020; 34:e14051. [PMID: 32946605 DOI: 10.1111/ctr.14051] [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: 07/12/2020] [Accepted: 07/20/2020] [Indexed: 11/27/2022]
Abstract
BACKGROUND To systematically assess the quality of reports of clinical trials of stem cell for heart diseases published in Chinese. METHODS The quality of reports was assessed according to the CONSORT statement and the Jadad score. The association between the CONSORT scores and the reported therapeutic effects was evaluated. RESULTS A total of 36 randomized clinical trials were identified, and 1552 patients were included. The mean CONSORT score was 7.06 (SD = 2.99). The proportion of reports with a Jadad score of 3 was 8.33%. The improvement of left ventricular function, myocardial perfusion area, left ventricular diastolic diameter, and cardiac output decreased with the increase in the CONSORT score. CONCLUSIONS The percentages of high-quality reports published in Chinese on stem cell therapy for heart diseases are low. Although stem cell transplantation seems promising for heart diseases, high-quality studies are needed to verify the conclusions．.
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Affiliation(s)
- Wan-Cai Que
- Department of Pharmacy, Fujian Medical University Union Hospital, Fuzhou, China
| | - Hong-Qiang Qiu
- Department of Pharmacy, Fujian Medical University Union Hospital, Fuzhou, China
| | - Hui-Yun Chen
- Affiliated People's Hospital of Fujian University of Traditional Chinese Medicine, Fuzhou, China
| | - Shao-Zhen Wang
- Affiliated People's Hospital of Fujian University of Traditional Chinese Medicine, Fuzhou, China
| | - Yu Cheng
- Department of Pharmacy, Fujian Medical University Union Hospital, Fuzhou, China
| | - Lian-Ming Liao
- Center of Laboratory Medicine, Fujian Medical University Union Hospital, Fuzhou, China
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18
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Gunata M, Parlakpinar H. A review of myocardial ischaemia/reperfusion injury: Pathophysiology, experimental models, biomarkers, genetics and pharmacological treatment. Cell Biochem Funct 2020; 39:190-217. [PMID: 32892450 DOI: 10.1002/cbf.3587] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2020] [Revised: 08/03/2020] [Accepted: 08/14/2020] [Indexed: 12/14/2022]
Abstract
Cardiovascular diseases are known to be the most fatal diseases worldwide. Ischaemia/reperfusion (I/R) injury is at the centre of the pathology of the most common cardiovascular diseases. According to the World Health Organization estimates, ischaemic heart disease is the leading global cause of death, causing more than 9 million deaths in 2016. After cardiovascular events, thrombolysis, percutaneous transluminal coronary angioplasty or coronary bypass surgery are applied as treatment. However, after restoring coronary blood flow, myocardial I/R injury may occur. It is known that this damage occurs due to many pathophysiological mechanisms, especially increasing reactive oxygen types. Besides causing cardiomyocyte death through multiple mechanisms, it may be an important reason for affecting other cell types such as platelets, fibroblasts, endothelial and smooth muscle cells and immune cells. Also, polymorphonuclear leukocytes are associated with myocardial I/R damage during reperfusion. This damage may be insufficient in patients with co-morbidity, as it is demonstrated that it can be prevented by various endogenous antioxidant systems. In this context, the resulting data suggest that optimal cardioprotection may require a combination of additional or synergistic multi-target treatments. In this review, we discussed the pathophysiology, experimental models, biomarkers, treatment and its relationship with genetics in myocardial I/R injury. SIGNIFICANCE OF THE STUDY: This review summarized current information on myocardial ischaemia/reperfusion injury (pathophysiology, experimental models, biomarkers, genetics and pharmacological therapy) for researchers and reveals guiding data for researchers, especially in the field of cardiovascular system and pharmacology.
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Affiliation(s)
- Mehmet Gunata
- Department of Medical Pharmacology, Faculty of Medicine, Inonu University, Malatya, Turkey
| | - Hakan Parlakpinar
- Department of Medical Pharmacology, Faculty of Medicine, Inonu University, Malatya, Turkey
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19
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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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20
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He L, Nguyen NB, Ardehali R, Zhou B. Heart Regeneration by Endogenous Stem Cells and Cardiomyocyte Proliferation: Controversy, Fallacy, and Progress. Circulation 2020; 142:275-291. [PMID: 32687441 DOI: 10.1161/circulationaha.119.045566] [Citation(s) in RCA: 89] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Ischemic heart disease is the leading cause of death worldwide. Myocardial infarction results in an irreversible loss of cardiomyocytes with subsequent adverse remodeling and heart failure. Identifying new sources for cardiomyocytes and promoting their formation represents a goal of cardiac biology and regenerative medicine. Within the past decade, many types of putative cardiac stem cells (CSCs) have been reported to regenerate the injured myocardium by differentiating into new cardiomyocytes. Some of these CSCs have been translated from bench to bed with reported therapeutic effectiveness. However, recent basic research studies on stem cell tracing have begun to question their fundamental biology and mechanisms of action, raising serious concerns over the myogenic potential of CSCs. We review the history of different types of CSCs within the past decade and provide an update of recent cell tracing studies that have challenged the origin and existence of CSCs. In addition to the potential role of CSCs in heart regeneration, proliferation of preexisting cardiomyocytes has recently gained more attention. This review will also evaluate the methodologic and technical aspects of past and current studies on CSCs and cardiomyocyte proliferation, with emphasis on technical strengths, advantages, and potential limitations of research approaches. While our understanding of cardiomyocyte generation and regeneration continues to evolve, it is important to address the shortcomings and inaccuracies in this field. This is best achieved by embracing technological advancements and improved methods to label single cardiomyocytes/progenitors and accurately investigate their developmental potential and fate/lineage commitment.
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Affiliation(s)
- Lingjuan He
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China (L.H., B.Z.)
| | - Ngoc B Nguyen
- Division of Cardiology, Department of Internal Medicine, David Geffen School of Medicine (N.B.N., R.A.), University of California, Los Angeles.,Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research (N.B.N., R.A.), University of California, Los Angeles
| | - Reza Ardehali
- Division of Cardiology, Department of Internal Medicine, David Geffen School of Medicine (N.B.N., R.A.), University of California, Los Angeles.,Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research (N.B.N., R.A.), University of California, Los Angeles
| | - Bin Zhou
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China (L.H., B.Z.).,School of Life Science and Technology, ShanghaiTech University, Shanghai, China (B.Z.).,School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China (B.Z.).,Key Laboratory of Regenerative Medicine of Ministry of Education, Jinan University, Guangzhou, China (B.Z.)
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21
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Abstract
Stem cell therapy offers a breakthrough opportunity for the improvement of ischemic heart diseases. Numerous clinical trials and meta-analyses appear to confirm its positive but variable effects on heart function. Whereas these trials widely differed in design, cell type, source, and doses reinjected, cell injection route and timing, and type of cardiac disease, crucial key factors that may favour the success of cell therapy emerge from the review of their data. Various types of cell have been delivered. Injection of myoblasts does not improve heart function and is often responsible for severe ventricular arrythmia occurrence. Using bone marrow mononuclear cells is a misconception, as they are not stem cells but mainly a mix of various cells of hematopoietic lineages and stromal cells, only containing very low numbers of cells that have stem cell-like features; this likely explain the neutral results or at best the modest improvement in heart function reported after their injection. The true existence of cardiac stem cells now appears to be highly discredited, at least in adults. Mesenchymal stem cells do not repair the damaged myocardial tissue but attenuate post-infarction remodelling and contribute to revascularization of the hibernated zone surrounding the scar. CD34+ stem cells - likely issued from pluripotent very small embryonic-like (VSEL) stem cells - emerge as the most convincing cell type, inducing structural and functional repair of the ischemic myocardial area, providing they can be delivered in large amounts via intra-myocardial rather than intra-coronary injection, and preferentially after myocardial infarct rather than chronic heart failure.
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Affiliation(s)
- Philippe Hénon
- CellProthera SAS and Institut de Recherche en Hématologie et Transplantation, CellProthera SAS 12 rue du Parc, 68100, Mulhouse, France.
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22
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Pölzl L, Nägele F, Graber M, Hirsch J, Lobenwein D, Mitrovic M, Mayr A, Theurl M, Schreinlechner M, Pamminger M, Dorfmüller C, Grimm M, Gollmann-Tepeköylü C, Holfeld J. Safety and efficacy of direct Cardiac Shockwave Therapy in patients with ischemic cardiomyopathy undergoing coronary artery bypass grafting (the CAST-HF trial): study protocol for a randomized controlled trial. Trials 2020; 21:447. [PMID: 32473644 PMCID: PMC7260800 DOI: 10.1186/s13063-020-04369-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Accepted: 05/05/2020] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Coronary artery diseases (CAD) remains a severe socio-economic burden in the Western world. Coronary obstruction and subsequent myocardial ischemia result in progressive replacement of contractile myocardium with dysfunctional, fibrotic scar tissue. Post-infarctional remodeling is causal for the concomitant decline of left-ventricular function and the fatal syndrome of heart failure. Available neurohumoral treatment strategies aim at the improvement of symptoms. Despite extensive research, therapeutic options for myocardial regeneration, including (stem)-cell therapy, gene therapy, cellular reprogramming or tissue engineering, remain purely experimental. Thus, there is an urgent clinical need for novel treatment options for inducing myocardial regeneration and improving left-ventricular function in ischemic cardiomyopathy. Shockwave Therapy (SWT) is a well-established regenerative tool that is effective for the treatment of chronic tendonitis, long-bone non-union and wound-healing disorders. In preclinical trials, SWT regenerated ischemic myocardium via the induction of angiogenesis and the reduction of fibrotic scar tissue, resulting in improved left-ventricular function. METHODS/DESIGN In this prospective, randomized controlled, single-blind, monocentric study, 80 patients with reduced left-ventricular ejection fraction (LVEF≤ 40%) are subjected to coronary-artery bypass-graft surgery (CABG) surgery and randomized in a 1:1 ratio to receive additional cardiac SWT (intervention group; 40 patients) or CABG surgery with sham treatment (control group; 40 patients). This study aims to evaluate (1) the safety and (2) the efficacy of cardiac SWT as adjunctive treatment during CABG surgery for the regeneration of ischemic myocardium. The primary endpoints of the study represent (1) major cardiac events and (2) changes in left-ventricular function 12 months after treatment. Secondary endpoints include 6-min Walk Test distance, improvement of symptoms and assessment of quality of life. DISCUSSION This study aims to investigate the safety and efficacy of cardiac SWT during CABG surgery for myocardial regeneration. The induction of angiogenesis, decrease of fibrotic scar tissue formation and, thus, improvement of left-ventricular function could lead to improved quality of life and prognosis for patients with ischemic heart failure. Thus, it could become the first clinically available treatment strategy for the regeneration of ischemic myocardium alleviating the socio-economic burden of heart failure. TRIAL REGISTRATION ClinicalTrials.gov, ID: NCT03859466. Registered on 1 March 2019.
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Affiliation(s)
- Leo Pölzl
- University Clinic of Cardiac Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Felix Nägele
- University Clinic of Cardiac Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Michael Graber
- University Clinic of Cardiac Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Jakob Hirsch
- University Clinic of Cardiac Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Daniela Lobenwein
- University Clinic of Cardiac Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Martina Mitrovic
- Clinical Trial Center, Medical University of Innsbruck, Innrain 52, 6020, Innsbruck, Austria
| | - Agnes Mayr
- University Clinic of Radiology, Medical University of Innsbruck, Innsbruck, Austria
| | - Markus Theurl
- University Clinic of Internal Medicine III, Medical University of Innsbruck, Innsbruck, Austria
| | - Michael Schreinlechner
- University Clinic of Internal Medicine III, Medical University of Innsbruck, Innsbruck, Austria
| | - Matthias Pamminger
- University Clinic of Radiology, Medical University of Innsbruck, Innsbruck, Austria
| | | | - Michael Grimm
- University Clinic of Cardiac Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Can Gollmann-Tepeköylü
- University Clinic of Cardiac Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Johannes Holfeld
- University Clinic of Cardiac Surgery, Medical University of Innsbruck, Innsbruck, Austria.
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23
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Ozaki Tan SJ, Floriano JF, Nicastro L, Emanueli C, Catapano F. Novel Applications of Mesenchymal Stem Cell-derived Exosomes for Myocardial Infarction Therapeutics. Biomolecules 2020; 10:E707. [PMID: 32370160 PMCID: PMC7277090 DOI: 10.3390/biom10050707] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 04/22/2020] [Accepted: 04/27/2020] [Indexed: 02/07/2023] Open
Abstract
Cardiovascular diseases (CVDs) are the leading cause of mortality and morbidity globally, representing approximately a third of all deaths every year. The greater part of these cases is represented by myocardial infarction (MI), or heart attack as it is better known, which occurs when declining blood flow to the heart causes injury to cardiac tissue. Mesenchymal stem cells (MSCs) are multipotent stem cells that represent a promising vector for cell therapies that aim to treat MI due to their potent regenerative effects. However, it remains unclear the extent to which MSC-based therapies are able to induce regeneration in the heart and even less clear the degree to which clinical outcomes could be improved. Exosomes, which are small extracellular vesicles (EVs) known to have implications in intracellular communication, derived from MSCs (MSC-Exos), have recently emerged as a novel cell-free vector that is capable of conferring cardio-protection and regeneration in target cardiac cells. In this review, we assess the current state of research of MSC-Exos in the context of MI. In particular, we place emphasis on the mechanisms of action by which MSC-Exos accomplish their therapeutic effects, along with commentary on the current difficulties faced with exosome research and the ongoing clinical applications of stem-cell derived exosomes in different medical contexts.
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Affiliation(s)
- Sho Joseph Ozaki Tan
- National Heart and Lung Institute, Imperial College London, London W12 0NN, UK; (S.J.O.T.); (J.F.F.); (L.N.)
| | - Juliana Ferreria Floriano
- National Heart and Lung Institute, Imperial College London, London W12 0NN, UK; (S.J.O.T.); (J.F.F.); (L.N.)
- Botucatu Medical School, Sao Paulo State University, Botucatu 18618687, Brazil
| | - Laura Nicastro
- National Heart and Lung Institute, Imperial College London, London W12 0NN, UK; (S.J.O.T.); (J.F.F.); (L.N.)
| | - Costanza Emanueli
- National Heart and Lung Institute, Imperial College London, London W12 0NN, UK; (S.J.O.T.); (J.F.F.); (L.N.)
| | - Francesco Catapano
- National Heart and Lung Institute, Imperial College London, London W12 0NN, UK; (S.J.O.T.); (J.F.F.); (L.N.)
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24
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Maslovaric M, Fatic N, Delević E. State of the art of stem cell therapy for ischaemic cardiomyopathy. Part 2. ANGIOLOGII︠A︡ I SOSUDISTAI︠A︡ KHIRURGII︠A︡ = ANGIOLOGY AND VASCULAR SURGERY 2020; 25:7-26. [PMID: 31855197 DOI: 10.33529/angio2019414] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
Ischemic cardiomyopathy is becoming a leading cause of morbidity and mortality in the whole world. Stem cell-based therapy is emerging as a promising option for treatment of ischemic cardiomyopathy. Several stem cell types, including cardiac-derived stem cells, bone marrow-derived stem cells, mesenchymal stem cells, skeletal myoblasts, CD34+ and CD133+ stem cells have been used in clinical trials. Clinical effects mostly depend on transdifferentiation and paracrine factors. One important issue is that a low survival and residential rate of transferred stem cells blocks the effective advances in cardiac improvement. Many other factors associated with the efficacy of cell replacement therapy for ischemic cardiomyopathy mainly including the route of delivery, the type and number of stem cell infusion, the timing of injection, patient's physical conditions, the particular microenvironment onto which the cells are delivered, and clinical conditions remain to be addressed. Here we provide an overview of modern methods of stem cell delivery, types of stem cells and discuss the current state of their therapeutic potential.
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Affiliation(s)
- Milica Maslovaric
- Prona-Montenegrin Science Promotion Foundation, Podgorica, Montenegro
| | - Nikola Fatic
- Department of Vascular Surgery, Clinical Centre of Montenegro, Podgorica, Montenegro
| | - Emilija Delević
- Medical Faculty in Podgorica, University of Montenegro, Podgorica, Montenegro
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25
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Guan S, Zhang K, Li J. Recent Advances in Extracellular Matrix for Engineering Stem Cell Responses. Curr Med Chem 2019; 26:6321-6338. [DOI: 10.2174/0929867326666190704121309] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2018] [Revised: 12/02/2018] [Accepted: 01/25/2019] [Indexed: 02/06/2023]
Abstract
Stem cell transplantation is an advanced medical technology, which brings hope for the
treatment of some difficult diseases in the clinic. Attributed to its self-renewal and differential
ability, stem cell research has been pushed to the forefront of regenerative medicine and has become
a hot topic in tissue engineering. The surrounding extracellular matrix has physical functions
and important biological significance in regulating the life activities of cells, which may play crucial
roles for in situ inducing specific differentiation of stem cells. In this review, we discuss the
stem cells and their engineering application, and highlight the control of the fate of stem cells, we
offer our perspectives on the various challenges and opportunities facing the use of the components
of extracellular matrix for stem cell attachment, growth, proliferation, migration and differentiation.
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Affiliation(s)
- Shuaimeng Guan
- School of Life Science, Zhengzhou University, Zhengzhou 450000, China
| | - Kun Zhang
- School of Life Science, Zhengzhou University, Zhengzhou 450000, China
| | - Jingan Li
- School of Materials Science and Engineering, Zhengzhou University, Zhengzhou 450000, China
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26
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Pagano F, Picchio V, Chimenti I, Sordano A, De Falco E, Peruzzi M, Miraldi F, Cavarretta E, Zoccai GB, Sciarretta S, Frati G, Marullo AGM. On the Road to Regeneration: "Tools" and "Routes" Towards Efficient Cardiac Cell Therapy for Ischemic Cardiomyopathy. Curr Cardiol Rep 2019; 21:133. [PMID: 31673821 DOI: 10.1007/s11886-019-1226-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
PURPOSE OF REVIEW Cardiac regenerative medicine is a field bridging together biotechnology and surgical science. In this review, we present the explored surgical roads to cell delivery and the known effects of each delivery method on cell therapy efficiency. We also list the more recent clinical trials, exploring the safety and efficacy of delivery routes used for cardiac cell therapy approaches. RECENT FINDINGS There is no consensus in defining which way is the most suitable for the delivery of the different therapeutic cell types to the damaged heart tissue. In addition, it emerged that the "delivery issue" has not been systematically addressed in each clinical trial and for each and every cell type capable of cardiac repair. Cardiac damage occurring after an ischemic insult triggers a cascade of cellular events, eventually leading to heart failure through fibrosis and maladaptive remodelling. None of the pharmacological or medical interventions approved so far can rescue or reverse this phenomenon, and cardiovascular diseases are still the leading cause of death in the western world. Therefore, for nearly 20 years, regenerative medicine approaches have focused on cell therapy as a promising road to pursue, with numerous preclinical and clinical testing of cell-based therapies being studied and developed. Nonetheless, consistent clinical results are still missing to reach consensus on the most effective strategy for ischemic cardiomyopathy, based on patient selection, diagnosis and stage of the disease, therapeutic cell type, and delivery route.
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Affiliation(s)
- Francesca Pagano
- Department of Medical Surgical Sciences and Biotechnologies, Sapienza University of Rome, Corso della Repubblica 79, 04100, Latina, Italy.
| | - Vittorio Picchio
- Department of Medical Surgical Sciences and Biotechnologies, Sapienza University of Rome, Corso della Repubblica 79, 04100, Latina, Italy
| | - Isotta Chimenti
- Department of Medical Surgical Sciences and Biotechnologies, Sapienza University of Rome, Corso della Repubblica 79, 04100, Latina, Italy
- Mediterranea Cardiocentro, Naples, Italy
| | - Alessia Sordano
- Department of Medical Surgical Sciences and Biotechnologies, Sapienza University of Rome, Corso della Repubblica 79, 04100, Latina, Italy
| | - Elena De Falco
- Department of Medical Surgical Sciences and Biotechnologies, Sapienza University of Rome, Corso della Repubblica 79, 04100, Latina, Italy
- Mediterranea Cardiocentro, Naples, Italy
| | | | - Fabio Miraldi
- Department of Cardiovascular, Respiratory, Nephrological, Anesthesiological, and Geriatric Sciences, Sapienza University of Rome, Latina, Italy
| | - Elena Cavarretta
- Department of Medical Surgical Sciences and Biotechnologies, Sapienza University of Rome, Corso della Repubblica 79, 04100, Latina, Italy
- Mediterranea Cardiocentro, Naples, Italy
| | - Giuseppe Biondi Zoccai
- Department of Medical Surgical Sciences and Biotechnologies, Sapienza University of Rome, Corso della Repubblica 79, 04100, Latina, Italy
- Mediterranea Cardiocentro, Naples, Italy
| | - Sebastiano Sciarretta
- Department of Medical Surgical Sciences and Biotechnologies, Sapienza University of Rome, Corso della Repubblica 79, 04100, Latina, Italy
- Department of AngioCardioNeurology, IRCCS Neuromed, Pozzilli, Italy
| | - Giacomo Frati
- Department of Medical Surgical Sciences and Biotechnologies, Sapienza University of Rome, Corso della Repubblica 79, 04100, Latina, Italy
- Department of AngioCardioNeurology, IRCCS Neuromed, Pozzilli, Italy
| | - Antonino G M Marullo
- Department of Medical Surgical Sciences and Biotechnologies, Sapienza University of Rome, Corso della Repubblica 79, 04100, Latina, Italy
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27
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Fujisawa T, Tura-Ceide O, Hunter A, Mitchell A, Vesey A, Medine C, Gallogly S, Hadoke PWF, Keith C, Sproul A, Roddie H, McQuaker G, Wilmut I, Mills NL, Brittan M. Endothelial Progenitor Cells Do Not Originate From the Bone Marrow. Circulation 2019; 140:1524-1526. [PMID: 31657952 PMCID: PMC6818974 DOI: 10.1161/circulationaha.119.042351] [Citation(s) in RCA: 65] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Affiliation(s)
- Takeshi Fujisawa
- British Heart Foundation Centre for Cardiovascular Science (T.F., A.H., A.M., A.V., C.M., S.G., P.W.F.H., N.L.M., M.B.), University of Edinburgh, United Kingdom
| | - Olga Tura-Ceide
- Department of Pulmonary Medicine, Hospital Clinic-Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona and Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Madrid, Spain (O.T.-C.)
| | - Amanda Hunter
- British Heart Foundation Centre for Cardiovascular Science (T.F., A.H., A.M., A.V., C.M., S.G., P.W.F.H., N.L.M., M.B.), University of Edinburgh, United Kingdom
| | - Andrew Mitchell
- British Heart Foundation Centre for Cardiovascular Science (T.F., A.H., A.M., A.V., C.M., S.G., P.W.F.H., N.L.M., M.B.), University of Edinburgh, United Kingdom
| | - Alex Vesey
- British Heart Foundation Centre for Cardiovascular Science (T.F., A.H., A.M., A.V., C.M., S.G., P.W.F.H., N.L.M., M.B.), University of Edinburgh, United Kingdom
| | - Claire Medine
- British Heart Foundation Centre for Cardiovascular Science (T.F., A.H., A.M., A.V., C.M., S.G., P.W.F.H., N.L.M., M.B.), University of Edinburgh, United Kingdom
| | - Susan Gallogly
- British Heart Foundation Centre for Cardiovascular Science (T.F., A.H., A.M., A.V., C.M., S.G., P.W.F.H., N.L.M., M.B.), University of Edinburgh, United Kingdom
| | - Patrick W F Hadoke
- British Heart Foundation Centre for Cardiovascular Science (T.F., A.H., A.M., A.V., C.M., S.G., P.W.F.H., N.L.M., M.B.), University of Edinburgh, United Kingdom
| | - Charlotte Keith
- South East Scotland Cytogenetics Service (C.K.), Western General Hospital, Edinburgh, United Kingdom
| | - Anne Sproul
- Department of Haematology (A.S., H.R.), Western General Hospital, Edinburgh, United Kingdom
| | - Huw Roddie
- Department of Haematology (A.S., H.R.), Western General Hospital, Edinburgh, United Kingdom
| | - Grant McQuaker
- Bone Marrow Transplant Unit, Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom (G.M.)
| | - Ian Wilmut
- MRC Centre for Regenerative Medicine, Scottish Centre for Regenerative Medicine (I.W.), University of Edinburgh, United Kingdom
| | - Nicholas L Mills
- British Heart Foundation Centre for Cardiovascular Science (T.F., A.H., A.M., A.V., C.M., S.G., P.W.F.H., N.L.M., M.B.), University of Edinburgh, United Kingdom.,Usher Institute for Population Health Sciences & Informatics (N.L.M.), University of Edinburgh, United Kingdom
| | - Mairi Brittan
- British Heart Foundation Centre for Cardiovascular Science (T.F., A.H., A.M., A.V., C.M., S.G., P.W.F.H., N.L.M., M.B.), University of Edinburgh, United Kingdom
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28
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Maliken BD, Kanisicak O, Karch J, Khalil H, Fu X, Boyer JG, Prasad V, Zheng Y, Molkentin JD. Gata4-Dependent Differentiation of c-Kit +-Derived Endothelial Cells Underlies Artefactual Cardiomyocyte Regeneration in the Heart. Circulation 2019; 138:1012-1024. [PMID: 29666070 PMCID: PMC6125755 DOI: 10.1161/circulationaha.118.033703] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Supplemental Digital Content is available in the text. Background: Although c-Kit+ adult progenitor cells were initially reported to produce new cardiomyocytes in the heart, recent genetic evidence suggests that such events are exceedingly rare. However, to determine if these rare events represent true de novo cardiomyocyte formation, we deleted the necessary cardiogenic transcription factors Gata4 and Gata6 from c-Kit–expressing cardiac progenitor cells. Methods: Kit allele–dependent lineage tracing and fusion analysis were performed in mice following simultaneous Gata4 and Gata6 cell type–specific deletion to examine rates of putative de novo cardiomyocyte formation from c-Kit+ cells. Bone marrow transplantation experiments were used to define the contribution of Kit allele–derived hematopoietic cells versus Kit lineage–dependent cells endogenous to the heart in contributing to apparent de novo lineage-traced cardiomyocytes. A Tie2CreERT2 transgene was also used to examine the global impact of Gata4 deletion on the mature cardiac endothelial cell network, which was further evaluated with select angiogenesis assays. Results: Deletion of Gata4 in Kit lineage–derived endothelial cells or in total endothelial cells using the Tie2CreERT2 transgene, but not from bone morrow cells, resulted in profound endothelial cell expansion, defective endothelial cell differentiation, leukocyte infiltration into the heart, and a dramatic increase in Kit allele–dependent lineage-traced cardiomyocytes. However, this increase in labeled cardiomyocytes was an artefact of greater leukocyte-cardiomyocyte cellular fusion because of defective endothelial cell differentiation in the absence of Gata4. Conclusions: Past identification of presumed de novo cardiomyocyte formation in the heart from c-Kit+ cells using Kit allele lineage tracing appears to be an artefact of labeled leukocyte fusion with cardiomyocytes. Deletion of Gata4 from c-Kit+ endothelial progenitor cells or adult endothelial cells negatively impacted angiogenesis and capillary network integrity.
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Affiliation(s)
- Bryan D Maliken
- Cincinnati Children's Hospital Medical Center, University of Cincinnati, OH (B.D.M., O.K., J.K., H.K., X.F., J.G.B., V.P., Y.Z., J.D.M.)
| | - Onur Kanisicak
- Cincinnati Children's Hospital Medical Center, University of Cincinnati, OH (B.D.M., O.K., J.K., H.K., X.F., J.G.B., V.P., Y.Z., J.D.M.)
| | - Jason Karch
- Cincinnati Children's Hospital Medical Center, University of Cincinnati, OH (B.D.M., O.K., J.K., H.K., X.F., J.G.B., V.P., Y.Z., J.D.M.)
| | - Hadi Khalil
- Cincinnati Children's Hospital Medical Center, University of Cincinnati, OH (B.D.M., O.K., J.K., H.K., X.F., J.G.B., V.P., Y.Z., J.D.M.)
| | | | - Justin G Boyer
- Cincinnati Children's Hospital Medical Center, University of Cincinnati, OH (B.D.M., O.K., J.K., H.K., X.F., J.G.B., V.P., Y.Z., J.D.M.).,Howard Hughes Medical Institute, Cincinnati Children's Hospital Research Foundation, OH (J.G.B., J.D.M)
| | - Vikram Prasad
- Cincinnati Children's Hospital Medical Center, University of Cincinnati, OH (B.D.M., O.K., J.K., H.K., X.F., J.G.B., V.P., Y.Z., J.D.M.)
| | - Yi Zheng
- Cincinnati Children's Hospital Medical Center, University of Cincinnati, OH (B.D.M., O.K., J.K., H.K., X.F., J.G.B., V.P., Y.Z., J.D.M.)
| | - Jeffery D Molkentin
- Cincinnati Children's Hospital Medical Center, University of Cincinnati, OH (B.D.M., O.K., J.K., H.K., X.F., J.G.B., V.P., Y.Z., J.D.M.).,Howard Hughes Medical Institute, Cincinnati Children's Hospital Research Foundation, OH (J.G.B., J.D.M)
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29
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Wong TW, Kan CD, Chiu WT, Fok KL, Ruan YC, Jiang X, Chen J, Kao CC, Chen IY, Lin HC, Chou CH, Lin CW, Yu CK, Tsao S, Lee YP, Chan HC, Wang JN. Progenitor Cells Derived from Drain Waste Product of Open-Heart Surgery in Children. J Clin Med 2019; 8:jcm8071028. [PMID: 31336927 PMCID: PMC6678880 DOI: 10.3390/jcm8071028] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2019] [Revised: 06/25/2019] [Accepted: 07/10/2019] [Indexed: 11/23/2022] Open
Abstract
Human cardiac progenitor cells isolated from the same host may have advantages over other sources of stem cells. The aim of this study is to establish a new source of human progenitor cells collected from a waste product, pericardiac effusion fluid, after open-heart surgery in children with congenital heart diseases. The fluid was collected every 24 h for 2 days after surgery in 37 children. Mononuclear cells were isolated and expanded in vitro. These pericardial effusion-derived progenitor cells (PEPCs) exhibiting cardiogenic lineage markers, were highly proliferative and enhanced angiogenesis in vitro. Three weeks after stem cell transplantation into the ischemic heart in mice, cardiac ejection fraction was improved significantly without detectable progenitor cells. Gene expression profiles of the repaired hearts revealed activation of several known repair mechanisms including paracrine effects, cell migration, and angiogenesis. These progenitor cells may have the potential for heart regeneration.
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Affiliation(s)
- Tak-Wah Wong
- Department of Dermatology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan
- Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan
- Center of Applied Nanomedicine, National Cheng Kung University, Tainan 701, Taiwan
| | - Chung-Dann Kan
- Department of Surgery, Institute of Cardiovascular Research Center, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan
| | - Wen-Tai Chiu
- Department of Biomedical Engineering, National Cheng Kung University, Tainan 701, Taiwan
| | - Kin Lam Fok
- Epithelial Cell Biology Research Center, School of Biomedical Sciences, Faculty of Medicine, the Chinese University of Hong Kong, Shatin, Hong Kong
| | - Ye Chun Ruan
- Epithelial Cell Biology Research Center, School of Biomedical Sciences, Faculty of Medicine, the Chinese University of Hong Kong, Shatin, Hong Kong
| | - Xiaohua Jiang
- Epithelial Cell Biology Research Center, School of Biomedical Sciences, Faculty of Medicine, the Chinese University of Hong Kong, Shatin, Hong Kong
- Key Laboratory for Regenerative Medicine, Ministry of Education of the People's Republic of China, Shatin, HongKong
| | - Junjiang Chen
- Epithelial Cell Biology Research Center, School of Biomedical Sciences, Faculty of Medicine, the Chinese University of Hong Kong, Shatin, Hong Kong
| | - Chiu-Ching Kao
- Department of Dermatology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan
| | - I-Yu Chen
- Department of Dermatology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan
| | - Hui-Chun Lin
- Department of Dermatology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan
| | - Chia-Hsuan Chou
- Department of Dermatology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan
| | - Chou-Wen Lin
- Biomedical Technology and Device Research Laboratories, Industrial Technology Research Institute, Liuo-Jia, Tainan 734, Taiwan
| | - Chun-Keung Yu
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan
- Department of Microbiology and Immunology, Center of Infectious Disease and Signaling Research, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan
- National Laboratory Animal Center, National Applied Research Laboratories, Taipei 11529, Taiwan
| | - Stephanie Tsao
- Department of Dermatology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan
| | - Yi-Ping Lee
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan
| | - Hsiao Chang Chan
- Epithelial Cell Biology Research Center, School of Biomedical Sciences, Faculty of Medicine, the Chinese University of Hong Kong, Shatin, Hong Kong
- Key Laboratory for Regenerative Medicine, Ministry of Education of the People's Republic of China, Shatin, HongKong
| | - Jieh-Neng Wang
- Department of Pediatrics, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan.
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30
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MacPherson A, Kimmelman J. Ethical development of stem-cell-based interventions. Nat Med 2019; 25:1037-1044. [PMID: 31270501 DOI: 10.1038/s41591-019-0511-6] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Accepted: 06/04/2019] [Indexed: 02/07/2023]
Abstract
The process of developing new and complex stem-cell-based therapeutics is incremental and requires decades of sustained collaboration among different stakeholders. In this Perspective, we address key ethical and policy challenges confronting the clinical translation of stem-cell-based interventions (SCBIs), including premature diffusion of SCBIs to clinical practice, assessment of risk in trials, obtaining valid informed consent for research participants, balanced and complete scientific reporting and public communications, regulation, and equitable access to treatment. We propose a way forward for translating these therapies with the above challenges in mind.
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Affiliation(s)
- Amanda MacPherson
- Biomedical Ethics Unit, STREAM Research Group, McGill University, Montreal, Canada
| | - Jonathan Kimmelman
- Biomedical Ethics Unit, STREAM Research Group, McGill University, Montreal, Canada.
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31
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Cardiac fibrosis: potential therapeutic targets. Transl Res 2019; 209:121-137. [PMID: 30930180 PMCID: PMC6545256 DOI: 10.1016/j.trsl.2019.03.001] [Citation(s) in RCA: 128] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2019] [Revised: 03/01/2019] [Accepted: 03/05/2019] [Indexed: 01/14/2023]
Abstract
Cardiovascular disease is a leading cause of mortality in the world and is exacerbated by the presence of cardiac fibrosis, defined by the accumulation of noncontractile extracellular matrix proteins. Cardiac fibrosis is directly linked to cardiac dysfunction and increased risk of arrhythmia. Despite its prevalence, there is a lack of efficacious therapies for inhibiting or reversing cardiac fibrosis, largely due to the complexity of the cell types and signaling pathways involved. Ongoing research has aimed to understand the mechanisms of cardiac fibrosis and develop new therapies for treating scar formation. Major approaches include preventing the formation of scar tissue and replacing fibrous tissue with functional cardiomyocytes. While targeting the renin-angiotensin-aldosterone system is currently used as the standard line of therapy for heart failure, there has been increased interest in inhibiting the transforming growth factor-β signaling pathway due its established role in cardiac fibrosis. Significant advances in cell transplantation therapy and biomaterials engineering have also demonstrated potential in regenerating the myocardium. Novel techniques, such as cellular direct reprogramming, and molecular targets, such as noncoding RNAs and epigenetic modifiers, are uncovering novel therapeutic options targeting fibrosis. This review provides an overview of current approaches and discuss future directions for treating cardiac fibrosis.
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32
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Affiliation(s)
- Amanda N Steele
- From the Departments of Cardiothoracic Surgery (A.N.S., J.W.M., Y.J.W.) and Bioengineering (A.N.S., Y.J.W.), Stanford University, CA
| | - John W MacArthur
- From the Departments of Cardiothoracic Surgery (A.N.S., J.W.M., Y.J.W.) and Bioengineering (A.N.S., Y.J.W.), Stanford University, CA
| | - Y Joseph Woo
- From the Departments of Cardiothoracic Surgery (A.N.S., J.W.M., Y.J.W.) and Bioengineering (A.N.S., Y.J.W.), Stanford University, CA.
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33
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Landers-Ramos RQ, Sapp RM, Shill DD, Hagberg JM, Prior SJ. Exercise and Cardiovascular Progenitor Cells. Compr Physiol 2019; 9:767-797. [PMID: 30892694 DOI: 10.1002/cphy.c180030] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Autologous stem/progenitor cell-based methods to restore blood flow and function to ischemic tissues are clinically appealing for the substantial proportion of the population with cardiovascular diseases. Early preclinical and case studies established the therapeutic potential of autologous cell therapies for neovascularization in ischemic tissues. However, trials over the past ∼15 years reveal the benefits of such therapies to be much smaller than originally estimated and a definitive clinical benefit is yet to be established. Recently, there has been an emphasis on improving the number and function of cells [herein generally referred to as circulating angiogenic cells (CACs)] used for autologous cell therapies. CACs include of several subsets of circulating cells, including endothelial progenitor cells, with proangiogenic potential that is largely exerted through paracrine functions. As exercise is known to improve CV outcomes such as angiogenesis and endothelial function, much attention is being given to exercise to improve the number and function of CACs. Accordingly, there is a growing body of evidence that acute, short-term, and chronic exercise have beneficial effects on the number and function of different subsets of CACs. In particular, recent studies show that aerobic exercise training can increase the number of CACs in circulation and enhance the function of isolated CACs as assessed in ex vivo assays. This review summarizes the roles of different subsets of CACs and the effects of acute and chronic exercise on CAC number and function, with a focus on the number and paracrine function of circulating CD34+ cells, CD31+ cells, and CD62E+ cells. © 2019 American Physiological Society. Compr Physiol 9:767-797, 2019.
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Affiliation(s)
- Rian Q Landers-Ramos
- University of Maryland School of Public Health, Department of Kinesiology, College Park, Maryland, USA.,Education and Clinical Center, Baltimore Veterans Affairs Geriatric Research, Baltimore, Maryland, USA.,University of Maryland School of Medicine, Department of Medicine, Baltimore, Maryland, USA
| | - Ryan M Sapp
- University of Maryland School of Public Health, Department of Kinesiology, College Park, Maryland, USA
| | - Daniel D Shill
- University of Maryland School of Public Health, Department of Kinesiology, College Park, Maryland, USA
| | - James M Hagberg
- University of Maryland School of Public Health, Department of Kinesiology, College Park, Maryland, USA
| | - Steven J Prior
- University of Maryland School of Public Health, Department of Kinesiology, College Park, Maryland, USA.,Education and Clinical Center, Baltimore Veterans Affairs Geriatric Research, Baltimore, Maryland, USA.,University of Maryland School of Medicine, Department of Medicine, Baltimore, Maryland, USA
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34
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Liao S, Zhang Y, Ting S, Zhen Z, Luo F, Zhu Z, Jiang Y, Sun S, Lai WH, Lian Q, Tse HF. Potent immunomodulation and angiogenic effects of mesenchymal stem cells versus cardiomyocytes derived from pluripotent stem cells for treatment of heart failure. Stem Cell Res Ther 2019; 10:78. [PMID: 30845990 PMCID: PMC6407247 DOI: 10.1186/s13287-019-1183-3] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2019] [Revised: 02/15/2019] [Accepted: 02/19/2019] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND Optimal cell type as cell-based therapies for heart failure (HF) remains unclear. We sought to compare the safety and efficacy of direct intramyocardial transplantation of human embryonic stem cell-derived cardiomyocytes (hESC-CMs) and human induced pluripotent stem cell-derived mesenchymal stem cells (hiPSC-MSCs) in a porcine model of HF. METHODS Eight weeks after induction of HF with myocardial infarction (MI) and rapid pacing, animals with impaired left ventricular ejection fraction (LVEF) were randomly assigned to receive direct intramyocardial injection of saline (MI group), 2 × 108 hESC-CMs (hESC-CM group), or 2 × 108 hiPSC-MSCs (hiPSC-MSC group). The hearts were harvested for immunohistochemical evaluation after serial echocardiography and hemodynamic evaluation and ventricular tachyarrhythmia (VT) induction by in vivo programmed electrical stimulation. RESULTS At 8 weeks post-transplantation, LVEF, left ventricular maximal positive pressure derivative, and end systolic pressure-volume relationship were significantly higher in the hiPSC-MSC group but not in the hESC-CM group compared with the MI group. The incidence of early spontaneous ventricular tachyarrhythmia (VT) episodes was higher in the hESC-CM group but the incidence of inducible VT was similar among the different groups. Histological examination showed no tumor formation but hiPSC-MSCs exhibited a stronger survival capacity by activating regulatory T cells and reducing the inflammatory cells. In vitro study showed that hiPSC-MSCs were insensitive to pro-inflammatory interferon-gamma-induced human leukocyte antigen class II expression compared with hESC-CMs. Moreover, hiPSC-MSCs also significantly enhanced angiogenesis compared with other groups via increasing expression of distinct angiogenic factors. CONCLUSIONS Our results demonstrate that transplantation of hiPSC-MSCs is safe and does not increase proarrhythmia or tumor formation and superior to hESC-CMs for the improvement of cardiac function in HF. This is due to their immunomodulation that improves in vivo survival and enhanced angiogenesis via paracrine effects.
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Affiliation(s)
- Songyan Liao
- Cardiology Division, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Rm 1928, Block K, Hong Kong SAR, China.,Shenzhen Institutes of Research and Innovation, The University of Hong Kong, Shenzhen, China
| | - Yuelin Zhang
- Cardiology Division, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Rm 1928, Block K, Hong Kong SAR, China.,Shenzhen Institutes of Research and Innovation, The University of Hong Kong, Shenzhen, China.,Department of Emergency, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China
| | - Sherwin Ting
- Bioprocessing Technology Institute, A*STAR (Agency for Science, Technology and Research), Singapore, 138668, Singapore
| | - Zhe Zhen
- Cardiology Division, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Rm 1928, Block K, Hong Kong SAR, China.,Shenzhen Institutes of Research and Innovation, The University of Hong Kong, Shenzhen, China
| | - Fan Luo
- Cardiology Division, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Rm 1928, Block K, Hong Kong SAR, China
| | - Ziyi Zhu
- Cardiology Division, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Rm 1928, Block K, Hong Kong SAR, China
| | - Yu Jiang
- Cardiology Division, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Rm 1928, Block K, Hong Kong SAR, China.,Shenzhen Institutes of Research and Innovation, The University of Hong Kong, Shenzhen, China
| | - Sijia Sun
- Cardiology Division, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Rm 1928, Block K, Hong Kong SAR, China.,Shenzhen Institutes of Research and Innovation, The University of Hong Kong, Shenzhen, China
| | - Wing-Hon Lai
- Cardiology Division, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Rm 1928, Block K, Hong Kong SAR, China.,Shenzhen Institutes of Research and Innovation, The University of Hong Kong, Shenzhen, China
| | - Qizhou Lian
- Cardiology Division, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Rm 1928, Block K, Hong Kong SAR, China. .,Shenzhen Institutes of Research and Innovation, The University of Hong Kong, Shenzhen, China. .,Research Center of Heart, Brain, Hormone and Healthy Aging, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China. .,Hong Kong-Guangdong Joint Laboratory on Stem Cell and Regenerative Medicine, The University of Hong Kong and Guangzhou Institutes of Biomedicine and Health, Hong Kong SAR, China.
| | - Hung-Fat Tse
- Cardiology Division, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Rm 1928, Block K, Hong Kong SAR, China. .,Shenzhen Institutes of Research and Innovation, The University of Hong Kong, Shenzhen, China. .,Research Center of Heart, Brain, Hormone and Healthy Aging, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China. .,Hong Kong-Guangdong Joint Laboratory on Stem Cell and Regenerative Medicine, The University of Hong Kong and Guangzhou Institutes of Biomedicine and Health, Hong Kong SAR, China.
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Regenerating the field of cardiovascular cell therapy. Nat Biotechnol 2019; 37:232-237. [PMID: 30778231 DOI: 10.1038/s41587-019-0042-1] [Citation(s) in RCA: 125] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Accepted: 01/18/2019] [Indexed: 01/11/2023]
Abstract
The retraction of >30 falsified studies by Anversa et al. has had a disheartening impact on the cardiac cell therapeutics field. The premise of heart muscle regeneration by the transdifferentiation of bone marrow cells or putative adult resident cardiac progenitors has been largely disproven. Over the past 18 years, a generation of physicians and scientists has lost years chasing these studies, and patients have been placed at risk with little scientific grounding. Funding agencies invested hundreds of millions of dollars in irreproducible work, and both academic institutions and the scientific community ignored troubling signals over a decade of questionable work. Our collective retrospective analysis identifies preventable problems at the level of the editorial and peer-review process, funding agencies and academic institutions. This Perspective provides a chronology of the forces that led to this scientific debacle, integrating direct knowledge of the process. We suggest a science-driven path forward that includes multiple novel approaches to the problem of heart muscle regeneration.
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Miklíková M, Jarkovská D, Čedíková M, Švíglerová J, Kuncová J, Nalos L, Kubíková T, Liška V, Holubová M, Lysák D, Králíčková M, Vištejnová L, Štengl M. Beneficial effects of mesenchymal stem cells on adult porcine cardiomyocytes in non-contact co-culture. Physiol Res 2018; 67:S619-S631. [PMID: 30607969 DOI: 10.33549/physiolres.934051] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Mesenchymal stem cells (MSCs) have been reported to improve survival of cardiomyocytes (CMCs) and overall regeneration of cardiac tissue. Despite promising preclinical results, interactions of MSCs and CMCs, both direct and indirect, remain unclear. In this study, porcine bone marrow MSCs and freshly isolated porcine primary adult CMCs were used for non-contact co-culture experiments. Morphology, viability and functional parameters of CMCs were measured over time and compared between CMCs cultured alone and CMCs co-cultured with MSCs. In non-contact co-culture, MSCs improved survival of CMCs. CMCs co-cultured with MSCs maintained CMCs morphology and viability in significantly higher percentage than CMCs cultured alone. In viable CMCs, mitochondrial respiration was preserved in both CMCs cultured alone and in CMCs co-cultured with MSCs. Comparison of cellular contractility and calcium handling, measured in single CMCs, revealed no significant differences between viable CMCs from co-culture and CMCs cultured alone. In conclusion, non-contact co-culture of porcine MSCs and CMCs improved survival of CMCs with a sufficient preservation of functional and mitochondrial parameters.
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Affiliation(s)
- M Miklíková
- Department of Physiology, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic.
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Lock MC, Tellam RL, Botting KJ, Wang KCW, Selvanayagam JB, Brooks DA, Seed M, Morrison JL. The role of miRNA regulation in fetal cardiomyocytes, cardiac maturation and the risk of heart disease in adults. J Physiol 2018; 596:5625-5640. [PMID: 29785790 PMCID: PMC6265572 DOI: 10.1113/jp276072] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Accepted: 05/15/2018] [Indexed: 12/14/2022] Open
Abstract
Myocardial infarction is a primary contributor towards the global burden of cardiovascular disease. Rather than repairing the existing damage of myocardial infarction, current treatments only address the symptoms of the disease and reducing the risk of a secondary infarction. Cardiac regenerative capacity is dependent on cardiomyocyte proliferation, which concludes soon after birth in humans and precocial species such as sheep. Human fetal cardiac tissue has some ability to repair following tissue damage, whereas a fully matured human heart has minimal capacity for cellular regeneration. This is in contrast to neonatal mice and adult zebrafish hearts, which retain the ability to undergo cardiomyocyte proliferation and can regenerate cardiac tissue after birth. In mice and zebrafish models, microRNAs (miRNAs) have been implicated in the regulation of genes involved in cardiac cell cycle progression and regeneration. However, the significance of miRNA regulation in cardiomyocyte proliferation for humans and other large mammals, where the timing of heart development in relation to birth is similar, remains unclear. miRNAs may be valuable targets for therapies that promote cardiac repair after injury. Therefore, elucidating the role of specific miRNAs in large animals, where heart development closely resembles that of humans, remains vitally important for identifying therapeutic targets that may be translated into clinical practice focused on tissue repair.
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Affiliation(s)
- Mitchell C. Lock
- Early Origins of Adult Health Research Group, School of Pharmacy & Medical SciencesUniversity of South AustraliaAdelaideSA 5001Australia
| | - Ross L. Tellam
- Early Origins of Adult Health Research Group, School of Pharmacy & Medical SciencesUniversity of South AustraliaAdelaideSA 5001Australia
| | - Kimberley J. Botting
- Early Origins of Adult Health Research Group, School of Pharmacy & Medical SciencesUniversity of South AustraliaAdelaideSA 5001Australia
| | - Kimberley C. W. Wang
- Early Origins of Adult Health Research Group, School of Pharmacy & Medical SciencesUniversity of South AustraliaAdelaideSA 5001Australia
- School of Human SciencesUniversity of Western AustraliaCrawleyWA 6009Australia
| | - Joseph B. Selvanayagam
- Cardiac Imaging Research Group, Department of Heart HealthSouth Australian Health & Medical Research Institute, and Flinders UniversityGPO Box 2100AdelaideSA 5001Australia
| | - Doug A. Brooks
- Mechanisms in Cell Biology and Disease Research Group, School of Pharmacy & Medical SciencesUniversity of South AustraliaAdelaideSA 5001Australia
| | - Mike Seed
- Hospital for Sick Children, Division of Cardiology555 University AvenueTorontoON M5G 1X8Canada
| | - Janna L. Morrison
- Early Origins of Adult Health Research Group, School of Pharmacy & Medical SciencesUniversity of South AustraliaAdelaideSA 5001Australia
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Barreto-Durán E, Mejía-Cruz CC, Leal-García E, Pérez-Núñez R, Rodríguez-Pardo VM. Impact of donor characteristics on the quality of bone marrow as a source of mesenchymal stromal cells. AMERICAN JOURNAL OF STEM CELLS 2018; 7:114-120. [PMID: 30697455 PMCID: PMC6334204] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 09/03/2018] [Accepted: 10/10/2018] [Indexed: 06/09/2023]
Abstract
In recent years, the therapeutic use of mesenchymal stromal cells (MSC) has generated a valuable number of scientific studies that delve into their biological characteristics and their potential in regenerative medicine; however, the impact of the clinical characteristics of tissue donors, from which these cells are isolated, on their potential in applied clinical research is not yet clear. The objective of this study was to evaluate the impact of the clinical characteristics of bone marrow donors on the quality of this tissue as a source of MSC for therapeutic use. Human MSC were isolated, characterized and cultured (according to ISCT criteria) from bone marrow samples from volunteer donors (n = 70) attending the Department of Orthopedics and Traumatology of the Hospital Universitario San Ignacio (Bogota, Colombia) for surgery of prosthetic hip replacement that agreed to participate voluntarily in the study. Donor data such as age, gender, weight, smoker and type of anesthesia used during the surgical procedure were recorded, and the impact of these characteristics on the volume of tissue collection, mononuclear cell count and confluence time of cells with fibroblastoid morphology was evaluated. Correlation coefficients between quantitative variables were calculated with Spearman's correlation test, and the association between qualitative and quantitative variables was evaluated with biserial correlation coefficient. A significant correlation was observed between the age of the donors and the time necessary to obtain confluent cells in vitro (r = 0.2489, P = 0.0377); similarly, the correlation between the volume of bone marrow collected and the number of mononuclear cells obtained was significant (r = 0.7101, P = 0.0001). Although a negative correlation tendency was observed between the mononuclear cell count and the confluence time, this was not significant (r = -0.2041, P = 0.0950). No significant associations were observed between gender, smoking status or type of anesthesia and the expansion characteristics of human mesenchymal stromal cells. Bone marrow donor age and the tissue collection volume impact the time of obtaining MSC in vitro and the mononuclear cell count with which the culture starts. These conditions must be considered when the bone marrow is selected as the tissue for obtaining MSC.
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Affiliation(s)
- Emilia Barreto-Durán
- Immunobiology and Cell Biology Group, Department of Microbiology, Science Faculty, Pontificia Universidad JaverianaBogotá D.C., Colombia, South America
| | - Claudia Camila Mejía-Cruz
- Immunobiology and Cell Biology Group, Department of Microbiology, Science Faculty, Pontificia Universidad JaverianaBogotá D.C., Colombia, South America
| | - Efrain Leal-García
- Department of Orthopedics and Traumatology, School of Medicine, Pontificia Universidad Javeriana, Hospital Universitario San IgnacioBogotá D.C., Colombia, South America
| | - Rafael Pérez-Núñez
- Department of Orthopedics and Traumatology, School of Medicine, Pontificia Universidad Javeriana, Hospital Universitario San IgnacioBogotá D.C., Colombia, South America
| | - Viviana Marcela Rodríguez-Pardo
- Immunobiology and Cell Biology Group, Department of Microbiology, Science Faculty, Pontificia Universidad JaverianaBogotá D.C., Colombia, South America
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Wang BH, Liew D, Huang KW, Huang L, Tang W, Kelly DJ, Reid C, Liu Z. The Challenges of Stem Cell Therapy in Myocardial Infarction and Heart Failure and the Potential Strategies to Improve the Outcomes. ACTA ACUST UNITED AC 2018. [DOI: 10.1142/s1793984418410088] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Cardiovascular disease remains the single highest global cause of death and a significant financial burden on the healthcare system. Despite the advances in medical treatments, the prevalence and mortality for heart failure remain unacceptably high. New approaches are urgently needed to reduce this burden and improve patient outcomes and quality of life. One such promising approach is stem cell therapy, including embryonic stem cells, bone marrow derived stem cells, induced pluripotent stem cells and mesenchymal stem cells. However, the cardiac microenvironment following myocardial infarction poses huge challenges with inflammation, adequate retention, engraftment and functional incorporation all crucial concerns. The lack of cardiac regeneration, cell viability and functional improvement has hindered the success of stem cell therapy in clinical settings. The use of biomaterial scaffolds in conjunction with stem cells has recently been shown to enhance the outcome of stem cell therapy for heart failure and myocardial infarction. This review outlines some of the current challenges in the treatment of heart failure and acute myocardial infarction through improving stem cell therapeutic strategies, as well as the prospect of suitable biomaterial scaffolds to enhance their efficacy and improve patient clinical outcomes.
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Affiliation(s)
- Bing Hui Wang
- Monash Centre of Cardiovascular Research and Education in Therapeutics, School of Public Health and Preventive Medicine, Monash University, Melbourne 3004, Australia
| | - Danny Liew
- Monash Centre of Cardiovascular Research and Education in Therapeutics, School of Public Health and Preventive Medicine, Monash University, Melbourne 3004, Australia
| | - Kevin W. Huang
- Monash Centre of Cardiovascular Research and Education in Therapeutics, School of Public Health and Preventive Medicine, Monash University, Melbourne 3004, Australia
| | - Li Huang
- Monash Centre of Cardiovascular Research and Education in Therapeutics, School of Public Health and Preventive Medicine, Monash University, Melbourne 3004, Australia
| | - Wenjie Tang
- Department of Cardiovascular and Thoracic Surgery, Research Center for Translational Medicine and Biomedical Multidisciplinary Innovation Research Institute, Shanghai East Hospital, Tongji University, Shanghai 200120, P. R. China
| | - Darren J. Kelly
- Department of Medicine, St Vincent’s Hospital, University of Melbourne, Fitzroy Victoria, Australia
| | - Christopher Reid
- Monash Centre of Cardiovascular Research and Education in Therapeutics, School of Public Health and Preventive Medicine, Monash University, Melbourne 3004, Australia
| | - Zhongmin Liu
- Department of Cardiovascular and Thoracic Surgery, Research Center for Translational Medicine and Biomedical Multidisciplinary Innovation Research Institute, Shanghai East Hospital, Tongji University, Shanghai 200120, P. R. China
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Brychtova M, Thiele JA, Lysak D, Holubova M, Kralickova M, Vistejnova L. Mesenchymal stem cells as the near future of cardiology medicine - truth or wish? Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2018; 163:8-18. [PMID: 30439932 DOI: 10.5507/bp.2018.071] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2018] [Accepted: 10/28/2018] [Indexed: 12/31/2022] Open
Abstract
Cardiac damage is one of major cause of worldwide morbidity and mortality. Despite the development in pharmacotherapy, cardiosurgery and interventional cardiology, many patients remain at increased risk of developing adverse cardiac remodeling. An alternative treatment approach is the application of stem cells. Mesenchymal stem cells are among the most promising cell types usable for cardiac regeneration. Their homing to the damaged area, differentiation into cardiomyocytes, paracrine and/or immunomodulatory effect on cardiac tissue was investigated extensively. Despite promising preclinical reports, clinical trials on human patients are not convincing. Meta-analyses of these trials open many questions and show that routine clinical application of mesenchymal stem cells as a cardiac treatment may be not as helpful as expected. This review summarizes contemporary knowledge about mesenchymal stem cells role in cardiac tissue repair and discusses the problems and perspectives of this experimental therapeutical approach.
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Affiliation(s)
- Michaela Brychtova
- Biomedical Center, Faculty of Medicine in Pilsen, Charles University in Prague, Alej Svobody 76, 323 00 Pilsen, Czech Republic
| | - Jana-Aletta Thiele
- Biomedical Center, Faculty of Medicine in Pilsen, Charles University in Prague, Alej Svobody 76, 323 00 Pilsen, Czech Republic
| | - Daniel Lysak
- Biomedical Center, Faculty of Medicine in Pilsen, Charles University in Prague, Alej Svobody 76, 323 00 Pilsen, Czech Republic
| | - Monika Holubova
- Biomedical Center, Faculty of Medicine in Pilsen, Charles University in Prague, Alej Svobody 76, 323 00 Pilsen, Czech Republic
| | - Milena Kralickova
- Biomedical Center, Faculty of Medicine in Pilsen, Charles University in Prague, Alej Svobody 76, 323 00 Pilsen, Czech Republic
| | - Lucie Vistejnova
- Biomedical Center, Faculty of Medicine in Pilsen, Charles University in Prague, Alej Svobody 76, 323 00 Pilsen, Czech Republic
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Nguyen PK, Rhee JW, Wu JC. Adult Stem Cell Therapy and Heart Failure, 2000 to 2016: A Systematic Review. JAMA Cardiol 2018; 1:831-841. [PMID: 27557438 DOI: 10.1001/jamacardio.2016.2225] [Citation(s) in RCA: 218] [Impact Index Per Article: 31.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Importance Stem cell therapy is a promising treatment strategy for patients with heart failure, which accounts for more than 10% of deaths in the United States annually. Despite more than a decade of research, further investigation is still needed to determine whether stem cell regenerative therapy is an effective treatment strategy and can be routinely implemented in clinical practice. Objective To describe the progress in cardiac stem cell regenerative therapy using adult stem cells and to highlight the merits and limitations of clinical trials performed to date. Evidence Review Information for this review was obtained through a search of PubMed and the Cochrane database for English-language studies published between January 1, 2000, and July 26, 2016. Twenty-nine randomized clinical trials and 7 systematic reviews and meta-analyses were included in this review. Findings Although adult stem cells were once believed to have the ability to create new heart tissue, preclinical studies suggest that these cells release cardioprotective paracrine factors that activate endogenous pathways, leading to myocardial repair. Subsequent randomized clinical trials, most of which used autologous bone marrow mononuclear cells, have found only a modest benefit in patients receiving stem cell therapy. The lack of a significant benefit may result from variations in trial methods, discrepancies in reporting, and an overreliance on surrogate end points. Conclusions and Relevance Although stem cell therapy for cardiovascular disease is not yet ready for routine clinical application, significant progress continues to be made. Physicians should be aware of the current status of this treatment so that they can better inform their patients who may be in search of alternative therapies.
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Affiliation(s)
- Patricia K Nguyen
- Stanford Cardiovascular Institute, Stanford University, Stanford, California2Division of Cardiovascular Medicine, Department of Medicine, Stanford University, Stanford, California3Veterans Affairs Palo Alto Health Care System, Stanford University, Stanford, California
| | - June-Wha Rhee
- Stanford Cardiovascular Institute, Stanford University, Stanford, California2Division of Cardiovascular Medicine, Department of Medicine, Stanford University, Stanford, California
| | - Joseph C Wu
- Stanford Cardiovascular Institute, Stanford University, Stanford, California2Division of Cardiovascular Medicine, Department of Medicine, Stanford University, Stanford, California4Department of Radiology, Stanford University, Stanford, California
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Langrzyk A, Nowak WN, Stępniewski J, Jaźwa A, Florczyk-Soluch U, Józkowicz A, Dulak J. Critical View on Mesenchymal Stromal Cells in Regenerative Medicine. Antioxid Redox Signal 2018; 29:169-190. [PMID: 28874054 DOI: 10.1089/ars.2017.7159] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
SIGNIFICANCE The belief in the potency of stem cells has resulted in the medical applications of numerous cell types for organ repair, often with the low adherence to methodological stringency. Such uncritical enthusiasm is mainly presented in the approaches employing so-called mesenchymal stem cells (MSC), for the treatment of numerous, unrelated conditions. However, it should be stressed that such broad clinical applications of MSC are mostly based on the belief that MSC can efficiently differentiate into multiple cell types, not only osteoblasts, chondrocytes and adipose cells. Recent Advances: Studies employing lineage tracing established more promising markers to characterize MSC identity and localization in vivo and confirmed the differences between MSC isolated from various organs. Furthermore, preclinical and clinical experiments proved that transdifferentiation of MSC is unlikely to contribute to repair of numerous tissues, including the heart. Therefore, the salvage hypotheses, like MSC fusion with cells in target organs or the paracrine mechanisms, were proposed to justify the widespread application of MSC and to explain transient, if any, effects. CRITICAL ISSUES The lack of standardization concerning the cells markers, their origin and particularly the absence of stringent functional characterization of MSC, leads to propagation of the worrying hype despite the lack of convincing therapeutic efficiency of MSC. FUTURE DIRECTIONS The adherence to rigorous methodological rules is necessary to prevent the application of procedures which can be dangerous for patients and scientific research on the medical application of stem cells. Antioxid. Redox Signal. 00, 000-000.
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Affiliation(s)
| | - Witold N Nowak
- 2 Cardiovascular Division, King's College London , London, United Kingdom .,3 Department of Medical Biotechnology, Faculty of Biochemistry Biophysics and Biotechnology, Jagiellonian University , Kraków, Poland
| | - Jacek Stępniewski
- 3 Department of Medical Biotechnology, Faculty of Biochemistry Biophysics and Biotechnology, Jagiellonian University , Kraków, Poland
| | - Agnieszka Jaźwa
- 3 Department of Medical Biotechnology, Faculty of Biochemistry Biophysics and Biotechnology, Jagiellonian University , Kraków, Poland
| | - Urszula Florczyk-Soluch
- 3 Department of Medical Biotechnology, Faculty of Biochemistry Biophysics and Biotechnology, Jagiellonian University , Kraków, Poland
| | - Alicja Józkowicz
- 3 Department of Medical Biotechnology, Faculty of Biochemistry Biophysics and Biotechnology, Jagiellonian University , Kraków, Poland
| | - Józef Dulak
- 1 Kardio-Med Silesia , Zabrze, Poland .,3 Department of Medical Biotechnology, Faculty of Biochemistry Biophysics and Biotechnology, Jagiellonian University , Kraków, Poland
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Heterocellular molecular contacts in the mammalian stem cell niche. Eur J Cell Biol 2018; 97:442-461. [PMID: 30025618 DOI: 10.1016/j.ejcb.2018.07.001] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2018] [Accepted: 07/03/2018] [Indexed: 12/16/2022] Open
Abstract
Adult tissue homeostasis and repair relies on prompt and appropriate intervention by tissue-specific adult stem cells (SCs). SCs have the ability to self-renew; upon appropriate stimulation, they proliferate and give rise to specialized cells. An array of environmental signals is important for maintenance of the SC pool and SC survival, behavior, and fate. Within this special microenvironment, commonly known as the stem cell niche (SCN), SC behavior and fate are regulated by soluble molecules and direct molecular contacts via adhesion molecules providing connections to local supporting cells and the extracellular matrix. Besides the extensively discussed array of soluble molecules, the expression of adhesion molecules and molecular contacts is another fundamental mechanism regulating niche occupancy and SC mobilization upon activation. Some adhesion molecules are differentially expressed and have tissue-specific consequences, likely reflecting the structural differences in niche composition and design, especially the presence or absence of a stromal counterpart. However, the distribution and identity of intercellular molecular contacts for adhesion and adhesion-mediated signaling within stromal and non-stromal SCN have not been thoroughly studied. This review highlights common details or significant differences in cell-to-cell contacts within representative stromal and non-stromal niches that could unveil new standpoints for stem cell biology and therapy.
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45
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Marbán E. A mechanistic roadmap for the clinical application of cardiac cell therapies. Nat Biomed Eng 2018; 2:353-361. [PMID: 30740264 DOI: 10.1038/s41551-018-0216-z] [Citation(s) in RCA: 69] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The development of cells for regenerative therapy has encountered many pitfalls on its path to clinical translation. In cardiology, clinical studies of heart-targeted cell therapies began two decades ago, yet progress towards reaching an approved product has been slow. In this Perspective, I provide an overview of recent cardiac cell therapies, with a focus on the hurdles limiting the translation of cell products from research laboratories to clinical practice. By focusing on heart failure as a target indication, I argue that strategies for overcoming limitations in clinical translation require an increasing emphasis on mechanism-supported efficacy, rather than on phenomenological observations. As research progresses from cells to paracrine mechanisms to defined factors, identifying those defined factors that are involved in achieving superior therapeutic efficacy will better inform the use of cells as therapeutic candidates. The next generation of cell-free biologics may provide the benefits of cell therapy without the intrinsic limitations of whole-cell products.
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Affiliation(s)
- Eduardo Marbán
- Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
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46
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Madigan M, Atoui R. Therapeutic Use of Stem Cells for Myocardial Infarction. Bioengineering (Basel) 2018; 5:bioengineering5020028. [PMID: 29642402 PMCID: PMC6027340 DOI: 10.3390/bioengineering5020028] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Revised: 03/29/2018] [Accepted: 04/04/2018] [Indexed: 12/15/2022] Open
Abstract
Myocardial infarction is a leading cause of morbidity and mortality worldwide. Although medical and surgical treatments can significantly improve patient outcomes, no treatment currently available is able to generate new contractile tissue or reverse ischemic myocardium. Driven by the recent/novel understanding that regenerative processes do exist in the myocardium—tissue previously thought not to possess regenerative properties—the use of stem cells has emerged as a promising therapeutic approach with high expectations. The literature describes the use of cells from various sources, categorizing them as either embryonic, induced pluripotent, or adult/tissue stem cells (mesenchymal, hematopoietic, skeletal myoblasts, cardiac stem cells). Many publications show the successful use of these cells to regenerate damaged myocardium in both animal and human models; however, more studies are needed to directly compare cells of various origins in efforts to draw conclusions on the ideal source. Although numerous challenges exist in this developing area of research and clinical practice, prospects are encouraging. The following aims to provide a concise review outlining the different types of stem cells used in patients after myocardial infarction.
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Affiliation(s)
- Mariah Madigan
- Northern Ontario School of Medicine, Sudbury, ON P3E 2C6, Canada.
| | - Rony Atoui
- Health Sciences North, Sudbury, ON P3E 5J1, Canada.
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Nicolau JC, Furtado RHM, Silva SA, Rochitte CE, Rassi A, Moraes JBMC, Quintella E, Costantini CR, Korman APM, Mattos MA, Castello HJ, Caixeta A, Dohmann HFR, de Carvalho ACC. Stem-cell therapy in ST-segment elevation myocardial infarction with reduced ejection fraction: A multicenter, double-blind randomized trial. Clin Cardiol 2018; 41:392-399. [PMID: 29569254 DOI: 10.1002/clc.22882] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2017] [Revised: 12/18/2017] [Accepted: 12/27/2017] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Left ventricular ejection fraction (LVEF) is a major determinant of long-term prognosis after ST-segment elevation myocardial infarction (STEMI). STEMI patients with reduced LVEF have a poor prognosis, despite successful reperfusion and the use of renin-angiotensin-aldosterone inhibitors. HYPOTHESIS Intracoronary infusion of bone marrow-derived mononuclear cells (BMMC) may improve LVEF in STEMI patients successfully reperfused. METHODS The main inclusion criteria for this double-blind, randomized, multicenter study were patient age 30 to 80 years, LVEF ≤50%, successful angioplasty of infarct-related artery, and regional dysfunction in the infarct-related area analyzed before cell injection. Cardiac magnetic resonance imaging was used to assess LVEF, left ventricular volumes, and infarct size at 7 to 9 days and 6 months post-myocardial infarction. RESULTS One hundred and twenty-one patients were included (66 patients in the BMMC group and 55 patients in the placebo group). The primary endpoint, mean LVEF, was similar between both groups at baseline (44.63% ± 10.74% vs 42.23% ± 10.33%; P = 0.21) and at 6 months (44.74% ± 12.95 % vs 43.50 ± 12.43%; P = 0.59). The groups were also similar regarding the difference between baseline and 6 months (0.11% ± 8.5% vs 1.27% ± 8.93%; P = 0.46). Other parameters of left ventricular remodeling, such as systolic and diastolic volumes, as well as infarct size, were also similar between groups. CONCLUSIONS In this randomized, multicenter, double-blind trial, BMMC intracoronary infusion did not improve left ventricular remodeling or decrease infarct size.
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Affiliation(s)
- José C Nicolau
- Coronary Care Unit, Instituto do Coração, Hospital das Clínicas, HCFMUSP, Universidade de São Paulo, São Paulo, Brazil
| | - Remo H M Furtado
- Coronary Care Unit, Instituto do Coração, Hospital das Clínicas, HCFMUSP, Universidade de São Paulo, São Paulo, Brazil
| | - Suzana A Silva
- Clinical Research Unit, Instituto Nacional de Cardiologia, Rio de Janeiro, Brazil
| | - Carlos E Rochitte
- Cardiovascular Imaging Department, Instituto do Coração, Hospital das Clínicas, HCFMUSP, Universidade de São Paulo, São Paulo, Brazil
| | - Anis Rassi
- Division of Cardiology, Anis Rassi Hospital, Goiânia, Brazil
| | | | - Edgard Quintella
- Cardiology Department, Instituto de Cardiologia Aloysio de Castro, Rio de Janeiro, Brazil
| | | | - Adrian P M Korman
- Cardiology Department, Sociedade Divina Providencia Hospital Santa Isabel, Blumenau, Brazil
| | - Marco A Mattos
- Clinical Research Unit, Instituto Nacional de Cardiologia, Rio de Janeiro, Brazil
| | | | - Adriano Caixeta
- Department of Interventional Cardiology, Instituto do Coração do Distrito Federal, Brasília, Brazil
| | - Hans F R Dohmann
- Cardiology Department, PROCEP/Amil Assistência Médica Internacional, Rio de Janeiro, Brazil
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ANGPTL8 reverses established adriamycin cardiomyopathy by stimulating adult cardiac progenitor cells. Oncotarget 2018; 7:80391-80403. [PMID: 27823982 PMCID: PMC5348328 DOI: 10.18632/oncotarget.13061] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2016] [Accepted: 10/07/2016] [Indexed: 12/18/2022] Open
Abstract
Established adriamycin cardiomyopathy is a lethal disease. When congestive heart failure develops, mortality is approximately 50% in a year. It has been known that ANGPTLs has various functions in lipid metabolism, inflammation, cancer cell invasion, hematopoietic stem activity and diabetes. We hypothesized that ANGPTL8 is capable of maintaining heart function by stimulating adult cardiac progenitor cells to initiate myocardial regeneration. We employed UTMD to deliver piggybac transposon plasmids with the human ANGPTL8 gene to the liver of rats with adriamycin cardiomyopathy. After ANGPTL8 gene liver delivery, overexpression of transgenic human ANGPTL8 was found in rat liver cells and blood. UTMD- ANGPTL8 gene therapy restored LV mass, fractional shortening index, and LV posterior wall diameter to nearly normal. Our results also showed that ANGPTL8 reversed established ADM cardiomyopathy. This was associated with activation of ISL-1 positive cardiac progenitor cells in the epicardium. A time-course experiment shown that ISL-1 cardiac progenitor cells proliferated and formed a niche in the epicardial layer and then migrated into sub-epicardium. The observed myocardial regeneration accompanying reversal of adriamycin cardiomyopathy was associated with upregulation of PirB expression on the cell membrane of cardiac muscle cells or progenitor cells stimulated by ANGPTL8.
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Abstract
Major cardiovascular events including myocardial infarction (MI) continue to dominate morbidity rates in the developed world. Although multiple device therapies and various pharmacological agents have been shown to improve patient care and reduce mortality rates, clinicians and researchers alike still lack a true panacea to regenerate damaged cardiac tissue. Over the previous two to three decades, cardiovascular stem cell therapies have held great promise. Several stem cell-based approaches have now been shown to improve ventricular function and are documented in preclinical animal models as well as phase I and phase II clinical trials. More recently, the cardiac progenitor cell has begun to gain momentum as an ideal candidate for stem cell therapy in heart disease. Here, we will highlight the most recent advances in cardiac stem/progenitor cell biology in regard to both the basics and applied settings.
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Biologically active constituents of the secretome of human W8B2 + cardiac stem cells. Sci Rep 2018; 8:1579. [PMID: 29371689 PMCID: PMC5785502 DOI: 10.1038/s41598-018-19855-4] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2017] [Accepted: 01/10/2018] [Indexed: 12/12/2022] Open
Abstract
The benefits of adult stem cells for repair of the heart have been attributed to the repertoire of salutary paracrine activities they appear to exert. We previously isolated human W8B2+ cardiac stem cells (CSCs) and found they powerfully influence cardiomyocytes and endothelial cells to collectively promote cardiac repair and regeneration. Here, the complexity of the W8B2+ CSC secretomes was characterised and examined in more detail. Using ion exchange chromatography to separate soluble proteins based on their net surface charge, the secreted factors responsible for the pro-survival activity of W8B2+ CSCs were found within the low and medium cation fractions. In addition to the soluble proteins, extracellular vesicles generated from W8B2+ CSCs not only exhibited pro-survival and pro-angiogenic activities, but also promoted proliferation of neonatal cardiomyocytes. These extracellular vesicles contain a cargo of proteins, mRNA and primary microRNA precursors that are enriched in exosomes and are capable of modulating collectively many of the cellular pathways involved in protein metabolism, cell growth, as well as cellular responses to stress and organisation of the extracellular matrix. Thus the W8B2+ CSC secretome contains a multitude of bioactive paracrine factors we have now characterised, that might well be harnessed for therapeutic application for cardiac repair and regeneration.
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