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1
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Maldonado M, Chen J, Duan H, Zhou S, Yang L, Raja MA, Huang T, Jiang G, Zhong Y. Effects of caloric overload before caloric restriction in the murine heart. Aging (Albany NY) 2022; 14:2695-2719. [PMID: 35347086 PMCID: PMC9004582 DOI: 10.18632/aging.203967] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Accepted: 03/10/2022] [Indexed: 02/05/2023]
Abstract
The beneficial effects of caloric restriction (CR) against cardiac aging and for prevention of cardiovascular diseases are numerous. However, to our knowledge, there is no scientific evidence about how a high-calorie diet (HCD) background influences the mechanisms underlying CR in whole heart tissue (WHT) in experimental murine models. In the current study, CR-treated mice with different alimentary backgrounds were subjected to transthoracic echocardiographic measurements. WHT was then analyzed to determine cardiac energetics, telomerase activity, the expression of energy-sensing networks, tissue-specific adiponectin, and cardiac precursor/cardiac stem cell markers. Animals with a balanced diet consumption before CR presented marked cardiac remodeling with improved ejection fraction (EF) and fractional shortening (FS), enhanced OXPHOS complex I, III, and IV, and CKMT2 enzymatic activity. Mice fed an HCD before CR presented moderate changes in cardiac geometry with diminished EF and FS values, but improved OXPHOS complex IV and CKMT2 activity. Differences in cardiac remodeling, left ventricular systolic/diastolic performance, and mitochondrial energetics, found in the CR-treated mice with contrasting alimentary backgrounds, were corroborated by inconsistencies in the expression of mitochondrial-biogenesis-related markers and associated regulatory networks. In particular, disruption of eNOS and AMPK -PGC-1α-mTOR-related axes. The impact of a past habit of caloric overload on the effects of CR in the WHT is a scarcely explored subject that requires deeper study in combination with analyses of other tissues and organs at higher levels of organization within the organ system. Such research will eventually lead to the development of preventative and therapeutic strategies to promote health and longevity.
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Affiliation(s)
- Martin Maldonado
- Reproductive Medicine and Genetics, Chengdu Jinjiang Hospital for Maternal and Child Health Care, Chengdu 610066, China
| | - Jianying Chen
- Reproductive Medicine and Genetics, Chengdu Jinjiang Hospital for Maternal and Child Health Care, Chengdu 610066, China
| | - Huiqin Duan
- Reproductive Medicine and Genetics, Chengdu Jinjiang Hospital for Maternal and Child Health Care, Chengdu 610066, China
| | - Shuling Zhou
- Reproductive Medicine and Genetics, Chengdu Jinjiang Hospital for Maternal and Child Health Care, Chengdu 610066, China
| | - Lujun Yang
- Translational Medical Center, Second Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong 515041, China
| | - Mazhar Ali Raja
- Reproductive Medicine and Genetics, Chengdu Jinjiang Hospital for Maternal and Child Health Care, Chengdu 610066, China
| | - Tianhua Huang
- Reproductive Medicine and Genetics, Chengdu Jinjiang Hospital for Maternal and Child Health Care, Chengdu 610066, China
| | - Gu Jiang
- Reproductive Medicine and Genetics, Chengdu Jinjiang Hospital for Maternal and Child Health Care, Chengdu 610066, China
| | - Ying Zhong
- Reproductive Medicine and Genetics, Chengdu Jinjiang Hospital for Maternal and Child Health Care, Chengdu 610066, China
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2
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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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3
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Cho HM, Cho JY. Cardiomyocyte Death and Genome-Edited Stem Cell Therapy for Ischemic Heart Disease. Stem Cell Rev Rep 2021; 17:1264-1279. [PMID: 33492627 PMCID: PMC8316208 DOI: 10.1007/s12015-020-10096-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/25/2020] [Indexed: 01/14/2023]
Abstract
Massive death of cardiomyocytes is a major feature of cardiovascular diseases. Since the regenerative capacity of cardiomyocytes is limited, the regulation of their death has been receiving great attention. The cell death of cardiomyocytes is a complex mechanism that has not yet been clarified, and it is known to appear in various forms such as apoptosis, necrosis, etc. In ischemic heart disease, the apoptosis and necrosis of cardiomyocytes appear in two types of programmed forms (intrinsic and extrinsic pathways) and they account for a large portion of cell death. To repair damaged cardiomyocytes, diverse stem cell therapies have been attempted. However, despite the many positive effects, the low engraftment and survival rates have clearly limited the application of stem cells in clinical therapy. To solve these challenges, the introduction of the desired genes in stem cells can be used to enhance their capacity and improve their therapeutic efficiency. Moreover, as genome engineering technologies have advanced significantly, safer and more stable delivery of target genes and more accurate deletion of genes have become possible, which facilitates the genetic modification of stem cells. Accordingly, stem cell therapy for damaged cardiac tissue is expected to further improve. This review describes myocardial cell death, stem cell therapy for cardiac repair, and genome-editing technologies. In addition, we introduce recent stem cell therapies that incorporate genome-editing technologies in the myocardial infarction model. Graphical Abstract.
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Affiliation(s)
- Hyun-Min Cho
- Department of Biochemistry, BK21 PLUS Program for Creative Veterinary Science Research and Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Gwanak-ro1, Gwanak-gu, Seoul, 151-742, South Korea
| | - Je-Yoel Cho
- Department of Biochemistry, BK21 PLUS Program for Creative Veterinary Science Research and Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Gwanak-ro1, Gwanak-gu, Seoul, 151-742, South Korea.
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4
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Dual recombinases-based genetic lineage tracing for stem cell research with enhanced precision. SCIENCE CHINA-LIFE SCIENCES 2021; 64:2060-2072. [PMID: 33847909 DOI: 10.1007/s11427-020-1889-9] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/28/2020] [Accepted: 01/04/2021] [Indexed: 12/24/2022]
Abstract
Stem cell research has become a hot topic in biology, as the understanding of stem cell biology can provide new insights for both regenerative medicine and clinical treatment of diseases. Accurately deciphering the fate of stem cells is the basis for understanding the mechanism and function of stem cells during tissue repair and regeneration. Cre-loxP-mediated recombination has been widely applied in fate mapping of stem cells for many years. However, nonspecific labeling by conventional cell lineage tracing strategies has led to discrepancies or even controversies in multiple fields. Recently, dual recombinase-mediated lineage tracing strategies have been developed to improve both the resolution and precision of stem cell fate mapping. These new genetic strategies also expand the application of lineage tracing in studying cell origin and fate. Here, we review cell lineage tracing methods, especially dual genetic approaches, and then provide examples to describe how they are used to study stem cell fate plasticity and function in vivo.
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5
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Kwon JS, Schumacher SM, Gao E, Chuprun JK, Ibetti J, Roy R, Khan M, Kishore R, Koch WJ. Characterization of βARKct engineered cellular extracellular vesicles and model specific cardioprotection. Am J Physiol Heart Circ Physiol 2021; 320:H1276-H1289. [PMID: 33513081 PMCID: PMC8260382 DOI: 10.1152/ajpheart.00571.2020] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Revised: 01/20/2021] [Accepted: 01/20/2021] [Indexed: 12/17/2022]
Abstract
Recent data supporting any benefit of stem cell therapy for ischemic heart disease have suggested paracrine-based mechanisms via extracellular vesicles (EVs) including exosomes. We have previously engineered cardiac-derived progenitor cells (CDCs) to express a peptide inhibitor, βARKct, of G protein-coupled receptor kinase 2, leading to improvements in cell proliferation, survival, and metabolism. In this study, we tested whether βARKct-CDC EVs would be efficacious when applied to stressed myocytes in vitro and in vivo. When isolated EVs from βARKct-CDCs and control GFP-CDCs were added to cardiomyocytes in culture, they both protected against hypoxia-induced apoptosis. We tested whether these EVs could protect the mouse heart in vivo, following exposure either to myocardial infarction (MI) or acute catecholamine toxicity. Both types of EVs significantly protected against ischemic injury and improved cardiac function after MI compared with mice treated with EVs from mouse embryonic fibroblasts; however, βARKct EVs treated mice did display some unique beneficial properties including significantly altered pro- and anti-inflammatory cytokines. Importantly, in a catecholamine toxicity model of heart failure (HF), myocardial injections of βARKct-containing EVs were superior at preventing HF compared with control EVs, and this catecholamine toxicity protection was recapitulated in vitro. Therefore, introduction of the βARKct into cellular EVs can have improved reparative properties in the heart especially against catecholamine damage, which is significant as sympathetic nervous system activity is increased in HF.NEW & NOTEWORTHY βARKct, the peptide inhibitor of GRK2, improves survival and metabolic functions of cardiac-derived progenitor cells. As any benefit of stem cells in the ischemic and injured heart suggests paracrine mechanisms via secreted EVs, we investigated whether CDC-βARKct engineered EVs would show any benefit over control CDC-EVs. Compared with control EVs, βARKct-containing EVs displayed some unique beneficial properties that may be due to altered pro- and anti-inflammatory cytokines within the vesicles.
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Affiliation(s)
- Jin-Sook Kwon
- Center for Translational Medicine, Department of Pharmacology, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania
| | - Sarah M Schumacher
- Center for Translational Medicine, Department of Pharmacology, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania
| | | | - J Kurt Chuprun
- Center for Translational Medicine, Department of Pharmacology, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania
| | - Jessica Ibetti
- Center for Translational Medicine, Department of Pharmacology, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania
| | - Rajika Roy
- Center for Translational Medicine, Department of Pharmacology, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania
| | - Mohsin Khan
- Center for Metabolic Disease Research, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania
| | - Raj Kishore
- Center for Translational Medicine, Department of Pharmacology, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania
| | - Walter J Koch
- Center for Translational Medicine, Department of Pharmacology, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania
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6
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A suite of new Dre recombinase drivers markedly expands the ability to perform intersectional genetic targeting. Cell Stem Cell 2021; 28:1160-1176.e7. [PMID: 33567267 DOI: 10.1016/j.stem.2021.01.007] [Citation(s) in RCA: 91] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Revised: 12/06/2020] [Accepted: 01/11/2021] [Indexed: 02/07/2023]
Abstract
The use of the dual recombinase-mediated intersectional genetic approach involving Cre-loxP and Dre-rox has significantly enhanced the precision of in vivo lineage tracing, as well as gene manipulation. However, this approach is limited by the small number of Dre recombinase driver constructs available. Here, we developed more than 70 new intersectional drivers to better target diverse cell lineages. To highlight their applicability, we used these new tools to study the in vivo adipogenic fate of perivascular progenitors, which revealed that PDGFRa+ but not PDGFRa-PDGFRb+ perivascular cells are the endogenous progenitors of adult adipocytes. In addition to lineage tracing, we used members of this new suite of drivers to more specifically knock out genes in complex tissues, such as white adipocytes and lymphatic vessels, that heretofore cannot be selectively targeted by conventional Cre drivers alone. In summary, these new transgenic tools expand the intersectional genetic approach while enhancing its precision.
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7
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Duddu S, Chakrabarti R, Ghosh A, Shukla PC. Hematopoietic Stem Cell Transcription Factors in Cardiovascular Pathology. Front Genet 2020; 11:588602. [PMID: 33193725 PMCID: PMC7596349 DOI: 10.3389/fgene.2020.588602] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Accepted: 09/21/2020] [Indexed: 12/14/2022] Open
Abstract
Transcription factors as multifaceted modulators of gene expression that play a central role in cell proliferation, differentiation, lineage commitment, and disease progression. They interact among themselves and create complex spatiotemporal gene regulatory networks that modulate hematopoiesis, cardiogenesis, and conditional differentiation of hematopoietic stem cells into cells of cardiovascular lineage. Additionally, bone marrow-derived stem cells potentially contribute to the cardiovascular cell population and have shown potential as a therapeutic approach to treat cardiovascular diseases. However, the underlying regulatory mechanisms are currently debatable. This review focuses on some key transcription factors and associated epigenetic modifications that modulate the maintenance and differentiation of hematopoietic stem cells and cardiac progenitor cells. In addition to this, we aim to summarize different potential clinical therapeutic approaches in cardiac regeneration therapy and recent discoveries in stem cell-based transplantation.
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Affiliation(s)
| | | | | | - Praphulla Chandra Shukla
- School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur, India
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8
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Nasser MI, Qi X, Zhu S, He Y, Zhao M, Guo H, Zhu P. Current situation and future of stem cells in cardiovascular medicine. Biomed Pharmacother 2020; 132:110813. [PMID: 33068940 DOI: 10.1016/j.biopha.2020.110813] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 09/22/2020] [Accepted: 09/25/2020] [Indexed: 12/21/2022] Open
Abstract
Cardiovascular disease (CVD) is one of the leading causes of death worldwide. Currently, many methods have been proposed by researchers for the prevention and treatment of CVD; among them, stem cell-based therapies are the most promising. As the cells of origin for various mature cells, stem cells have the ability to self-renew and differentiate. Stem cells have a powerful ability to regenerate biologically, self-repair, and enhance damaged functional tissues or organs. Allogeneic stem cells and somatic stem cells are two types of cells that can be used for cardiac repair. Theoretically, dilated cardiomyopathy and acute myocardial infarction can be treated with such cells. In addition, stem cell transplantation procedures, including intravenous, epicardial, cardiac, and endocardial injections, have been reported to provide significant benefits in clinical practice; however, there are still a number of issues that need further study and consideration, such as the form and quantity of transplanted cells and post-transplantation health. The goal of this analysis was to summarize the recent advances in stem cell-based therapies and their efficacy in cardiovascular regenerative medicine.
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Affiliation(s)
- M I Nasser
- Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, 510100, China. Address: 106 Zhongshan Er Road, Guangzhou, 510080, PR China
| | - Xiao Qi
- Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, 510100, China. Address: 106 Zhongshan Er Road, Guangzhou, 510080, PR China
| | - Shuoji Zhu
- Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, 510100, China. Address: 106 Zhongshan Er Road, Guangzhou, 510080, PR China
| | - Yin He
- Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, 510100, China. Address: 106 Zhongshan Er Road, Guangzhou, 510080, PR China
| | - Mingyi Zhao
- Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, 510100, China. Address: 106 Zhongshan Er Road, Guangzhou, 510080, PR China
| | - Huiming Guo
- Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, 510100, China. Address: 106 Zhongshan Er Road, Guangzhou, 510080, PR China
| | - Ping Zhu
- Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, 510100, China. Address: 106 Zhongshan Er Road, Guangzhou, 510080, PR China.
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9
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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: 90] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
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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10
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Li X, Li J, Martinez EC, Froese A, Passariello CL, Henshaw K, Rusconi F, Li Y, Yu Q, Thakur H, Nikolaev VO, Kapiloff MS. Calcineurin Aβ-Specific Anchoring Confers Isoform-Specific Compartmentation and Function in Pathological Cardiac Myocyte Hypertrophy. Circulation 2020; 142:948-962. [PMID: 32611257 DOI: 10.1161/circulationaha.119.044893] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND The Ca2+/calmodulin-dependent phosphatase calcineurin is a key regulator of cardiac myocyte hypertrophy in disease. An unexplained paradox is how the β isoform of the calcineurin catalytic A-subunit (CaNAβ) is required for induction of pathological myocyte hypertrophy, despite calcineurin Aα expression in the same cells. It is unclear how the pleiotropic second messenger Ca2+ drives excitation-contraction coupling while not stimulating hypertrophy by calcineurin in the normal heart. Elucidation of the mechanisms conferring this selectivity in calcineurin signaling should reveal new strategies for targeting the phosphatase in disease. METHODS Primary adult rat ventricular myocytes were studied for morphology and intracellular signaling. New Förster resonance energy transfer reporters were used to assay Ca2+ and calcineurin activity in living cells. Conditional gene deletion and adeno-associated virus-mediated gene delivery in the mouse were used to study calcineurin signaling after transverse aortic constriction in vivo. RESULTS CIP4 (Cdc42-interacting protein 4)/TRIP10 (thyroid hormone receptor interactor 10) was identified as a new polyproline domain-dependent scaffold for CaNAβ2 by yeast 2-hybrid screen. Cardiac myocyte-specific CIP4 gene deletion in mice attenuated pressure overload-induced pathological cardiac remodeling and heart failure. Blockade of CaNAβ polyproline-dependent anchoring using a competing peptide inhibited concentric hypertrophy in cultured myocytes; disruption of anchoring in vivo using an adeno-associated virus gene therapy vector inhibited cardiac hypertrophy and improved systolic function after pressure overload. Live cell Förster resonance energy transfer biosensor imaging of cultured myocytes revealed that Ca2+ levels and calcineurin activity associated with the CIP4 compartment were increased by neurohormonal stimulation, but minimally by pacing. Conversely, Ca2+ levels and calcineurin activity detected by nonlocalized Förster resonance energy transfer sensors were induced by pacing and minimally by neurohormonal stimulation, providing functional evidence for differential intracellular compartmentation of Ca2+ and calcineurin signal transduction. CONCLUSIONS These results support a structural model for Ca2+ and CaNAβ compartmentation in cells based on an isoform-specific mechanism for calcineurin protein-protein interaction and localization. This mechanism provides an explanation for the specific role of CaNAβ in hypertrophy and its selective activation under conditions of pathologic stress. Disruption of CaNAβ polyproline-dependent anchoring constitutes a rational strategy for therapeutic targeting of CaNAβ-specific signaling responsible for pathological cardiac remodeling in cardiovascular disease deserving of further preclinical investigation.
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Affiliation(s)
- Xiaofeng Li
- Interdisciplinary Stem Cell Institute, Department of Pediatrics, Leonard M. Miller School of Medicine, University of Miami, FL (X.L., J.L., E.C.M., C.L.P., K.H., F.R., H.T., M.S.K.)
| | - Jinliang Li
- Interdisciplinary Stem Cell Institute, Department of Pediatrics, Leonard M. Miller School of Medicine, University of Miami, FL (X.L., J.L., E.C.M., C.L.P., K.H., F.R., H.T., M.S.K.).,Departments of Ophthalmology and Medicine, Stanford Cardiovascular Institute, Stanford University, Palo Alto, CA (J.L., Y.L., Q.Y., H.T., M.S.K.)
| | - Eliana C Martinez
- Interdisciplinary Stem Cell Institute, Department of Pediatrics, Leonard M. Miller School of Medicine, University of Miami, FL (X.L., J.L., E.C.M., C.L.P., K.H., F.R., H.T., M.S.K.)
| | - Alexander Froese
- Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (A.F., V.O.N.)
| | - Catherine L Passariello
- Interdisciplinary Stem Cell Institute, Department of Pediatrics, Leonard M. Miller School of Medicine, University of Miami, FL (X.L., J.L., E.C.M., C.L.P., K.H., F.R., H.T., M.S.K.)
| | - Kathryn Henshaw
- Interdisciplinary Stem Cell Institute, Department of Pediatrics, Leonard M. Miller School of Medicine, University of Miami, FL (X.L., J.L., E.C.M., C.L.P., K.H., F.R., H.T., M.S.K.)
| | - Francesca Rusconi
- Interdisciplinary Stem Cell Institute, Department of Pediatrics, Leonard M. Miller School of Medicine, University of Miami, FL (X.L., J.L., E.C.M., C.L.P., K.H., F.R., H.T., M.S.K.)
| | - Yang Li
- Departments of Ophthalmology and Medicine, Stanford Cardiovascular Institute, Stanford University, Palo Alto, CA (J.L., Y.L., Q.Y., H.T., M.S.K.)
| | - Qian Yu
- Departments of Ophthalmology and Medicine, Stanford Cardiovascular Institute, Stanford University, Palo Alto, CA (J.L., Y.L., Q.Y., H.T., M.S.K.)
| | - Hrishikesh Thakur
- Interdisciplinary Stem Cell Institute, Department of Pediatrics, Leonard M. Miller School of Medicine, University of Miami, FL (X.L., J.L., E.C.M., C.L.P., K.H., F.R., H.T., M.S.K.).,Departments of Ophthalmology and Medicine, Stanford Cardiovascular Institute, Stanford University, Palo Alto, CA (J.L., Y.L., Q.Y., H.T., M.S.K.)
| | - Viacheslav O Nikolaev
- Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (A.F., V.O.N.)
| | - Michael S Kapiloff
- Interdisciplinary Stem Cell Institute, Department of Pediatrics, Leonard M. Miller School of Medicine, University of Miami, FL (X.L., J.L., E.C.M., C.L.P., K.H., F.R., H.T., M.S.K.).,Departments of Ophthalmology and Medicine, Stanford Cardiovascular Institute, Stanford University, Palo Alto, CA (J.L., Y.L., Q.Y., H.T., M.S.K.)
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11
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Zhao H, Zhou B. Dual genetic approaches for deciphering cell fate plasticity in vivo: more than double. Curr Opin Cell Biol 2019; 61:101-109. [DOI: 10.1016/j.ceb.2019.07.004] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Revised: 07/01/2019] [Accepted: 07/04/2019] [Indexed: 12/16/2022]
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12
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Zhang L, Sultana N, Yan J, Yang F, Chen F, Chepurko E, Yang FC, Du Q, Zangi L, Xu M, Bu L, Cai CL. Cardiac Sca-1 + Cells Are Not Intrinsic Stem Cells for Myocardial Development, Renewal, and Repair. Circulation 2019; 138:2919-2930. [PMID: 30566018 DOI: 10.1161/circulationaha.118.035200] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
BACKGROUND For more than a decade, Sca-1+ cells within the mouse heart have been widely recognized as a stem cell population with multipotency that can give rise to cardiomyocytes, endothelial cells, and smooth muscle cells in vitro and after cardiac grafting. However, the developmental origin and authentic nature of these cells remain elusive. METHODS Here, we used a series of high-fidelity genetic mouse models to characterize the identity and regenerative potential of cardiac resident Sca-1+ cells. RESULTS With these novel genetic tools, we found that Sca-1 does not label cardiac precursor cells during early embryonic heart formation. Postnatal cardiac resident Sca-1+ cells are in fact a pure endothelial cell population. They retain endothelial properties and exhibit minimal cardiomyogenic potential during development, normal aging and upon ischemic injury. CONCLUSIONS Our study provides definitive insights into the nature of cardiac resident Sca-1+ cells. The observations challenge the current dogma that cardiac resident Sca-1+ cells are intrinsic stem cells for myocardial development, renewal, and repair, and suggest that the mechanisms of transplanted Sca-1+ cells in heart repair need to be reassessed.
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Affiliation(s)
- Lu Zhang
- Riley Heart Research Center and Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis (L. Zhang, F.Y., C.-L.C.).,Department of Developmental and Regenerative Biology and The Black Family Stem Cell Institute (L. Zhang, N.S., F.Y., C.-L.C.), Icahn School of Medicine at Mount Sinai, New York
| | - Nishat Sultana
- Department of Developmental and Regenerative Biology and The Black Family Stem Cell Institute (L. Zhang, N.S., F.Y., C.-L.C.), Icahn School of Medicine at Mount Sinai, New York.,Department of Medicine and Cardiovascular Research Center (N.S., E.C., L. Zangi), Icahn School of Medicine at Mount Sinai, New York
| | - Jianyun Yan
- Department of Cardiology, Laboratory of Heart Center, Zhujiang Hospital, Southern Medical University, Guangdong Provincial Biomedical Engineering Technology Research Center for Cardiovascular Disease, and Sino-Japanese Cooperation Platform for Translational Research in Heart Failure, Guangzhou, China (J.Y.)
| | - Fan Yang
- Riley Heart Research Center and Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis (L. Zhang, F.Y., C.-L.C.).,Department of Developmental and Regenerative Biology and The Black Family Stem Cell Institute (L. Zhang, N.S., F.Y., C.-L.C.), Icahn School of Medicine at Mount Sinai, New York
| | - Fuxue Chen
- College of Life Sciences, Shanghai University, China (F.C.)
| | - Elena Chepurko
- Department of Medicine and Cardiovascular Research Center (N.S., E.C., L. Zangi), Icahn School of Medicine at Mount Sinai, New York
| | - Feng-Chun Yang
- Department of Biochemistry and Molecular Biology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, FL (F.-C.Y., Q.D., M.X.)
| | - Qinghua Du
- Department of Biochemistry and Molecular Biology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, FL (F.-C.Y., Q.D., M.X.)
| | - Lior Zangi
- Department of Medicine and Cardiovascular Research Center (N.S., E.C., L. Zangi), Icahn School of Medicine at Mount Sinai, New York
| | - Mingjiang Xu
- Department of Biochemistry and Molecular Biology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, FL (F.-C.Y., Q.D., M.X.)
| | - Lei Bu
- Leon H. Charney Division of Cardiology, New York University School of Medicine, New York, NY (L.B.)
| | - Chen-Leng Cai
- Riley Heart Research Center and Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis (L. Zhang, F.Y., C.-L.C.).,Department of Developmental and Regenerative Biology and The Black Family Stem Cell Institute (L. Zhang, N.S., F.Y., C.-L.C.), Icahn School of Medicine at Mount Sinai, New York
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13
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c-kit Haploinsufficiency impairs adult cardiac stem cell growth, myogenicity and myocardial regeneration. Cell Death Dis 2019; 10:436. [PMID: 31164633 PMCID: PMC6547756 DOI: 10.1038/s41419-019-1655-5] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2018] [Revised: 04/17/2019] [Accepted: 04/30/2019] [Indexed: 12/11/2022]
Abstract
An overdose of Isoproterenol (ISO) causes acute cardiomyocyte (CM) dropout and activates the resident cardiac c-kitpos stem/progenitor cells (CSCs) generating a burst of new CM formation that replaces those lost to ISO. Recently, unsuccessful attempts to reproduce these findings using c-kitCre knock-in (KI) mouse models were reported. We tested whether c-kit haploinsufficiency in c-kitCreKI mice was the cause of the discrepant results in response to ISO. Male C57BL/6J wild-type (wt) mice and c-kitCreKI mice were given a single dose of ISO (200 and/or 400 mg/Kg s.c.). CM formation was measured with different doses and duration of BrdU or EdU. We compared the myogenic and regenerative potential of the c-kitCreCSCs with wtCSCs. Acute ISO overdose causes LV dysfunction with dose-dependent CM death by necrosis and apoptosis, whose intensity follows a basal-apical and epicardium to sub-endocardium gradient, with the most severe damage confined to the apical sub-endocardium. The damage triggers significant new CM formation mainly in the apical sub-endocardial layer. c-kit haploinsufficiency caused by c-kitCreKIs severely affects CSCs myogenic potential. c-kitCreKI mice post-ISO fail to respond with CSC activation and show reduced CM formation and suffer chronic cardiac dysfunction. Transplantation of wtCSCs rescued the defective regenerative cardiac phenotype of c-kitCreKI mice. Furthermore, BAC-mediated transgenesis of a single c-kit gene copy normalized the functional diploid c-kit content of c-kitCreKI CSCs and fully restored their regenerative competence. Overall, these data show that c-kit haploinsufficiency impairs the endogenous cardioregenerative response after injury affecting CSC activation and CM replacement. Repopulation of c-kit haploinsufficient myocardial tissue with wtCSCs as well c-kit gene deficit correction of haploinsufficient CSCs restores CM replacement and functional cardiac repair. Thus, adult neo-cardiomyogenesis depends on and requires a diploid level of c-kit.
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14
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Abstract
Unraveling the fates of resident stem cells during tissue regeneration is an important objective in clinical and basic research. Genetic lineage tracing based on Cre-loxP recombination provides an effective strategy for inferring cell fate and cell conversion in vivo. However, the determination of the exact fates of resident stem cells or their derivatives in disease states and during tissue regeneration remains controversial in many fields of study, partly because of technical limitations associated with Cre-based lineage tracing, such as, for example, off-target labeling. Recently, we generated a new lineage-tracing platform we named DeaLT (dual-recombinase-activated lineage tracing) that uses the Dre-rox recombination system to enhance the precision of Cre-mediated lineage tracing. Here, we describe as an example a detailed protocol using DeaLT to trace the fate of c-Kit+ cardiac stem cells and their derivatives, in the absence of any interference from nontarget cells such as cardiomyocytes, during organ homeostasis and after tissue injury. This lineage-tracing protocol can also be used to delineate the fate of resident stem cells of other organ systems, and takes ~10 months to complete, from mouse crossing to final tissue analysis.
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15
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Sayed A, Valente M, Sassoon D. Does cardiac development provide heart research with novel therapeutic approaches? F1000Res 2018; 7. [PMID: 30450195 PMCID: PMC6221076 DOI: 10.12688/f1000research.15609.1] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/24/2018] [Indexed: 01/04/2023] Open
Abstract
Embryonic heart progenitors arise at specific spatiotemporal periods that contribute to the formation of distinct cardiac structures. In mammals, the embryonic and fetal heart is hypoxic by comparison to the adult heart. In parallel, the cellular metabolism of the cardiac tissue, including progenitors, undergoes a glycolytic to oxidative switch that contributes to cardiac maturation. While oxidative metabolism is energy efficient, the glycolytic-hypoxic state may serve to maintain cardiac progenitor potential. Consistent with this proposal, the adult epicardium has been shown to contain a reservoir of quiescent cardiac progenitors that are activated in response to heart injury and are hypoxic by comparison to adjacent cardiac tissues. In this review, we discuss the development and potential of the adult epicardium and how this knowledge may provide future therapeutic approaches for cardiac repair.
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Affiliation(s)
- Angeliqua Sayed
- Cellular, Molecular, and Physiological Mechanisms of Heart Failure, Paris-Cardiovascular Research Center (PARCC), European Georges Pompidou Hospital (HEGP), INSERM U970, F-75737 Paris Cedex 15, Paris, France
| | - Mariana Valente
- Cellular, Molecular, and Physiological Mechanisms of Heart Failure, Paris-Cardiovascular Research Center (PARCC), European Georges Pompidou Hospital (HEGP), INSERM U970, F-75737 Paris Cedex 15, Paris, France
| | - David Sassoon
- Cellular, Molecular, and Physiological Mechanisms of Heart Failure, Paris-Cardiovascular Research Center (PARCC), European Georges Pompidou Hospital (HEGP), INSERM U970, F-75737 Paris Cedex 15, Paris, France
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16
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Malandraki-Miller S, Lopez CA, Al-Siddiqi H, Carr CA. Changing Metabolism in Differentiating Cardiac Progenitor Cells-Can Stem Cells Become Metabolically Flexible Cardiomyocytes? Front Cardiovasc Med 2018; 5:119. [PMID: 30283788 PMCID: PMC6157401 DOI: 10.3389/fcvm.2018.00119] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2018] [Accepted: 08/10/2018] [Indexed: 12/15/2022] Open
Abstract
The heart is a metabolic omnivore and the adult heart selects the substrate best suited for each circumstance, with fatty acid oxidation preferred in order to fulfill the high energy demand of the contracting myocardium. The fetal heart exists in an hypoxic environment and obtains the bulk of its energy via glycolysis. After birth, the "fetal switch" to oxidative metabolism of glucose and fatty acids has been linked to the loss of the regenerative phenotype. Various stem cell types have been used in differentiation studies, but most are cultured in high glucose media. This does not change in the majority of cardiac differentiation protocols. Despite the fact that metabolic state affects marker expression and cellular function and activity, the substrate composition is currently being overlooked. In this review we discuss changes in cardiac metabolism during development, the various protocols used to differentiate progenitor cells to cardiomyocytes, what is known about stem cell metabolism and how consideration of metabolism can contribute toward maturation of stem cell-derived cardiomyocytes.
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Affiliation(s)
| | | | | | - Carolyn A. Carr
- Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom
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17
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Li Y, He L, Huang X, Bhaloo SI, Zhao H, Zhang S, Pu W, Tian X, Li Y, Liu Q, Yu W, Zhang L, Liu X, Liu K, Tang J, Zhang H, Cai D, Ralf AH, Xu Q, Lui KO, Zhou B. Genetic Lineage Tracing of Nonmyocyte Population by Dual Recombinases. Circulation 2018; 138:793-805. [DOI: 10.1161/circulationaha.118.034250] [Citation(s) in RCA: 128] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Background:
Whether the adult mammalian heart harbors cardiac stem cells for regeneration of cardiomyocytes is an important yet contentious topic in the field of cardiovascular regeneration. The putative myocyte stem cell populations recognized without specific cell markers, such as the cardiosphere-derived cells, or with markers such as Sca1
+
, Bmi1
+
, Isl1
+
, or Abcg2
+
cardiac stem cells have been reported. Moreover, it remains unclear whether putative cardiac stem cells with unknown or unidentified markers exist and give rise to de novo cardiomyocytes in the adult heart.
Methods:
To address this question without relying on a particular stem cell marker, we developed a new genetic lineage tracing system to label all nonmyocyte populations that contain putative cardiac stem cells. Using dual lineage tracing system, we assessed whether nonmyocytes generated any new myocytes during embryonic development, during adult homeostasis, and after myocardial infarction. Skeletal muscle was also examined after injury for internal control of new myocyte generation from nonmyocytes.
Results:
By this stem cell marker–free and dual recombinases–mediated cell tracking approach, our fate mapping data show that new myocytes arise from nonmyocytes in the embryonic heart, but not in the adult heart during homeostasis or after myocardial infarction. As positive control, our lineage tracing system detected new myocytes derived from nonmyocytes in the skeletal muscle after injury.
Conclusions:
This study provides in vivo genetic evidence for nonmyocyte to myocyte conversion in embryonic but not adult heart, arguing again the myogenic potential of putative stem cell populations for cardiac regeneration in the adult stage. This study also provides a new genetic strategy to identify endogenous stem cells, if any, in other organ systems for tissue repair and regeneration.
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Affiliation(s)
- Yan Li
- The State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, and Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, China (Yan Li, L.H., X.H., H.Z., S.Z., W.P., X.T., Yi Li, Q.L., W.Y., L.Z., X.L., K.L., J.T., H.Z., B.Z.)
| | - Lingjuan He
- The State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, and Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, China (Yan Li, L.H., X.H., H.Z., S.Z., W.P., X.T., Yi Li, Q.L., W.Y., L.Z., X.L., K.L., J.T., H.Z., B.Z.)
| | - Xiuzhen Huang
- The State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, and Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, China (Yan Li, L.H., X.H., H.Z., S.Z., W.P., X.T., Yi Li, Q.L., W.Y., L.Z., X.L., K.L., J.T., H.Z., B.Z.)
| | - Shirin Issa Bhaloo
- Cardiovascular Division, British Heart Foundation Centre, King’s College London, United Kingdom (S.I.B. Q.X.)
| | - Huan Zhao
- The State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, and Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, China (Yan Li, L.H., X.H., H.Z., S.Z., W.P., X.T., Yi Li, Q.L., W.Y., L.Z., X.L., K.L., J.T., H.Z., B.Z.)
| | - Shaohua Zhang
- The State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, and Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, China (Yan Li, L.H., X.H., H.Z., S.Z., W.P., X.T., Yi Li, Q.L., W.Y., L.Z., X.L., K.L., J.T., H.Z., B.Z.)
| | - Wenjuan Pu
- The State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, and Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, China (Yan Li, L.H., X.H., H.Z., S.Z., W.P., X.T., Yi Li, Q.L., W.Y., L.Z., X.L., K.L., J.T., H.Z., B.Z.)
| | - Xueying Tian
- The State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, and Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, China (Yan Li, L.H., X.H., H.Z., S.Z., W.P., X.T., Yi Li, Q.L., W.Y., L.Z., X.L., K.L., J.T., H.Z., B.Z.)
- Key Laboratory of Regenerative Medicine of Ministry of Education, Jinan University, China (X.T., D.C., B.Z.)
| | - Yi Li
- The State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, and Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, China (Yan Li, L.H., X.H., H.Z., S.Z., W.P., X.T., Yi Li, Q.L., W.Y., L.Z., X.L., K.L., J.T., H.Z., B.Z.)
| | - Qiaozhen Liu
- The State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, and Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, China (Yan Li, L.H., X.H., H.Z., S.Z., W.P., X.T., Yi Li, Q.L., W.Y., L.Z., X.L., K.L., J.T., H.Z., B.Z.)
| | - Wei Yu
- The State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, and Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, China (Yan Li, L.H., X.H., H.Z., S.Z., W.P., X.T., Yi Li, Q.L., W.Y., L.Z., X.L., K.L., J.T., H.Z., B.Z.)
| | - Libo Zhang
- The State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, and Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, China (Yan Li, L.H., X.H., H.Z., S.Z., W.P., X.T., Yi Li, Q.L., W.Y., L.Z., X.L., K.L., J.T., H.Z., B.Z.)
| | - Xiuxiu Liu
- The State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, and Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, China (Yan Li, L.H., X.H., H.Z., S.Z., W.P., X.T., Yi Li, Q.L., W.Y., L.Z., X.L., K.L., J.T., H.Z., B.Z.)
| | - Kuo Liu
- The State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, and Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, China (Yan Li, L.H., X.H., H.Z., S.Z., W.P., X.T., Yi Li, Q.L., W.Y., L.Z., X.L., K.L., J.T., H.Z., B.Z.)
| | - Juan Tang
- The State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, and Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, China (Yan Li, L.H., X.H., H.Z., S.Z., W.P., X.T., Yi Li, Q.L., W.Y., L.Z., X.L., K.L., J.T., H.Z., B.Z.)
| | - Hui Zhang
- The State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, and Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, China (Yan Li, L.H., X.H., H.Z., S.Z., W.P., X.T., Yi Li, Q.L., W.Y., L.Z., X.L., K.L., J.T., H.Z., B.Z.)
| | - Dongqing Cai
- Key Laboratory of Regenerative Medicine of Ministry of Education, Jinan University, China (X.T., D.C., B.Z.)
| | - Adams H. Ralf
- Max Planck Institute for Molecular Biomedicine, Department of Tissue Morphogenesis, Faculty of Medicine, University of Muenster, Germany (A.H.R.)
| | - Qingbo Xu
- Cardiovascular Division, British Heart Foundation Centre, King’s College London, United Kingdom (S.I.B. Q.X.)
| | - Kathy O. Lui
- Department of Chemical Pathology, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China (K.O.L.)
| | - Bin Zhou
- The State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, and Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, China (Yan Li, L.H., X.H., H.Z., S.Z., W.P., X.T., Yi Li, Q.L., W.Y., L.Z., X.L., K.L., J.T., H.Z., B.Z.)
- School of Life Science and Technology, ShanghaiTech University, China (B.Z.)
- Key Laboratory of Regenerative Medicine of Ministry of Education, Jinan University, China (X.T., D.C., B.Z.)
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18
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Abstract
Death of adult cardiac myocytes and supportive tissues resulting from cardiovascular diseases such as myocardial infarction is the proximal driver of pathological ventricular remodeling that often culminates in heart failure. Unfortunately, no currently available therapeutic barring heart transplantation can directly replenish myocytes lost from the injured heart. For decades, the field has struggled to define the intrinsic capacity and cellular sources for endogenous myocyte turnover in pursuing more innovative therapeutic strategies aimed at regenerating the injured heart. Although controversy persists to this day as to the best therapeutic regenerative strategy to use, a growing consensus has been reached that the very limited capacity for new myocyte formation in the adult mammalian heart is because of proliferation of existing cardiac myocytes but not because of the activity of an endogenous progenitor cell source of some sort. Hence, future therapeutic approaches should take into consideration the fundamental biology of myocyte renewal in designing strategies to potentially replenish these cells in the injured heart.
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Affiliation(s)
| | - Jeffery D Molkentin
- From the Department of Pediatrics (R.J.V., J.D.M.)
- Howard Hughes Medical Institute (J.D.M.)
| | - Steven R Houser
- Cincinnati Children's Hospital Medical Center, OH; and the Lewis Katz School of Medicine, Cardiovascular Research Center, Temple University, Philadelphia, PA (S.R.H.)
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19
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Sun Y, Xu R, Huang J, Yao Y, Pan X, Chen Z, Ma G. Insulin-like growth factor-1-mediated regulation of miR-193a expression promotes the migration and proliferation of c-kit-positive mouse cardiac stem cells. Stem Cell Res Ther 2018; 9:41. [PMID: 29467020 PMCID: PMC5822561 DOI: 10.1186/s13287-017-0762-4] [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: 09/15/2017] [Revised: 12/13/2017] [Accepted: 12/22/2017] [Indexed: 12/13/2022] Open
Abstract
Background C-kit-positive cardiac stem cells (CSCs) have been shown to be a promising candidate treatment for myocardial infarction and heart failure. Insulin-like growth factor (IGF)-1 is an anabolic growth hormone that regulates cellular proliferation, differentiation, senescence, and death in various tissues. Although IGF-1 promotes the migration and proliferation of c-kit-positive mouse CSCs, the underlying mechanism remains unclear. Methods Cells were isolated from adult mouse hearts, and c-kit-positive CSCs were separated using magnetic beads. The cells were cultured with or without IGF-1, and c-kit expression was measured by Western blotting. IGF-1 induced CSC proliferation and migration, as measured through Cell Counting Kit-8 (CCK-8) and Transwell assays, respectively. The miR-193a expression was measured by quantitative real-time PCR (qPCR) assays. Results IGF-1 enhanced c-kit expression in c-kit-positive CSCs. The activities of the phosphoinositol 3-kinase (PI3K)/AKT signaling pathway and DNA methyltransferases (DNMTs) were enhanced, and their respective inhibitors LY294002 and 5-azacytidine (5-AZA) blunted c-kit expression. Based on the results of quantitative real-time PCR (qPCR) assays, the expression of miR-193a, which is embedded in a CpG island, was down-regulated in the IGF-1-stimulated group and negatively correlated with c-kit expression, whereas c-kit-positive CSCs infected with lentivirus carrying micro-RNA193a displayed reduced c-kit expression, migration and proliferation. Conclusions IGF-1 upregulated c-kit expression in c-kit-positive CSCs resulting in enhanced CSC proliferation and migration by activating the PI3K/AKT/DNMT signaling pathway to epigenetically silence miR-193a, which negatively modifies the c-kit expression level. Electronic supplementary material The online version of this article (10.1186/s13287-017-0762-4) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Yuning Sun
- Department of Cardiology, Zhongda Hospital, Medical School of Southeast University, DingjiaQiao No. 87, Hunan Road, Nanjing, 210009, Jiangsu, China
| | - Rongfeng Xu
- Department of Cardiology, Zhongda Hospital, Medical School of Southeast University, DingjiaQiao No. 87, Hunan Road, Nanjing, 210009, Jiangsu, China
| | - Jia Huang
- Department of Cardiology, Zhongda Hospital, Medical School of Southeast University, DingjiaQiao No. 87, Hunan Road, Nanjing, 210009, Jiangsu, China
| | - Yuyu Yao
- Department of Cardiology, Zhongda Hospital, Medical School of Southeast University, DingjiaQiao No. 87, Hunan Road, Nanjing, 210009, Jiangsu, China
| | - Xiaodong Pan
- Department of Cardiology, Zhongda Hospital, Medical School of Southeast University, DingjiaQiao No. 87, Hunan Road, Nanjing, 210009, Jiangsu, China
| | - Zhongpu Chen
- Department of Cardiology, Zhongda Hospital, Medical School of Southeast University, DingjiaQiao No. 87, Hunan Road, Nanjing, 210009, Jiangsu, China.
| | - Genshan Ma
- Department of Cardiology, Zhongda Hospital, Medical School of Southeast University, DingjiaQiao No. 87, Hunan Road, Nanjing, 210009, Jiangsu, China.
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20
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Recchia FA, Sharp TE. Combination Cell Therapy for Ischemic Cardiomyopathy: Is the Whole Greater Than Sum of Its Parts? J Am Coll Cardiol 2017; 70:2516-2518. [PMID: 29145951 DOI: 10.1016/j.jacc.2017.09.1065] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2017] [Accepted: 09/20/2017] [Indexed: 11/30/2022]
Affiliation(s)
- Fabio A Recchia
- Cardiovascular Research Center, Department of Physiology, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania; Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa, Italy, Fondazione Toscana Gabriele Monasterio, Pisa, Italy.
| | - Thomas E Sharp
- Cardiovascular Center of Excellence, School of Medicine, LSU Health Sciences Center, New Orleans, Louisiana
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21
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Enhancing the precision of genetic lineage tracing using dual recombinases. Nat Med 2017; 23:1488-1498. [PMID: 29131159 DOI: 10.1038/nm.4437] [Citation(s) in RCA: 206] [Impact Index Per Article: 25.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2017] [Accepted: 10/11/2017] [Indexed: 12/11/2022]
Abstract
The Cre-loxP recombination system is the most widely used technology for in vivo tracing of stem or progenitor cell lineages. The precision of this genetic system largely depends on the specificity of Cre recombinase expression in targeted stem or progenitor cells. However, Cre expression in nontargeted cell types can complicate the interpretation of lineage-tracing studies and has caused controversy in many previous studies. Here we describe a new genetic lineage tracing system that incorporates the Dre-rox recombination system to enhance the precision of conventional Cre-loxP-mediated lineage tracing. The Dre-rox system permits rigorous control of Cre-loxP recombination in lineage tracing, effectively circumventing potential uncertainty of the cell-type specificity of Cre expression. Using this new system we investigated two topics of recent debates-the contribution of c-Kit+ cardiac stem cells to cardiomyocytes in the heart and the contribution of Sox9+ hepatic progenitor cells to hepatocytes in the liver. By overcoming the technical hurdle of nonspecific Cre-loxP-mediated recombination, this new technology provides more precise analysis of cell lineage and fate decisions and facilitates the in vivo study of stem and progenitor cell plasticity in disease and regeneration.
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22
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Bianconi V, Sahebkar A, Kovanen P, Bagaglia F, Ricciuti B, Calabrò P, Patti G, Pirro M. Endothelial and cardiac progenitor cells for cardiovascular repair: A controversial paradigm in cell therapy. Pharmacol Ther 2017; 181:156-168. [PMID: 28827151 DOI: 10.1016/j.pharmthera.2017.08.004] [Citation(s) in RCA: 94] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/09/2023]
Abstract
Stem cells have the potential to differentiate into cardiovascular cell lineages and to stimulate tissue regeneration in a paracrine/autocrine manner; thus, they have been extensively studied as candidate cell sources for cardiovascular regeneration. Several preclinical and clinical studies addressing the therapeutic potential of endothelial progenitor cells (EPCs) and cardiac progenitor cells (CPCs) in cardiovascular diseases have been performed. For instance, autologous EPC transplantation and EPC mobilization through pharmacological agents contributed to vascular repair and neovascularization in different animal models of limb ischemia and myocardial infarction. Also, CPC administration and in situ stimulation of resident CPCs have been shown to improve myocardial survival and function in experimental models of ischemic heart disease. However, clinical studies using EPC- and CPC-based therapeutic approaches have produced mixed results. In this regard, intracoronary, intra-myocardial or intramuscular injection of either bone marrow-derived or peripheral blood progenitor cells has improved pathological features of tissue ischemia in humans, despite modest or no clinical benefit has been observed in most cases. Also, the intriguing scientific background surrounding the potential clinical applications of EPC capture stenting is still waiting for a confirmatory proof. Moreover, clinical findings on the efficacy of CPC-based cell therapy in heart diseases are still very preliminary and based on small-size studies. Despite promising evidence, widespread clinical application of both EPCs and CPCs remains delayed due to several unresolved issues. The present review provides a summary of the different applications of EPCs and CPCs for cardiovascular cell therapy and underlies their advantages and limitations.
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Affiliation(s)
- Vanessa Bianconi
- Unit of Internal Medicine, Department of Medicine, University of Perugia, Perugia, Italy
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Francesco Bagaglia
- Unit of Internal Medicine, Department of Medicine, University of Perugia, Perugia, Italy
| | - Biagio Ricciuti
- Department of Medical Oncology, S. Maria della Misericordia Hospital, Perugia, Italy
| | - Paolo Calabrò
- Division of Cardiology, Second University of Naples, Department of Cardio-Thoracic and Respiratory Sciences, Italy
| | - Giuseppe Patti
- Unit of Cardiovascular Science, Campus Bio-Medico University of Rome, Italy
| | - Matteo Pirro
- Unit of Internal Medicine, Department of Medicine, University of Perugia, Perugia, Italy.
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23
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Cai CL, Molkentin JD. The Elusive Progenitor Cell in Cardiac Regeneration: Slip Slidin' Away. Circ Res 2017; 120:400-406. [PMID: 28104772 DOI: 10.1161/circresaha.116.309710] [Citation(s) in RCA: 57] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2016] [Revised: 12/12/2016] [Accepted: 12/13/2016] [Indexed: 12/31/2022]
Abstract
The adult human heart is unable to regenerate after various forms of injury, suggesting that this organ lacks a biologically meaningful endogenous stem cell pool. However, injecting the infarcted area of the adult mammalian heart with exogenously prepared progenitor cells of various types has been reported to create new myocardium by the direct conversion of these progenitor cells into cardiomyocytes. These reports remain controversial because follow-up studies from independent laboratories failed to observe such an effect. Also, the exact nature of various putative myocyte-producing progenitor cells remains elusive and undefined across laboratories. By comparison, the field has gradually worked toward a consensus viewpoint that proposes that the adult mammalian myocardium can undergo a low level of new cardiomyocyte renewal of ≈1% per year, which is primarily because of proliferation of existing cardiomyocytes but not from the differentiation of putative progenitor cells. This review will weigh the emerging evidence, suggesting that the adult mammalian heart lacks a definable myocyte-generating progenitor cell of biological significance.
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Affiliation(s)
- Chen-Leng Cai
- From the Department of Developmental and Regenerative Biology, and Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY (C.-L.C.); and Department of Pediatrics, University of Cincinnati, Cincinnati Children's Hospital Medical Center and Howard Hughes Medical Institute, OH (J.D.M.).
| | - Jeffery D Molkentin
- From the Department of Developmental and Regenerative Biology, and Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY (C.-L.C.); and Department of Pediatrics, University of Cincinnati, Cincinnati Children's Hospital Medical Center and Howard Hughes Medical Institute, OH (J.D.M.).
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24
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Santini MP, Forte E, Harvey RP, Kovacic JC. Developmental origin and lineage plasticity of endogenous cardiac stem cells. Development 2016; 143:1242-58. [PMID: 27095490 DOI: 10.1242/dev.111591] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Over the past two decades, several populations of cardiac stem cells have been described in the adult mammalian heart. For the most part, however, their lineage origins and in vivo functions remain largely unexplored. This Review summarizes what is known about different populations of embryonic and adult cardiac stem cells, including KIT(+), PDGFRα(+), ISL1(+)and SCA1(+)cells, side population cells, cardiospheres and epicardial cells. We discuss their developmental origins and defining characteristics, and consider their possible contribution to heart organogenesis and regeneration. We also summarize the origin and plasticity of cardiac fibroblasts and circulating endothelial progenitor cells, and consider what role these cells have in contributing to cardiac repair.
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Affiliation(s)
- Maria Paola Santini
- Cardiovascular Research Centre, Icahn School of Medicine at Mount Sinai, New York City, NY, USA
| | - Elvira Forte
- Developmental and Stem Cell Biology Division, Victor Chang Cardiac Research Institute, 405 Liverpool Street, Darlinghurst 2010, Australia St Vincent's Clinical School, University of New South Wales, Kensington 2052, Australia Stem Cells Australia, Melbourne Brain Centre, The University of Melbourne, Parkville, Victoria 3010, Australia
| | - Richard P Harvey
- Developmental and Stem Cell Biology Division, Victor Chang Cardiac Research Institute, 405 Liverpool Street, Darlinghurst 2010, Australia St Vincent's Clinical School, University of New South Wales, Kensington 2052, Australia Stem Cells Australia, Melbourne Brain Centre, The University of Melbourne, Parkville, Victoria 3010, Australia School of Biotechnology and Biomolecular Sciences, University of New South Wales, Kensington 2052, Australia
| | - Jason C Kovacic
- Cardiovascular Research Centre, Icahn School of Medicine at Mount Sinai, New York City, NY, USA Stem Cells Australia, Melbourne Brain Centre, The University of Melbourne, Parkville, Victoria 3010, Australia
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25
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Bruyneel AAN, Sehgal A, Malandraki-Miller S, Carr C. Stem Cell Therapy for the Heart: Blind Alley or Magic Bullet? J Cardiovasc Transl Res 2016; 9:405-418. [PMID: 27542008 PMCID: PMC5153828 DOI: 10.1007/s12265-016-9708-y] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2016] [Accepted: 08/05/2016] [Indexed: 12/15/2022]
Abstract
When stressed by ageing or disease, the adult human heart is unable to regenerate, leading to scarring and hypertrophy and eventually heart failure. As a result, stem cell therapy has been proposed as an ultimate therapeutic strategy, as stem cells could limit adverse remodelling and give rise to new cardiomyocytes and vasculature. Unfortunately, the results from clinical trials to date have been largely disappointing. In this review, we discuss the current status of the field and describe various limitations and how future work may attempt to resolve these to make way to successful clinical translation.
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Affiliation(s)
- Arne A N Bruyneel
- Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, UK
| | | | | | - Carolyn Carr
- Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, UK.
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26
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Malliaras K, Vakrou S, Kapelios CJ, Nanas JN. Innate heart regeneration: endogenous cellular sources and exogenous therapeutic amplification. Expert Opin Biol Ther 2016; 16:1341-1352. [PMID: 27484198 DOI: 10.1080/14712598.2016.1218846] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
INTRODUCTION The -once viewed as heretical- concept of the adult mammalian heart as a dynamic organ capable of endogenous regeneration has recently gained traction. However, estimated rates of myocyte turnover vary wildly and the underlying mechanisms of cardiac plasticity remain controversial. It is still unclear whether the adult mammalian heart gives birth to new myocytes through proliferation of resident myocytes, through cardiomyogenic differentiation of endogenous progenitors or through both mechanisms. AREAS COVERED In this review, the authors discuss the cellular origins of postnatal mammalian cardiomyogenesis and touch upon therapeutic strategies that could potentially amplify innate cardiac regeneration. EXPERT OPINION The adult mammalian heart harbors a limited but detectable capacity for spontaneous endogenous regeneration. During normal aging, proliferation of pre-existing cardiomyocytes is the dominant mechanism for generation of new cardiomyocytes. Following myocardial injury, myocyte proliferation increases modestly, but differentiation of endogenous progenitor cells appears to also contribute to cardiomyogenesis (although agreement on the latter point is not universal). Since cardiomyocyte deficiency underlies almost all types of heart disease, development of therapeutic strategies that amplify endogenous regeneration to a clinically-meaningful degree is of utmost importance.
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Affiliation(s)
- Konstantinos Malliaras
- a 3rd Department of Cardiology , University of Athens School of Medicine , Athens , Greece
| | - Styliani Vakrou
- a 3rd Department of Cardiology , University of Athens School of Medicine , Athens , Greece
| | - Chris J Kapelios
- a 3rd Department of Cardiology , University of Athens School of Medicine , Athens , Greece
| | - John N Nanas
- a 3rd Department of Cardiology , University of Athens School of Medicine , Athens , Greece
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27
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Nuquantus: Machine learning software for the characterization and quantification of cell nuclei in complex immunofluorescent tissue images. Sci Rep 2016; 6:23431. [PMID: 27005843 PMCID: PMC4804284 DOI: 10.1038/srep23431] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2015] [Accepted: 03/04/2016] [Indexed: 01/27/2023] Open
Abstract
Determination of fundamental mechanisms of disease often hinges on histopathology visualization and quantitative image analysis. Currently, the analysis of multi-channel fluorescence tissue images is primarily achieved by manual measurements of tissue cellular content and sub-cellular compartments. Since the current manual methodology for image analysis is a tedious and subjective approach, there is clearly a need for an automated analytical technique to process large-scale image datasets. Here, we introduce Nuquantus (Nuclei quantification utility software) - a novel machine learning-based analytical method, which identifies, quantifies and classifies nuclei based on cells of interest in composite fluorescent tissue images, in which cell borders are not visible. Nuquantus is an adaptive framework that learns the morphological attributes of intact tissue in the presence of anatomical variability and pathological processes. Nuquantus allowed us to robustly perform quantitative image analysis on remodeling cardiac tissue after myocardial infarction. Nuquantus reliably classifies cardiomyocyte versus non-cardiomyocyte nuclei and detects cell proliferation, as well as cell death in different cell classes. Broadly, Nuquantus provides innovative computerized methodology to analyze complex tissue images that significantly facilitates image analysis and minimizes human bias.
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Abstract
PURPOSE OF REVIEW The purpose of this review is to provide an update on the cardiac stem cell field with an emphasis on aging and to suggest some relevant strategies directed toward rejuvenation of the senescent heart. RECENT FINDINGS Stem cells were long considered as a fountain of youth and were assumed to be equipped against any form of aging effect. However, it is now clear that stem cells suffer the consequences of aging as well. With the discovery that cardiac stem cells reside in the heart comes the question whether these cells are also impaired upon aging. As cardiac stem cell properties are also altered with age, autologous stem cell-based therapy to treat heart failure will benefit from new improved strategies. SUMMARY With the goal to improve stem cell properties that are impaired upon aging, some strategies are highlighted. Genetic modification of adult human cardiac progenitor cells prior to autologous stem cell-based therapy, delivery of the next generation of stem cells such as CardioChimeras and CardioClusters, and improvement of the myocardial environment with rejuvenating factors constitute some of the possibilities and are discussed in more detail in this review.
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29
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Genetic lineage tracing identifies in situ Kit-expressing cardiomyocytes. Cell Res 2015; 26:119-30. [PMID: 26634606 PMCID: PMC4816131 DOI: 10.1038/cr.2015.143] [Citation(s) in RCA: 107] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2015] [Revised: 10/26/2015] [Accepted: 10/27/2015] [Indexed: 12/28/2022] Open
Abstract
Cardiac cells marked by c-Kit or Kit, dubbed cardiac stem cells (CSCs), are in clinical trials to investigate their ability to stimulate cardiac regeneration and repair. These studies were initially motivated by the purported cardiogenic activity of these cells. Recent lineage tracing studies using Kit promoter to drive expression of the inducible Cre recombinase showed that these CSCs had highly limited cardiogenic activity, inadequate to support efficient cardiac repair. Here we reassess the lineage tracing data by investigating the identity of cells immediately after Cre labeling. Our instant lineage tracing approach identifies Kit-expressing cardiomyocytes, which are labeled immediately after tamoxifen induction. In combination with long-term lineage tracing experiments, these data reveal that the large majority of long-term labeled cardiomyocytes are pre-existing Kit-expressing cardiomyocytes rather than cardiomyocytes formed de novo from CSCs. This study presents a new interpretation for the contribution of Kit+ cells to cardiomyocytes and shows that Kit genetic lineage tracing over-estimates the cardiogenic activity of Kit+ CSCs.
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30
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Affiliation(s)
- Sujith Dassanayaka
- From the Division of Cardiovascular Medicine, Department of Medicine and Department of Physiology and Biophysics, Institute of Molecular Cardiology, Diabetes and Obesity Center, University of Louisville, KY
| | - Steven P Jones
- From the Division of Cardiovascular Medicine, Department of Medicine and Department of Physiology and Biophysics, Institute of Molecular Cardiology, Diabetes and Obesity Center, University of Louisville, KY.
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31
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Sultana N, Zhang L, Yan J, Chen J, Cai W, Razzaque S, Jeong D, Sheng W, Bu L, Xu M, Huang GY, Hajjar RJ, Zhou B, Moon A, Cai CL. Resident c-kit(+) cells in the heart are not cardiac stem cells. Nat Commun 2015; 6:8701. [PMID: 26515110 PMCID: PMC4846318 DOI: 10.1038/ncomms9701] [Citation(s) in RCA: 232] [Impact Index Per Article: 23.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2015] [Accepted: 09/22/2015] [Indexed: 12/20/2022] Open
Abstract
Identifying a bona fide population of cardiac stem cells (CSCs) is a critical step for developing cell-based therapies for heart failure patients. Previously, cardiac c-kit+ cells were reported to be CSCs with a potential to become myocardial, endothelial and smooth muscle cells in vitro and after cardiac injury. Here we provide further insights into the nature of cardiac c-kit+ cells. By targeting the c-kit locus with multiple reporter genes in mice, we find that c-kit expression rarely co-localizes with the expression of the cardiac progenitor and myogenic marker Nkx2.5, or that of the myocardial marker, cardiac troponin T (cTnT). Instead, c-kit predominantly labels a cardiac endothelial cell population in developing and adult hearts. After acute cardiac injury, c-kit+ cells retain their endothelial identity and do not become myogenic progenitors or cardiomyocytes. Thus, our work strongly suggests that c-kit+ cells in the murine heart are endothelial cells and not CSCs. The issue whether the cell surface protein c-kit identifies resident cardiac stem cells (CSC) is controversial. By using novel reporter mouse models, Sultana et al. show that c-kit+ cells represent a subpopulation of endothelial cells in the developing and adult heart and do not exhibit CSC traits in health or disease.
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Affiliation(s)
- Nishat Sultana
- Department of Developmental and Regenerative Biology, The Black Family Stem Cell Institute, and The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA
| | - Lu Zhang
- Department of Developmental and Regenerative Biology, The Black Family Stem Cell Institute, and The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA
| | - Jianyun Yan
- Department of Developmental and Regenerative Biology, The Black Family Stem Cell Institute, and The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA
| | - Jiqiu Chen
- Department of Medicine, Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA
| | - Weibin Cai
- Department of Developmental and Regenerative Biology, The Black Family Stem Cell Institute, and The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA
| | - Shegufta Razzaque
- Department of Developmental and Regenerative Biology, The Black Family Stem Cell Institute, and The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA
| | - Dongtak Jeong
- Department of Medicine, Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA
| | - Wei Sheng
- Cardiovascular Center, Children's Hospital of Fudan University, Shanghai 201102, China
| | - Lei Bu
- Leon H. Charney Division of Cardiology, Department of Medicine, New York University School of Medicine, New York, New York 10016, USA
| | - Mingjiang Xu
- Department of Biochemistry and Molecular Biology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida 33136, USA
| | - Guo-Ying Huang
- Cardiovascular Center, Children's Hospital of Fudan University, Shanghai 201102, China
| | - Roger J Hajjar
- Department of Medicine, Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA
| | - Bin Zhou
- Department of Genetics, Albert Einstein College of Medicine of Yeshiva University, Bronx, New York 10461, USA
| | - Anne Moon
- Weis Center for Research, Geisinger Clinic, Danville, Pennsylvania 17822, USA
| | - Chen-Leng Cai
- Department of Developmental and Regenerative Biology, The Black Family Stem Cell Institute, and The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA
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32
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Germani A, Foglio E, Capogrossi MC, Russo MA, Limana F. Generation of cardiac progenitor cells through epicardial to mesenchymal transition. J Mol Med (Berl) 2015; 93:735-48. [PMID: 25943780 DOI: 10.1007/s00109-015-1290-2] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2014] [Revised: 04/16/2015] [Accepted: 04/17/2015] [Indexed: 12/23/2022]
Abstract
The epithelial to mesenchymal transition (EMT) is a biological process that drives the formation of cells involved both in tissue repair and in pathological conditions, including tissue fibrosis and tumor metastasis by providing cancer cells with stem cell properties. Recent findings suggest that EMT is reactivated in the heart following ischemic injury. Specifically, epicardial EMT might be involved in the formation of cardiac progenitor cells (CPCs) that can differentiate into endothelial cells, smooth muscle cells, and, possibly, cardiomyocytes. The identification of mechanisms and signaling pathways governing EMT-derived CPC generation and differentiation may contribute to the development of a more efficient regenerative approach for adult heart repair. Here, we summarize key literature in the field.
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Affiliation(s)
- Antonia Germani
- Laboratorio di Patologia Vascolare, Istituto Dermopatico dell'Immacolata, IRCCS, Rome, Italy
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Nigro P, Perrucci GL, Gowran A, Zanobini M, Capogrossi MC, Pompilio G. c-kit(+) cells: the tell-tale heart of cardiac regeneration? Cell Mol Life Sci 2015; 72:1725-40. [PMID: 25575564 PMCID: PMC11113938 DOI: 10.1007/s00018-014-1832-8] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2014] [Revised: 12/18/2014] [Accepted: 12/30/2014] [Indexed: 12/21/2022]
Abstract
Cardiovascular disease is the leading cause of morbidity and mortality in the developed world. Although ongoing therapeutic strategies ameliorate symptoms and prolong life for patients with cardiovascular diseases, they do not solve the critical issue related to the loss of cardiac tissue. Accordingly, stem/progenitor cell therapy has emerged as a paramount approach for cardiac repair and regeneration. In this regard, c-kit(+) cells have animated much interest and controversy. These cells are self-renewing, clonogenic, and multipotent and display a noteworthy potential to differentiate into all cardiovascular lineages. However, their functional contribution to cardiomyocyte turnover is one of the centrally debated issues concerning their regenerative potential. Regardless, plentiful preclinical and clinical studies have been conducted which provide evidence for the capacity of c-kit(+) cells to improve cardiac function. The purpose of this review is to give a comprehensive, impartial, critical description and evaluation of the literature on c-kit(+) cells from bench to bedside in order to address their true potential, benefits and controversies.
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Affiliation(s)
- Patrizia Nigro
- Laboratory of Vascular Biology and Regenerative Medicine, Centro Cardiologico Monzino-IRCCS, Via Parea 4, 20138, Milan, Italy,
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Abstract
The latest discoveries and advanced knowledge in the fields of stem cell biology and developmental cardiology hold great promise for cardiac regenerative medicine, enabling researchers to design novel therapeutic tools and approaches to regenerate cardiac muscle for diseased hearts. However, progress in this arena has been hampered by a lack of reproducible and convincing evidence, which at best has yielded modest outcomes and is still far from clinical practice. To address current controversies and move cardiac regenerative therapeutics forward, it is crucial to gain a deeper understanding of the key cellular and molecular programs involved in human cardiogenesis and cardiac regeneration. In this review, we consider the fundamental principles that govern the "programming" and "reprogramming" of a human heart cell and discuss updated therapeutic strategies to regenerate a damaged heart.
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Affiliation(s)
- Makoto Sahara
- Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden Department of Medicine-Cardiology, Karolinska Institute, Stockholm, Sweden
| | - Federica Santoro
- Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden
| | - Kenneth R Chien
- Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden Department of Medicine-Cardiology, Karolinska Institute, Stockholm, Sweden
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35
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Molkentin JD. Letter by Molkentin regarding article, "The absence of evidence is not evidence of absence: the pitfalls of Cre Knock-Ins in the c-Kit Locus". Circ Res 2014; 115:e21-3. [PMID: 25258403 DOI: 10.1161/circresaha.114.305011] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Affiliation(s)
- Jeffery D Molkentin
- Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Howard Hughes Medical Institute, OH
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36
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Madonna R, Ferdinandy P, De Caterina R, Willerson JT, Marian AJ. Recent developments in cardiovascular stem cells. Circ Res 2014; 115:e71-8. [PMID: 25477490 DOI: 10.1161/circresaha.114.305567] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Affiliation(s)
- Rosalinda Madonna
- From the Center of Excellence on Aging, Institute of Cardiology, Department of Neuroscience and Imaging, "G. d'Annunzio" University, Chieti, Italy (R.M., R.D.C.); Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary (P.F.); Pharmahungary Group, Szeged, Hungary (P.F.); Texas Heart Institute, Houston (R.M., J.T.W.); Division of Cardiology, Department of Internal Medicine (R.M., J.T.W., A.J.M.), and Institute of Molecular Medicine, The University of Texas Health Science Center, Houston (A.J.M.)
| | - Peter Ferdinandy
- From the Center of Excellence on Aging, Institute of Cardiology, Department of Neuroscience and Imaging, "G. d'Annunzio" University, Chieti, Italy (R.M., R.D.C.); Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary (P.F.); Pharmahungary Group, Szeged, Hungary (P.F.); Texas Heart Institute, Houston (R.M., J.T.W.); Division of Cardiology, Department of Internal Medicine (R.M., J.T.W., A.J.M.), and Institute of Molecular Medicine, The University of Texas Health Science Center, Houston (A.J.M.)
| | - Raffaele De Caterina
- From the Center of Excellence on Aging, Institute of Cardiology, Department of Neuroscience and Imaging, "G. d'Annunzio" University, Chieti, Italy (R.M., R.D.C.); Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary (P.F.); Pharmahungary Group, Szeged, Hungary (P.F.); Texas Heart Institute, Houston (R.M., J.T.W.); Division of Cardiology, Department of Internal Medicine (R.M., J.T.W., A.J.M.), and Institute of Molecular Medicine, The University of Texas Health Science Center, Houston (A.J.M.)
| | - James T Willerson
- From the Center of Excellence on Aging, Institute of Cardiology, Department of Neuroscience and Imaging, "G. d'Annunzio" University, Chieti, Italy (R.M., R.D.C.); Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary (P.F.); Pharmahungary Group, Szeged, Hungary (P.F.); Texas Heart Institute, Houston (R.M., J.T.W.); Division of Cardiology, Department of Internal Medicine (R.M., J.T.W., A.J.M.), and Institute of Molecular Medicine, The University of Texas Health Science Center, Houston (A.J.M.)
| | - Ali J Marian
- From the Center of Excellence on Aging, Institute of Cardiology, Department of Neuroscience and Imaging, "G. d'Annunzio" University, Chieti, Italy (R.M., R.D.C.); Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary (P.F.); Pharmahungary Group, Szeged, Hungary (P.F.); Texas Heart Institute, Houston (R.M., J.T.W.); Division of Cardiology, Department of Internal Medicine (R.M., J.T.W., A.J.M.), and Institute of Molecular Medicine, The University of Texas Health Science Center, Houston (A.J.M.).
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Abstract
During development, cardiogenesis is orchestrated by a family of heart progenitors that build distinct regions of the heart. Each region contains diverse cell types that assemble to form the complex structures of the individual cardiac compartments. Cardiomyocytes are the main cell type found in the heart and ensure contraction of the chambers and efficient blood flow throughout the body. Injury to the cardiac muscle often leads to heart failure due to the loss of a large number of cardiomyocytes and its limited intrinsic capacity to regenerate the damaged tissue, making it one of the leading causes of morbidity and mortality worldwide. In this Primer we discuss how insights into the molecular and cellular framework underlying cardiac development can be used to guide the in vitro specification of cardiomyocytes, whether by directed differentiation of pluripotent stem cells or via direct lineage conversion. Additional strategies to generate cardiomyocytes in situ, such as reactivation of endogenous cardiac progenitors and induction of cardiomyocyte proliferation, will also be discussed.
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Affiliation(s)
- Daniela Später
- Department of Stem Cell and Regenerative Biology, Harvard University and Harvard Medical School, 7 Divinity Avenue, Cambridge, MA 02138, USA Department of Bioscience, CVMD iMED, AstraZeneca, Pepparedsleden 1, Mölndal 43150, Sweden
| | - Emil M Hansson
- Department of Stem Cell and Regenerative Biology, Harvard University and Harvard Medical School, 7 Divinity Avenue, Cambridge, MA 02138, USA Department of Cell and Molecular Biology and Medicine, Karolinska Institutet, 35 Berzelius Vag, Stockholm 171 77, Sweden
| | - Lior Zangi
- Department of Stem Cell and Regenerative Biology, Harvard University and Harvard Medical School, 7 Divinity Avenue, Cambridge, MA 02138, USA Department of Cardiology, Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA Cardiovascular Research Center, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA
| | - Kenneth R Chien
- Department of Stem Cell and Regenerative Biology, Harvard University and Harvard Medical School, 7 Divinity Avenue, Cambridge, MA 02138, USA Department of Cell and Molecular Biology and Medicine, Karolinska Institutet, 35 Berzelius Vag, Stockholm 171 77, Sweden
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Chong JJ, Forte E, Harvey RP. Developmental origins and lineage descendants of endogenous adult cardiac progenitor cells. Stem Cell Res 2014; 13:592-614. [DOI: 10.1016/j.scr.2014.09.008] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2014] [Revised: 09/24/2014] [Accepted: 09/26/2014] [Indexed: 12/30/2022] Open
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Bergmann O, Jovinge S. Cardiac regeneration in vivo: Mending the heart from within? Stem Cell Res 2014; 13:523-31. [DOI: 10.1016/j.scr.2014.07.002] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2014] [Revised: 07/03/2014] [Accepted: 07/09/2014] [Indexed: 10/25/2022] Open
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Torella D, Ellison GM, Nadal-Ginard B. Adult c-kit
pos
Cardiac Stem Cells Fulfill Koch’s Postulates as Causal Agents for Cardiac Regeneration. Circ Res 2014; 114:e24-6. [DOI: 10.1161/circresaha.113.303313] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Affiliation(s)
- Daniele Torella
- Molecular and Cellular Cardiology, Department of Medical and Surgical Sciences, Magna Graecia University
Catanzaro, Italy
| | - Georgina M. Ellison
- Department of Physiology, School of Biomedical Sciences, King’s College
London, UK
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