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Allouh MZ, Rizvi SFA, Alamri A, Jimoh Y, Aouda S, Ouda ZH, Hamad MIK, Perez-Cruet M, Chaudhry GR. Mesenchymal stromal/stem cells from perinatal sources: biological facts, molecular biomarkers, and therapeutic promises. Stem Cell Res Ther 2025; 16:127. [PMID: 40055783 PMCID: PMC11889844 DOI: 10.1186/s13287-025-04254-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Accepted: 02/25/2025] [Indexed: 05/13/2025] Open
Abstract
The use of mesenchymal stem cells (MSCs) from perinatal tissue sources has gained attention due to their availability and lack of significant ethical or moral concerns. These cells have a higher proliferative capability than adult MSCs and less immunogenic or tumorigenesis risk than fetal and embryonic stem cells. Additionally, they do not require invasive isolation methods like fetal and adult MSCs. We reviewed the main biological and therapeutic aspects of perinatal MSCs in a three-part article. In the first part, we revised the main biological features and characteristics of MSCs and the advantages of perinatal MSCs over other types of SCs. In the second part, we provided a detailed molecular background for the main biomarkers that can be used to identify MSCs. In the final part, we appraised the therapeutic application of perinatal MSCs in four major degenerative disorders: degenerative disc disease, retinal degenerative diseases, ischemic heart disease, and neurodegenerative diseases. In conclusion, there is no single specific molecular marker to identify MSCs. We recommend using at least two positive markers of stemness (CD29, CD73, CD90, or CD105) and two negative markers (CD34, CD45, or CD14) to exclude the hematopoietic origin. Moreover, utilizing perinatal MSCs for managing degenerative diseases presents a promising therapeutic approach. This review emphasizes the significance of employing more specialized progenitor cells that originated from the perinatal MSCs. The review provides scientific evidence from the literature that applying these progenitor cells in therapeutic procedures provides a greater regenerative capacity than the original primitive MSCs. Finally, this review provides a valuable reference for researchers exploring perinatal MSCs and their therapeutic applications.
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Affiliation(s)
- Mohammed Z Allouh
- Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, P. O. Box: 15551, Al Ain, UAE.
- OU-WB Institute for Stem Cell and Regenerative Medicine, Oakland University, Rochester, MI, 48309, USA.
| | - Syed Faizan Ali Rizvi
- OU-WB Institute for Stem Cell and Regenerative Medicine, Oakland University, Rochester, MI, 48309, USA
- Department of Biological Sciences, Oakland University, Rochester, MI, 48309, USA
| | - Ali Alamri
- OU-WB Institute for Stem Cell and Regenerative Medicine, Oakland University, Rochester, MI, 48309, USA
- Department of Biological Sciences, Oakland University, Rochester, MI, 48309, USA
| | - Yusuf Jimoh
- OU-WB Institute for Stem Cell and Regenerative Medicine, Oakland University, Rochester, MI, 48309, USA
- Department of Biological Sciences, Oakland University, Rochester, MI, 48309, USA
| | - Salma Aouda
- College of Medicine and Health Sciences, Khalifa University, Abu Dhabi, UAE
| | - Zakaria H Ouda
- Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, P. O. Box: 15551, Al Ain, UAE
| | - Mohammad I K Hamad
- Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, P. O. Box: 15551, Al Ain, UAE
| | - Mick Perez-Cruet
- OU-WB Institute for Stem Cell and Regenerative Medicine, Oakland University, Rochester, MI, 48309, USA
- Department of Neurosurgery, Corewell Health, Royal Oak, MI, USA
| | - G Rasul Chaudhry
- OU-WB Institute for Stem Cell and Regenerative Medicine, Oakland University, Rochester, MI, 48309, USA.
- Department of Biological Sciences, Oakland University, Rochester, MI, 48309, USA.
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Farag A, Hendawy H, Emam MH, Hasegawa M, Mandour AS, Tanaka R. Stem Cell Therapies in Canine Cardiology: Comparative Efficacy, Emerging Trends, and Clinical Integration. Biomolecules 2025; 15:371. [PMID: 40149907 PMCID: PMC11940628 DOI: 10.3390/biom15030371] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2025] [Revised: 02/26/2025] [Accepted: 02/27/2025] [Indexed: 03/29/2025] Open
Abstract
Cardiovascular diseases are a leading cause of morbidity and mortality in dogs, with limited options available for reversing myocardial damage. Stem cell therapies have shown significant potential for cardiac repair, owing to their immunomodulatory, antifibrotic, and regenerative properties. This review evaluates the therapeutic applications of mesenchymal stem cells (MSCs) derived from bone marrow, adipose tissue, and Wharton's jelly with a focus on their role in canine cardiology and their immunoregulatory properties. Preclinical studies have highlighted their efficacy in enhancing cardiac function, reducing fibrosis, and promoting angiogenesis. Various delivery methods, including intracoronary and intramyocardial injections, are assessed for their safety and efficacy. Challenges such as low cell retention, differentiation efficiency, and variability in therapeutic responses are also discussed. Emerging strategies, including genetic modifications and combination therapies, aim to enhance the efficacy of MSCs. Additionally, advances in delivery systems and regulatory frameworks are reviewed to support clinical translation. This comprehensive evaluation underscores the potential of stem cell therapies to revolutionize canine cardiovascular disease management while identifying critical areas for future research and clinical integration.
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Affiliation(s)
- Ahmed Farag
- Faculty of Agriculture, Veterinary Teaching Hospital, Tokyo University of Agriculture and Technology, Tokyo 183-8509, Japan
- Department of Surgery, Anesthesiology, and Radiology, Faculty of Veterinary Medicine, Zagazig University, Zagazig 44519, Egypt
| | - Hanan Hendawy
- Department of Veterinary Surgery, Faculty of Veterinary Medicine, Suez Canal University, Ismailia 41522, Egypt
| | - Mahmoud H. Emam
- Animal Medicine Department, Faculty of Veterinary Medicine, Zagazig University, Zagazig 44519, Egypt
| | - Mizuki Hasegawa
- Faculty of Agriculture, Veterinary Teaching Hospital, Tokyo University of Agriculture and Technology, Tokyo 183-8509, Japan
| | - Ahmed S. Mandour
- Department of Animal Medicine (Internal Medicine), Faculty of Veterinary Medicine, Suez Canal University, Ismailia 41522, Egypt
| | - Ryou Tanaka
- Faculty of Agriculture, Veterinary Teaching Hospital, Tokyo University of Agriculture and Technology, Tokyo 183-8509, Japan
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Li J, Lin A, Jiang R, Chen P, Xu C, Hou Y. Exosomes-mediated drug delivery for the treatment of myocardial injury. Ann Med Surg (Lond) 2024; 86:292-299. [PMID: 38222684 PMCID: PMC10783224 DOI: 10.1097/ms9.0000000000001473] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Accepted: 10/25/2023] [Indexed: 01/16/2024] Open
Abstract
Cardiovascular disease has become a major cause of death worldwide. Myocardial injury (MI) caused by myocardial infarction, myocarditis, and drug overdose can lead to impaired cardiac function, culminating in serious consequences such as angina pectoris, arrhythmias, and heart failure. Exosomes exhibit high biocompatibility and target specificity, rendering them an important non-cellular therapy for improving MI. Exosomes are diminutive vesicles that encapsulate nucleic acids and proteins. Exosomes derived from cardiac stem cells themselves have therapeutic effects, and they can also serve as carriers to deliver therapeutic drugs to recipient cells, thereby exerting a therapeutic effect. The molecules within exosomes are encapsulated in a lipid bilayer, allowing them to stably exist in body fluids without being affected by nucleases. Therefore, the utilization of exosomes as drug delivery systems (DDS) for disease treatment has been extensively investigated and is currently undergoing clinical trials. This review summarizes the therapeutic effects of exosomes on MI and provides an overview of current research progress on their use as DDS in MI.
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Affiliation(s)
- Jiang Li
- Zhengzhou Railway Vocational and Technical College
| | - Aiqin Lin
- Zhengzhou Railway Vocational and Technical College
| | - Rui Jiang
- Zhengzhou Railway Vocational and Technical College
| | | | - Chengyang Xu
- Henan Provincial People's Hospital, Zhengzhou, P.R. China
| | - Yuanyuan Hou
- Zhengzhou Railway Vocational and Technical College
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4
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Yang X, Xiong M, Fu X, Sun X. Bioactive materials for in vivo sweat gland regeneration. Bioact Mater 2024; 31:247-271. [PMID: 37637080 PMCID: PMC10457517 DOI: 10.1016/j.bioactmat.2023.07.025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Revised: 07/30/2023] [Accepted: 07/30/2023] [Indexed: 08/29/2023] Open
Abstract
Loss of sweat glands (SwGs) commonly associated with extensive skin defects is a leading cause of hyperthermia and heat stroke. In vivo tissue engineering possesses the potential to take use of the body natural ability to regenerate SwGs, making it more conducive to clinical translation. Despite recent advances in regenerative medicine, reconstructing SwG tissue with the same structure and function as native tissue remains challenging. Elucidating the SwG generation mechanism and developing biomaterials for in vivo tissue engineering is essential for understanding and developing in vivo SwG regenerative strategies. Here, we outline the cell biology associated with functional wound healing and the characteristics of bioactive materials. We critically summarize the recent progress in bioactive material-based cell modulation approaches for in vivo SwG regeneration, including the recruitment of endogenous cells to the skin lesion for SwG regeneration and in vivo cellular reprogramming for SwG regeneration. We discussed the re-establishment of microenvironment via bioactive material-mediated regulators. Besides, we offer promising perspectives for directing in situ SwG regeneration via bioactive material-based cell-free strategy, which is a simple and effective approach to regenerate SwG tissue with both fidelity of structure and function. Finally, we discuss the opportunities and challenges of in vivo SwG regeneration in detail. The molecular mechanisms and cell fate modulation of in vivo SwG regeneration will provide further insights into the regeneration of patient-specific SwGs and the development of potential intervention strategies for gland-derived diseases.
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Affiliation(s)
- Xinling Yang
- Research Center for Tissue Repair and Regeneration Affiliated to Medical Innovation Research Department and 4th Medical Center, PLA General Hospital and PLA Medical College, China
- PLA Key Laboratory of Tissue Repair and Regenerative Medicine and Beijing Key Research Laboratory of Skin Injury, Repair and Regeneration, China
- Research Unit of Trauma Care, Tissue Repair and Regeneration, Chinese Academy of Medical Sciences, 2019RU051, Beijing, 100048, PR China
| | - Mingchen Xiong
- Research Center for Tissue Repair and Regeneration Affiliated to Medical Innovation Research Department and 4th Medical Center, PLA General Hospital and PLA Medical College, China
- PLA Key Laboratory of Tissue Repair and Regenerative Medicine and Beijing Key Research Laboratory of Skin Injury, Repair and Regeneration, China
- Research Unit of Trauma Care, Tissue Repair and Regeneration, Chinese Academy of Medical Sciences, 2019RU051, Beijing, 100048, PR China
| | - Xiaobing Fu
- Research Center for Tissue Repair and Regeneration Affiliated to Medical Innovation Research Department and 4th Medical Center, PLA General Hospital and PLA Medical College, China
- PLA Key Laboratory of Tissue Repair and Regenerative Medicine and Beijing Key Research Laboratory of Skin Injury, Repair and Regeneration, China
- Research Unit of Trauma Care, Tissue Repair and Regeneration, Chinese Academy of Medical Sciences, 2019RU051, Beijing, 100048, PR China
| | - Xiaoyan Sun
- Research Center for Tissue Repair and Regeneration Affiliated to Medical Innovation Research Department and 4th Medical Center, PLA General Hospital and PLA Medical College, China
- PLA Key Laboratory of Tissue Repair and Regenerative Medicine and Beijing Key Research Laboratory of Skin Injury, Repair and Regeneration, China
- Research Unit of Trauma Care, Tissue Repair and Regeneration, Chinese Academy of Medical Sciences, 2019RU051, Beijing, 100048, PR China
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Chepeleva EV. Cell Therapy in the Treatment of Coronary Heart Disease. Int J Mol Sci 2023; 24:16844. [PMID: 38069167 PMCID: PMC10706847 DOI: 10.3390/ijms242316844] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 11/24/2023] [Accepted: 11/27/2023] [Indexed: 12/18/2023] Open
Abstract
Heart failure is a leading cause of death in patients who have suffered a myocardial infarction. Despite the timely use of modern reperfusion therapies such as thrombolysis, surgical revascularization and balloon angioplasty, they are sometimes unable to prevent the development of significant areas of myocardial damage and subsequent heart failure. Research efforts have focused on developing strategies to improve the functional status of myocardial injury areas. Consequently, the restoration of cardiac function using cell therapy is an exciting prospect. This review describes the characteristics of various cell types relevant to cellular cardiomyoplasty and presents findings from experimental and clinical studies investigating cell therapy for coronary heart disease. Cell delivery methods, optimal dosage and potential treatment mechanisms are discussed.
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Affiliation(s)
- Elena V. Chepeleva
- Federal State Budgetary Institution National Medical Research Center Named after Academician E.N. Meshalkin of the Ministry of Health of the Russian Federation, 15, Rechkunovskaya Str., 630055 Novosibirsk, Russia;
- Research Institute of Clinical and Experimental Lymphology—Branch of the Institute of Cytology and Genetics Siberian Branch of Russian Academy of Sciences, 2, Timakova Str., 630060 Novosibirsk, Russia
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Markina YV, Kirichenko TV, Tolstik TV, Bogatyreva AI, Zotova US, Cherednichenko VR, Postnov AY, Markin AM. Target and Cell Therapy for Atherosclerosis and CVD. Int J Mol Sci 2023; 24:10308. [PMID: 37373454 DOI: 10.3390/ijms241210308] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 06/06/2023] [Accepted: 06/16/2023] [Indexed: 06/29/2023] Open
Abstract
Cardiovascular diseases (CVD) and, in particular, atherosclerosis, remain the main cause of death in the world today. Unfortunately, in most cases, CVD therapy begins after the onset of clinical symptoms and is aimed at eliminating them. In this regard, early pathogenetic therapy for CVD remains an urgent problem in modern science and healthcare. Cell therapy, aimed at eliminating tissue damage underlying the pathogenesis of some pathologies, including CVD, by replacing it with various cells, is of the greatest interest. Currently, cell therapy is the most actively developed and potentially the most effective treatment strategy for CVD associated with atherosclerosis. However, this type of therapy has some limitations. In this review, we have tried to summarize the main targets of cell therapy for CVD and atherosclerosis in particular based on the analysis using the PubMed and Scopus databases up to May 2023.
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Affiliation(s)
- Yuliya V Markina
- Petrovsky National Research Center of Surgery, Moscow 119991, Russia
| | | | - Taisiya V Tolstik
- Petrovsky National Research Center of Surgery, Moscow 119991, Russia
| | | | - Ulyana S Zotova
- Petrovsky National Research Center of Surgery, Moscow 119991, Russia
| | | | - Anton Yu Postnov
- Petrovsky National Research Center of Surgery, Moscow 119991, Russia
| | - Alexander M Markin
- Petrovsky National Research Center of Surgery, Moscow 119991, Russia
- Peoples' Friendship University of Russia named after Patrice Lumumba (RUDN University), Moscow 117198, Russia
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Femminò S, Bonelli F, Brizzi MF. Extracellular vesicles in cardiac repair and regeneration: Beyond stem-cell-based approaches. Front Cell Dev Biol 2022; 10:996887. [PMID: 36120584 PMCID: PMC9479097 DOI: 10.3389/fcell.2022.996887] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Accepted: 08/16/2022] [Indexed: 11/13/2022] Open
Abstract
The adult human heart poorly regenerate after injury due to the low self-renewal capability retained by adult cardiomyocytes. In the last two decades, several clinical studies have reported the ability of stem cells to induce cardiac regeneration. However, low cell integration and survival into the tissue has limited stem-cell-based clinical approaches. More recently, the release of paracrine mediators including extracellular vesicles (EV) has been recognized as the most relevant mechanism driving benefits upon cell-based therapy. In particular, EV have emerged as key mediators of cardiac repair after damage, in terms of reduction of apoptosis, resolution of inflammation and new blood vessel formation. Herein, mechanisms involved in cardiac damage and regeneration, and current applications of EV and their small non-coding RNAs (miRNAs) in regenerative medicine are discussed.
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Omatsu-Kanbe M, Fukunaga R, Mi X, Matsuura H. Atypically Shaped Cardiomyocytes (ACMs): The Identification, Characterization and New Insights into a Subpopulation of Cardiomyocytes. Biomolecules 2022; 12:biom12070896. [PMID: 35883452 PMCID: PMC9313223 DOI: 10.3390/biom12070896] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 06/17/2022] [Accepted: 06/24/2022] [Indexed: 02/01/2023] Open
Abstract
In the adult mammalian heart, no data have yet shown the existence of cardiomyocyte-differentiable stem cells that can be used to practically repair the injured myocardium. Atypically shaped cardiomyocytes (ACMs) are found in cultures of the cardiomyocyte-removed fraction obtained from cardiac ventricles from neonatal to aged mice. ACMs are thought to be a subpopulation of cardiomyocytes or immature cardiomyocytes, most closely resembling cardiomyocytes due to their spontaneous beating, well-organized sarcomere and the expression of cardiac-specific proteins, including some fetal cardiac gene proteins. In this review, we focus on the characteristics of ACMs compared with ventricular myocytes and discuss whether these cells can be substitutes for damaged cardiomyocytes. ACMs reside in the interstitial spaces among ventricular myocytes and survive under severely hypoxic conditions fatal to ventricular myocytes. ACMs have not been observed to divide or proliferate, similar to cardiomyocytes, but they maintain their ability to fuse with each other. Thus, it is worthwhile to understand the role of ACMs and especially how these cells perform cell fusion or function independently in vivo. It may aid in the development of new approaches to cell therapy to protect the injured heart or the clarification of the pathogenesis underlying arrhythmia in the injured heart.
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In vitro CSC-derived cardiomyocytes exhibit the typical microRNA-mRNA blueprint of endogenous cardiomyocytes. Commun Biol 2021; 4:1146. [PMID: 34593953 PMCID: PMC8484596 DOI: 10.1038/s42003-021-02677-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 09/15/2021] [Indexed: 02/08/2023] Open
Abstract
miRNAs modulate cardiomyocyte specification by targeting mRNAs of cell cycle regulators and acting in cardiac muscle lineage gene regulatory loops. It is unknown if or to-what-extent these miRNA/mRNA networks are operative during cardiomyocyte differentiation of adult cardiac stem/progenitor cells (CSCs). Clonally-derived mouse CSCs differentiated into contracting cardiomyocytes in vitro (iCMs). Comparison of "CSCs vs. iCMs" mRNome and microRNome showed a balanced up-regulation of CM-related mRNAs together with a down-regulation of cell cycle and DNA replication mRNAs. The down-regulation of cell cycle genes and the up-regulation of the mature myofilament genes in iCMs reached intermediate levels between those of fetal and neonatal cardiomyocytes. Cardiomyo-miRs were up-regulated in iCMs. The specific networks of miRNA/mRNAs operative in iCMs closely resembled those of adult CMs (aCMs). miR-1 and miR-499 enhanced myogenic commitment toward terminal differentiation of iCMs. In conclusions, CSC specification/differentiation into contracting iCMs follows known cardiomyo-MiR-dependent developmental cardiomyocyte differentiation trajectories and iCMs transcriptome/miRNome resembles that of CMs.
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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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Arjmand B, Abedi M, Arabi M, Alavi-Moghadam S, Rezaei-Tavirani M, Hadavandkhani M, Tayanloo-Beik A, Kordi R, Roudsari PP, Larijani B. Regenerative Medicine for the Treatment of Ischemic Heart Disease; Status and Future Perspectives. Front Cell Dev Biol 2021; 9:704903. [PMID: 34568321 PMCID: PMC8461329 DOI: 10.3389/fcell.2021.704903] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Accepted: 07/19/2021] [Indexed: 12/20/2022] Open
Abstract
Cardiovascular disease is now the leading cause of adult death in the world. According to new estimates from the World Health Organization, myocardial infarction (MI) is responsible for four out of every five deaths due to cardiovascular disease. Conventional treatments of MI are taking aspirin and nitroglycerin as intermediate treatments and injecting antithrombotic agents within the first 3 h after MI. Coronary artery bypass grafting and percutaneous coronary intervention are the most common long term treatments. Since none of these interventions will fully regenerate the infarcted myocardium, there is value in pursuing more innovative therapeutic approaches. Regenerative medicine is an innovative interdisciplinary method for rebuilding, replacing, or repairing the missed part of different organs in the body, as similar as possible to the primary structure. In recent years, regenerative medicine has been widely utilized as a treatment for ischemic heart disease (one of the most fatal factors around the world) to repair the lost part of the heart by using stem cells. Here, the development of mesenchymal stem cells causes a breakthrough in the treatment of different cardiovascular diseases. They are easily obtainable from different sources, and expanded and enriched easily, with no need for immunosuppressing agents before transplantation, and fewer possibilities of genetic abnormality accompany them through multiple passages. The production of new cardiomyocytes can result from the transplantation of different types of stem cells. Accordingly, due to its remarkable benefits, stem cell therapy has received attention in recent years as it provides a drug-free and surgical treatment for patients and encourages a more safe and feasible cardiac repair. Although different clinical trials have reported on the promising benefits of stem cell therapy, there is still uncertainty about its mechanism of action. It is important to conduct different preclinical and clinical studies to explore the exact mechanism of action of the cells. After reviewing the pathophysiology of MI, this study addresses the role of tissue regeneration using various materials, including different types of stem cells. It proves some appropriate data about the importance of ethical problems, which leads to future perspectives on this scientific method.
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Affiliation(s)
- Babak Arjmand
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
- Metabolomics and Genomics Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Mina Abedi
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Maryam Arabi
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Sepideh Alavi-Moghadam
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Mahdieh Hadavandkhani
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Akram Tayanloo-Beik
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Ramin Kordi
- Sports Medicine Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Peyvand Parhizkar Roudsari
- Metabolomics and Genomics Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Bagher Larijani
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
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Bektik E, Fu JD. Production of Cardiomyocyte-Like Cells by Fibroblast Reprogramming with Defined Factors. Methods Mol Biol 2021; 2239:33-46. [PMID: 33226611 DOI: 10.1007/978-1-0716-1084-8_3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Over the last decade, great achievements have been made in the field of direct epigenetic reprogramming, which converts one type of adult somatic cells into another type of differentiated cells, such as direct reprogramming of fibroblasts into cardiomyocytes, without passage through an undifferentiated pluripotent stage. Discovery of direct cardiac reprogramming offers a promising therapeutic strategy to prevent/attenuate cardiac fibrotic remodeling in a diseased heart. Furthermore, in vitro reprogramming of fibroblasts into cardiomyocyte-like cells provides new avenues to conduct basic mechanistic studies, to test drugs, and to model cardiac diseases in a dish. Here, we describe a detailed step-by-step protocol for in vitro production of induced cardiomyocyte-like cells (iCMs) from fibroblasts. The related procedures include high-quality fibroblast isolation of different origins (neonatal cardiac, tail-tip, and adult cardiac fibroblasts), retroviral preparation of reprogramming factors, and iCM generation by fibroblast reprogramming via retroviral transduction of Gata4, Mef2c, and Tbx5. A detailed written protocol will help many other laboratories, inexperienced in this area, to use and further improve this technology in their studies of cardiac regenerative medicine.
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Affiliation(s)
- Emre Bektik
- The Dorothy M. Davis Heart and Lung Research Institute, Frick Center for Heart Failure and Arrhythmia, The Ohio State University Wexner Medical Center, Columbus, OH, USA.,Department of Physiology and Cell Biology, The Ohio State University, Columbus, OH, USA
| | - Ji-Dong Fu
- The Dorothy M. Davis Heart and Lung Research Institute, Frick Center for Heart Failure and Arrhythmia, The Ohio State University Wexner Medical Center, Columbus, OH, USA. .,Department of Physiology and Cell Biology, The Ohio State University, Columbus, OH, USA.
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Cianflone E, Cappetta D, Mancuso T, Sabatino J, Marino F, Scalise M, Albanese M, Salatino A, Parrotta EI, Cuda G, De Angelis A, Berrino L, Rossi F, Nadal-Ginard B, Torella D, Urbanek K. Statins Stimulate New Myocyte Formation After Myocardial Infarction by Activating Growth and Differentiation of the Endogenous Cardiac Stem Cells. Int J Mol Sci 2020; 21:ijms21217927. [PMID: 33114544 PMCID: PMC7663580 DOI: 10.3390/ijms21217927] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Revised: 10/21/2020] [Accepted: 10/22/2020] [Indexed: 12/20/2022] Open
Abstract
The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) exert pleiotropic effects on cardiac cell biology which are not yet fully understood. Here we tested whether statin treatment affects resident endogenous cardiac stem/progenitor cell (CSC) activation in vitro and in vivo after myocardial infarction (MI). Statins (Rosuvastatin, Simvastatin and Pravastatin) significantly increased CSC expansion in vitro as measured by both BrdU incorporation and cell growth curve. Additionally, statins increased CSC clonal expansion and cardiosphere formation. The effects of statins on CSC growth and differentiation depended on Akt phosphorylation. Twenty-eight days after myocardial infarction by permanent coronary ligation in rats, the number of endogenous CSCs in the infarct border zone was significantly increased by Rosuvastatin-treatment as compared to untreated controls. Additionally, commitment of the activated CSCs into the myogenic lineage (c-kitpos/Gata4pos CSCs) was increased by Rosuvastatin administration. Accordingly, Rosuvastatin fostered new cardiomyocyte formation after MI. Finally, Rosuvastatin treatment reversed the cardiomyogenic defects of CSCs in c-kit haploinsufficient mice, increasing new cardiomyocyte formation by endogenous CSCs in these mice after myocardial infarction. In summary, statins, by sustaining Akt activation, foster CSC growth and differentiation in vitro and in vivo. The activation and differentiation of the endogenous CSC pool and consequent new myocyte formation by statins improve myocardial remodeling after coronary occlusion in rodents. Similar effects might contribute to the beneficial effects of statins on human cardiovascular diseases.
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Affiliation(s)
- Eleonora Cianflone
- Department of Medical and Surgical Sciences, Magna Graecia University, 88100 Catanzaro, Italy; (E.C.); (J.S.); (M.A.); (E.I.P.); (B.N.-G.)
| | - Donato Cappetta
- Department of Experimental Medicine, University of Campania “L. Vanvitelli”, 80138 Naples, Italy; (D.C.); (A.D.A.); (L.B.); (F.R.)
| | - Teresa Mancuso
- Department of Experimental and Clinical Medicine, Magna Graecia University, 88100 Catanzaro, Italy; (T.M.); (F.M.); (M.S.); (A.S.); (G.C.)
| | - Jolanda Sabatino
- Department of Medical and Surgical Sciences, Magna Graecia University, 88100 Catanzaro, Italy; (E.C.); (J.S.); (M.A.); (E.I.P.); (B.N.-G.)
| | - Fabiola Marino
- Department of Experimental and Clinical Medicine, Magna Graecia University, 88100 Catanzaro, Italy; (T.M.); (F.M.); (M.S.); (A.S.); (G.C.)
| | - Mariangela Scalise
- Department of Experimental and Clinical Medicine, Magna Graecia University, 88100 Catanzaro, Italy; (T.M.); (F.M.); (M.S.); (A.S.); (G.C.)
| | - Michele Albanese
- Department of Medical and Surgical Sciences, Magna Graecia University, 88100 Catanzaro, Italy; (E.C.); (J.S.); (M.A.); (E.I.P.); (B.N.-G.)
| | - Alessandro Salatino
- Department of Experimental and Clinical Medicine, Magna Graecia University, 88100 Catanzaro, Italy; (T.M.); (F.M.); (M.S.); (A.S.); (G.C.)
| | - Elvira Immacolata Parrotta
- Department of Medical and Surgical Sciences, Magna Graecia University, 88100 Catanzaro, Italy; (E.C.); (J.S.); (M.A.); (E.I.P.); (B.N.-G.)
| | - Giovanni Cuda
- Department of Experimental and Clinical Medicine, Magna Graecia University, 88100 Catanzaro, Italy; (T.M.); (F.M.); (M.S.); (A.S.); (G.C.)
| | - Antonella De Angelis
- Department of Experimental Medicine, University of Campania “L. Vanvitelli”, 80138 Naples, Italy; (D.C.); (A.D.A.); (L.B.); (F.R.)
| | - Liberato Berrino
- Department of Experimental Medicine, University of Campania “L. Vanvitelli”, 80138 Naples, Italy; (D.C.); (A.D.A.); (L.B.); (F.R.)
| | - Francesco Rossi
- Department of Experimental Medicine, University of Campania “L. Vanvitelli”, 80138 Naples, Italy; (D.C.); (A.D.A.); (L.B.); (F.R.)
| | - Bernardo Nadal-Ginard
- Department of Medical and Surgical Sciences, Magna Graecia University, 88100 Catanzaro, Italy; (E.C.); (J.S.); (M.A.); (E.I.P.); (B.N.-G.)
| | - Daniele Torella
- Department of Experimental and Clinical Medicine, Magna Graecia University, 88100 Catanzaro, Italy; (T.M.); (F.M.); (M.S.); (A.S.); (G.C.)
- Correspondence: (D.T.); (K.U.)
| | - Konrad Urbanek
- Department of Experimental and Clinical Medicine, Magna Graecia University, 88100 Catanzaro, Italy; (T.M.); (F.M.); (M.S.); (A.S.); (G.C.)
- Correspondence: (D.T.); (K.U.)
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14
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White SJ, Chong JJH. Mesenchymal Stem Cells in Cardiac Repair: Effects on Myocytes, Vasculature, and Fibroblasts. Clin Ther 2020; 42:1880-1891. [PMID: 32938532 DOI: 10.1016/j.clinthera.2020.08.010] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Revised: 08/09/2020] [Accepted: 08/17/2020] [Indexed: 12/31/2022]
Abstract
PURPOSE Cardiac pathologies remain a dominant cause of morbidity and mortality within the community. The drive to develop therapies capable of repairing damaged heart tissue to achieve clinically significant restoration of function has motivated the pursuit of novel approaches such as cell therapy. To this end, evidence of therapeutic benefits achieved by using mesenchymal stem cells (MSCs) has captured considerable interest despite a relative lack of information regarding the mechanisms involved. This narrative review synthesizes and interprets the current literature describing mechanisms by which MSCs can elicit cardiac repair, thereby directing attention to avenues of further inquiry. METHODS OVID versions of MEDLINE and EMBASE were searched for studies describing the role of MSCs in mammalian cardiac repair. Additional studies were sourced from the reference lists of relevant articles and other personal files. FINDINGS MSCs elicit cardiac repair in a range of in vitro systems and animal models of diseases such as myocardial infarction and heart failure. Important mechanisms include the preservation of myocardial contractility, the promotion of angiogenesis, and the modulation of fibrosis. Exposing in vitro MSCs to a microenvironment reflective of that encountered in the injured heart seems to potentiate these therapeutic mechanisms. IMPLICATIONS Promising results in animal studies warrant continuation of clinical MSC cardiac therapy studies. Paracrine functions of MSCs seem to be the dominant mechanism of cardiac repair over direct cellular effects. Although integral, the MSC secretome remains poorly defined. In addition, most of the mechanistic data within the literature have been derived from animal MSC research, necessitating more human MSC-based work.
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Affiliation(s)
- Samuel J White
- Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Camperdown, New South Wales, Australia
| | - James J H Chong
- Centre for Heart Research, Westmead Institute for Medical Research, The University of Sydney, Westmead, New South Wales, Australia; Department of Cardiology, Westmead Hospital, Westmead, New South Wales, Australia.
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15
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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: 92] [Impact Index Per Article: 18.4] [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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16
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Fathi E, Valipour B, Vietor I, Farahzadi R. An overview of the myocardial regeneration potential of cardiac c-Kit + progenitor cells via PI3K and MAPK signaling pathways. Future Cardiol 2020; 16:199-209. [PMID: 32125173 DOI: 10.2217/fca-2018-0049] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
In recent years, several studies have investigated cell transplantation as an innovative strategy to restore cardiac function following heart failure. Previous studies have also shown cardiac progenitor cells as suitable candidates for cardiac cell therapy compared with other stem cells. Cellular kit (c-kit) plays an important role in the survival and migration of cardiac progenitor cells. Like other types of cells, in the heart, cellular responses to various stimuli are mediated via coordinated pathways. Activation of c-kit+ cells leads to subsequent activation of several downstream mediators such as PI3K and the MAPK pathways. This review aims to outline current research findings on the role of PI3K/AKT and the MAPK pathways in myocardial regeneration potential of c-kit+.
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Affiliation(s)
- Ezzatollah Fathi
- Department of Clinical Sciences, Faculty of Veterinary Medicine, University of Tabriz, Tabriz, Iran
| | - Behnaz Valipour
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ilja Vietor
- Division of Cell Biology, Biocenter, Medical University Innsbruck, Innrain 80-82, A-6020, Innsbruck, Austria
| | - Raheleh Farahzadi
- Cardiovascular Research Center, Tabriz University of Medical Sciences, Tabriz 5166616471, Iran.,Hematology & Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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17
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Liu Z, Mikrani R, Zubair HM, Taleb A, Naveed M, Baig MMFA, Zhang Q, Li C, Habib M, Cui X, Sembatya KR, Lei H, Zhou X. Systemic and local delivery of mesenchymal stem cells for heart renovation: Challenges and innovations. Eur J Pharmacol 2020; 876:173049. [PMID: 32142771 DOI: 10.1016/j.ejphar.2020.173049] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Revised: 02/20/2020] [Accepted: 02/27/2020] [Indexed: 02/07/2023]
Abstract
In the beginning stage of heart disease, the blockage of blood flow frequently occurs due to the persistent damage and even death of myocardium. Cicatricial tissue developed after the death of myocardium can affect heart function, which ultimately leads to heart failure. In recent years, several studies carried out about the use of stem cells such as embryonic, pluripotent, cardiac and bone marrow-derived stem cells as well as myoblasts to repair injured myocardium. Current studies focus more on finding appropriate measures to enhance cell homing and survival in order to increase paracrine function. Until now, there is no universal delivery route for mesenchymal stem cells (MSCs) for different diseases. In this review, we summarize the advantages and challenges of the systemic and local pathways of MSC delivery. In addition, we also describe some advanced measures of cell delivery to improve the efficiency of transplantation. The combination of cells and therapeutic substances could be the most reliable method, which allows donor cells to deliver sufficient amounts of paracrine factors and provide long-lasting effects. The cardiac support devices or tissue engineering techniques have the potential to facilitate the controlled release of stem cells on local tissue for a sustained period. A novel promising epicardial drug delivery system is highlighted here, which not only provides MSCs with a favorable environment to promote retention but also increases the contact area and a number of cells recruited in the heart muscle.
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Affiliation(s)
- Ziwei Liu
- Department of Clinical Pharmacy, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu Province, 211198, PR China
| | - Reyaj Mikrani
- Department of Clinical Pharmacy, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu Province, 211198, PR China
| | | | - Abdoh Taleb
- School of Pharmacy, Nanjing Medical University, Nanjing, Jiangsu, 211166, PR China
| | - Muhammad Naveed
- School of Pharmacy, Nanjing Medical University, Nanjing, Jiangsu, 211166, PR China
| | - Mirza Muhammad Faran Asraf Baig
- State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, Jiangsu, 210023, PR China
| | - Qin Zhang
- Department of Clinical Pharmacy, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu Province, 211198, PR China
| | - Cuican Li
- Department of Clinical Pharmacy, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu Province, 211198, PR China
| | - Murad Habib
- Department of Surgery, Ayub Teaching Hospital, Abbottabad, Pakistan
| | - Xingxing Cui
- Department of Clinical Pharmacy, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu Province, 211198, PR China
| | - Kiganda Raymond Sembatya
- Department of Clinical Pharmacy, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu Province, 211198, PR China
| | - Han Lei
- Department of Pharmacy, Jiangsu Worker Medical University, Nanjing, Jiangsu Province, 211198, PR China
| | - Xiaohui Zhou
- Department of Clinical Pharmacy, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu Province, 211198, PR China; Department of Surgery, Zhongda Hospital Affiliated to Southeast University, Nanjing, Jiangsu Province, 210017, PR China; Department of Surgery, Nanjing Shuiximen Hospital, Nanjing, Jiangsu Province, 210017, PR China.
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18
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Gorabi AM, Bianconi V, Pirro M, Banach M, Sahebkar A. Regulation of cardiac stem cells by microRNAs: State-of-the-art. Biomed Pharmacother 2019; 120:109447. [PMID: 31580971 DOI: 10.1016/j.biopha.2019.109447] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Revised: 09/05/2019] [Accepted: 09/06/2019] [Indexed: 12/27/2022] Open
Abstract
Stem cells have a therapeutic potential in various medical conditions. In cases without sufficient response to conventional drug treatments, stem cells represent a next generation therapeutic strategy in cardiovascular diseases. Cardiac stem cells (CSCs), among a wide variety of stem cell sources, have been identified as a valid option for stem cell-based therapy in cardiovascular diseases. CSCs mainly act as a cell source to supply the physiological need for cardiovascular cells. However, they have been demonstrated to reproduce the myocardial cells under pathological settings. Despite their roles and functions have somewhat been clarified, molecular pathways underlying the regulatory mechanisms of CSCs are still not fully elucidated. Several studies have recently shown that different microRNAs (miRNAs) play a substantial role in regulating and controlling both the physiological and pathological proliferation and differentiation of stem cells. MiRNAs are small non-coding RNA molecules that regulate gene expression and may undergo aberrant expression levels during pathological conditions. Understanding the way through which miRNAs regulate CSC behavior may open up new horizons in modulating these cells in vitro to devise sophisticated approaches for treating patients with cardiovascular diseases. In this review article, we tried to discuss available evidence about the role of miRNAs in regulating CSCs.
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Affiliation(s)
- Armita Mahdavi Gorabi
- Research Center for Advanced Technologies in Cardiovascular Medicine, Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Vanessa Bianconi
- Unit of Internal Medicine, Angiology and Arteriosclerosis Diseases, Department of Medicine, University of Perugia, Perugia, Italy
| | - Matteo Pirro
- Unit of Internal Medicine, Angiology and Arteriosclerosis Diseases, Department of Medicine, University of Perugia, Perugia, Italy
| | - Maciej Banach
- Department of Hypertension, WAM University Hospital in Lodz, Medical University of Lodz, Zeromskiego 113, Lodz, Poland; Polish Mother's Memorial Hospital Research Institute (PMMHRI), Lodz, Poland
| | - Amirhossein Sahebkar
- Halal Research Center of IRI, FDA, Tehran, Iran; Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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19
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Zamani P, Fereydouni N, Butler AE, Navashenaq JG, Sahebkar A. The therapeutic and diagnostic role of exosomes in cardiovascular diseases. Trends Cardiovasc Med 2019; 29:313-323. [PMID: 30385010 DOI: 10.1016/j.tcm.2018.10.010] [Citation(s) in RCA: 115] [Impact Index Per Article: 19.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2018] [Revised: 10/17/2018] [Accepted: 10/17/2018] [Indexed: 12/20/2022]
Abstract
Exosomes are nano-sized membranous vesicles that are secreted by cells. They have an important role in transferring proteins, mRNA, miRNA and other bioactive molecules between cells and regulate gene expression in recipient cells. Therefore, exosomes are a mechanism by which communication between cells is achieved and they are involved in a wide range of physiological processes, especially those requiring cell-cell communication. In the cardiovascular system, exosomes are associated with endothelial cells, cardiac myocytes, vascular cells, stem and progenitor cells, and play an essential role in development, injury and disease of the cardiovascular system. In recent years, accumulating evidence implicates exosomes in the development and progression of cardiovascular disease. Additionally, exosomal microRNAs are considered to be key players in cardiac regeneration and confer cardioprotective and regenerative properties on both cardiac and non-cardiac cells and, additionally, stem and progenitor cells. Notably, miRNAs may be isolated from blood and offer a potential source of novel diagnostic and prognostic biomarkers for cardiovascular disease. In this review, we summarize and assess the functional roles of exosomes in cardiovascular physiology, cell-to-cell communication and cardio-protective effects in cardiovascular disease.
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Affiliation(s)
- Parvin Zamani
- Nanotechnology Research Center, Student Research Committee, Department of Medical biotechnology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Narges Fereydouni
- Student Research Committee, Department of Modern Sciences and Technologies, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Alexandra E Butler
- Diabetes Research Center, Qatar Biomedical Research Institute, Doha, Qatar
| | | | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
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20
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Ameliorating the Fibrotic Remodeling of the Heart through Direct Cardiac Reprogramming. Cells 2019; 8:cells8070679. [PMID: 31277520 PMCID: PMC6679082 DOI: 10.3390/cells8070679] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2019] [Revised: 06/21/2019] [Accepted: 06/23/2019] [Indexed: 12/20/2022] Open
Abstract
Coronary artery disease is the most common form of cardiovascular diseases, resulting in the loss of cardiomyocytes (CM) at the site of ischemic injury. To compensate for the loss of CMs, cardiac fibroblasts quickly respond to injury and initiate cardiac remodeling in an injured heart. In the remodeling process, cardiac fibroblasts proliferate and differentiate into myofibroblasts, which secrete extracellular matrix to support the intact structure of the heart, and eventually differentiate into matrifibrocytes to form chronic scar tissue. Discovery of direct cardiac reprogramming offers a promising therapeutic strategy to prevent/attenuate this pathologic remodeling and replace the cardiac fibrotic scar with myocardium in situ. Since the first discovery in 2010, many progresses have been made to improve the efficiency and efficacy of reprogramming by understanding the mechanisms and signaling pathways that are activated during direct cardiac reprogramming. Here, we overview the development and recent progresses of direct cardiac reprogramming and discuss future directions in order to translate this promising technology into an effective therapeutic paradigm to reverse cardiac pathological remodeling in an injured heart.
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21
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Hameed A, Gallagher LB, Dolan E, O’Sullivan J, Ruiz-Hernandez E, Duffy GP, Kelly H. Insulin-like growth factor-1 (IGF-1) poly (lactic-co-glycolic acid) (PLGA) microparticles – development, characterisation, and in vitro assessment of bioactivity for cardiac applications. J Microencapsul 2019; 36:267-277. [DOI: 10.1080/02652048.2019.1622605] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Affiliation(s)
- Aamir Hameed
- Tissue Engineering Research Group (TERG), Department of Anatomy, Royal College of Surgeons in Ireland (RSCI), Dublin, Ireland
- Trinity Centre for Bioengineering (TCBE), Trinity College Dublin (TCD), Dublin, Ireland
| | - Laura B. Gallagher
- Tissue Engineering Research Group (TERG), Department of Anatomy, Royal College of Surgeons in Ireland (RSCI), Dublin, Ireland
- School of Pharmacy, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Eimear Dolan
- Department of Biomedical Engineering, College of Engineering and Informatics, National University of Ireland Galway, Galway, Ireland
| | - Janice O’Sullivan
- Tissue Engineering Research Group (TERG), Department of Anatomy, Royal College of Surgeons in Ireland (RSCI), Dublin, Ireland
- Department of Anatomy, School of Medicine, College of Medicine, Nursing and Health Science, National University of Ireland Galway, Galway, Ireland
| | - Eduardo Ruiz-Hernandez
- School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin (TCD), Dublin, Ireland
| | - Garry P. Duffy
- Tissue Engineering Research Group (TERG), Department of Anatomy, Royal College of Surgeons in Ireland (RSCI), Dublin, Ireland
- Trinity Centre for Bioengineering (TCBE), Trinity College Dublin (TCD), Dublin, Ireland
- Department of Anatomy, School of Medicine, College of Medicine, Nursing and Health Science, National University of Ireland Galway, Galway, Ireland
- Advanced Materials for Biomedical Engineering and Regenerative Medicine (AMBER), Trinity College Dublin (TCD), Dublin, Ireland
| | - Helena Kelly
- Tissue Engineering Research Group (TERG), Department of Anatomy, Royal College of Surgeons in Ireland (RSCI), Dublin, Ireland
- School of Pharmacy, Royal College of Surgeons in Ireland, Dublin, Ireland
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22
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Abstract
Non-communicable diseases, such as cardiovascular diseases, are the leading cause of mortality worldwide. For this reason, a tremendous effort is being made worldwide to effectively circumvent these afflictions, where insulin-like growth factor 1 (IGF1) is being proposed both as a marker and as a central cornerstone in these diseases, making it an interesting molecule to focus on. Firstly, at the initiation of metabolic deregulation by overfeeding, IGF1 is decreased/inhibited. Secondly, such deficiency seems to be intimately related to the onset of MetS and establishment of vascular derangements leading to atherosclerosis and finally playing a definitive part in cerebrovascular and myocardial accidents, where IGF1 deficiency seems to render these organs vulnerable to oxidative and apoptotic/necrotic damage. Several human cohort correlations together with basic/translational experimental data seem to confirm deep IGF1 implication, albeit with controversy, which might, in part, be given by experimental design leading to blurred result interpretation.
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23
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Malandraki-Miller S, Lopez CA, Alonaizan R, Purnama U, Perbellini F, Pakzad K, Carr CA. Metabolic flux analyses to assess the differentiation of adult cardiac progenitors after fatty acid supplementation. Stem Cell Res 2019; 38:101458. [PMID: 31102832 PMCID: PMC6618003 DOI: 10.1016/j.scr.2019.101458] [Citation(s) in RCA: 13] [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: 09/21/2018] [Revised: 04/11/2019] [Accepted: 05/06/2019] [Indexed: 12/13/2022] Open
Abstract
Myocardial infarction is the most prevalent of cardiovascular diseases and pharmacological interventions do not lead to restoration of the lost cardiomyocytes. Despite extensive stem cell therapy studies, clinical trials using cardiac progenitor cells have shown moderate results. Furthermore, differentiation of endogenous progenitors to mature cardiomyocytes is rarely reported. A metabolic switch from glucose to fatty acid oxidation occurs during cardiac development and cardiomyocyte maturation, however in vitro differentiation protocols do not consider the lack of fatty acids in cell culture media. The aim of this study was to assess the effect of this metabolic switch on control and differentiated adult cardiac progenitors, by fatty acid supplementation. Addition of oleic acid stimulated the peroxisome proliferator-activated receptor alpha pathway and led to maturation of the cardiac progenitors, both before and after transforming growth factor-beta 1 differentiation. Addition of oleic acid following differentiation increased expression of myosin heavy chain 7 and connexin 43. Also, total glycolytic metabolism increased, as did mitochondrial membrane potential and glucose and fatty acid transporter expression. This work provides new insights into the importance of fatty acids, and of peroxisome proliferator-activated receptor alpha, in cardiac progenitor differentiation. Harnessing the oxidative metabolic switch induced maturation of differentiated endogenous stem cells. (200 words).
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Affiliation(s)
- Sophia Malandraki-Miller
- Department of Physiology, Anatomy, and Genetics,Sherrington Building, University of Oxford, Oxford, UK.
| | - Colleen A Lopez
- Department of Physiology, Anatomy, and Genetics,Sherrington Building, University of Oxford, Oxford, UK.
| | - Rita Alonaizan
- Department of Physiology, Anatomy, and Genetics,Sherrington Building, University of Oxford, Oxford, UK.
| | - Ujang Purnama
- Department of Physiology, Anatomy, and Genetics,Sherrington Building, University of Oxford, Oxford, UK.
| | - Filippo Perbellini
- National Heart and Lung Institute, Imperial College London, London, W12 0NN, UK.
| | - Kathy Pakzad
- Department of Physiology, Anatomy, and Genetics,Sherrington Building, University of Oxford, Oxford, UK.
| | - Carolyn A Carr
- Department of Physiology, Anatomy, and Genetics,Sherrington Building, University of Oxford, Oxford, UK.
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24
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Gugjoo MB, Amarpal A, Sharma GT. Mesenchymal stem cell basic research and applications in dog medicine. J Cell Physiol 2019; 234:16779-16811. [PMID: 30790282 DOI: 10.1002/jcp.28348] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2018] [Revised: 01/25/2019] [Accepted: 01/28/2019] [Indexed: 12/13/2022]
Abstract
The stem cells, owing to their special characteristics like self-renewal, multiplication, homing, immunomodulation, anti-inflammatory, and dedifferentiation are considered to carry an "all-in-one-solution" for diverse clinical problems. However, the limited understanding of cellular physiology currently limits their definitive therapeutic use. Among various stem cell types, currently mesenchymal stem cells are extensively studied for dog clinical applications owing to their readily available sources, easy harvesting, and ability to differentiate both into mesodermal, as well as extramesodermal tissues. The isolated, culture expanded, and characterized cells have been applied both at preclinical as well as clinical settings in dogs with variable but mostly positive results. The results, though positive, are currently inconclusive and demands further intensive research on the properties and their dependence on the applications. Further, numerous clinical conditions of dog resemble to that of human counterparts and thus, if proved rewarding in the former may act as basis of therapy for the latter. The current review throws some light on dog mesenchymal stem cell properties and their potential therapeutic applications.
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Affiliation(s)
- Mudasir Bashir Gugjoo
- Division of Veterinary Clinical Complex, Faculty of Veterinary Sciences and Animal Husbandry, SKUAST-K, Jammu and Kashmir, India
| | - Amarpal Amarpal
- Division of Surgery, Indian Veterinary Research Institute, Izatnagar, India
| | - Gutulla Taru Sharma
- Division of Physiology and Climatology, Indian Veterinary Research Institute, Izatnagar, India
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25
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Regenerating the field of cardiovascular cell therapy. Nat Biotechnol 2019; 37:232-237. [PMID: 30778231 DOI: 10.1038/s41587-019-0042-1] [Citation(s) in RCA: 107] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Accepted: 01/18/2019] [Indexed: 01/11/2023]
Abstract
The retraction of >30 falsified studies by Anversa et al. has had a disheartening impact on the cardiac cell therapeutics field. The premise of heart muscle regeneration by the transdifferentiation of bone marrow cells or putative adult resident cardiac progenitors has been largely disproven. Over the past 18 years, a generation of physicians and scientists has lost years chasing these studies, and patients have been placed at risk with little scientific grounding. Funding agencies invested hundreds of millions of dollars in irreproducible work, and both academic institutions and the scientific community ignored troubling signals over a decade of questionable work. Our collective retrospective analysis identifies preventable problems at the level of the editorial and peer-review process, funding agencies and academic institutions. This Perspective provides a chronology of the forces that led to this scientific debacle, integrating direct knowledge of the process. We suggest a science-driven path forward that includes multiple novel approaches to the problem of heart muscle regeneration.
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26
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Scalise M, Marino F, Cianflone E, Mancuso T, Marotta P, Aquila I, Torella M, Nadal-Ginard B, Torella D. Heterogeneity of Adult Cardiac Stem Cells. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1169:141-178. [PMID: 31487023 DOI: 10.1007/978-3-030-24108-7_8] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Cardiac biology and heart regeneration have been intensively investigated and debated in the last 15 years. Nowadays, the well-established and old dogma that the adult heart lacks of any myocyte-regenerative capacity has been firmly overturned by the evidence of cardiomyocyte renewal throughout the mammalian life as part of normal organ cell homeostasis, which is increased in response to injury. Concurrently, reproducible evidences from independent laboratories have convincingly shown that the adult heart possesses a pool of multipotent cardiac stem/progenitor cells (CSCs or CPCs) capable of sustaining cardiomyocyte and vascular tissue refreshment after injury. CSC transplantation in animal models displays an effective regenerative potential and may be helpful to treat chronic heart failure (CHF), obviating at the poor/modest results using non-cardiac cells in clinical trials. Nevertheless, the degree/significance of cardiomyocyte turnover in the adult heart, which is insufficient to regenerate extensive damage from ischemic and non-ischemic origin, remains strongly disputed. Concurrently, different methodologies used to detect CSCs in situ have created the paradox of the adult heart harboring more than seven different cardiac progenitor populations. The latter was likely secondary to the intrinsic heterogeneity of any regenerative cell agent in an adult tissue but also to the confusion created by the heterogeneity of the cell population identified by a single cell marker used to detect the CSCs in situ. On the other hand, some recent studies using genetic fate mapping strategies claimed that CSCs are an irrelevant endogenous source of new cardiomyocytes in the adult. On the basis of these contradictory findings, here we critically reviewed the available data on adult CSC biology and their role in myocardial cell homeostasis and repair.
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Affiliation(s)
- Mariangela Scalise
- Molecular and Cellular Cardiology Laboratory, Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro, Italy
| | - Fabiola Marino
- Molecular and Cellular Cardiology Laboratory, Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro, Italy
| | - Eleonora Cianflone
- Molecular and Cellular Cardiology Laboratory, Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro, Italy
| | - Teresa Mancuso
- Molecular and Cellular Cardiology Laboratory, Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro, Italy
| | - Pina Marotta
- Molecular and Cellular Cardiology Laboratory, Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro, Italy
| | - Iolanda Aquila
- Molecular and Cellular Cardiology Laboratory, Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro, Italy
| | - Michele Torella
- Department of Cardiothoracic Surgery, University of Campania "L.Vanvitelli", Naples, Italy
| | - Bernardo Nadal-Ginard
- Molecular and Cellular Cardiology Laboratory, Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro, Italy
| | - Daniele Torella
- Molecular and Cellular Cardiology Laboratory, Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro, Italy.
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27
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Dergilev KV, Zubkova ЕS, Beloglazova IB, Menshikov МY, Parfyonova ЕV. Notch signal pathway - therapeutic target for regulation of reparative processes in the heart. TERAPEVT ARKH 2018; 90:112-121. [PMID: 30701843 DOI: 10.26442/00403660.2018.12.000014] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Notch signaling pathway is a universal regulator of cell fate in embryogenesis and in maintaining the cell homeostasis of adult tissue. Through local cell-cell interactions, he controls neighboring cells behavior and determines their capacity for self-renewal, growth, survival, differentiation, and apoptosis. Recent studies have shown that the control of regenerative processes in the heart is also carried out with the participation of Notch system. At the heart of Notch regulates migration bone marrow progenitors and stimulates the proliferation of cardiomyocytes, cardiac progenitor cell activity, limits cardiomyocyte hypertrophy and fibrosis progression and stimulates angiogenesis. Notch signaling pathway may be regarded as a very promising target for the development of drugs for the stimulation of regeneration in the myocardium.
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Affiliation(s)
- K V Dergilev
- National Medical Research Center for Cardiology of the Ministry of Health of the Russian Federation, Moscow, Russia
| | - Е S Zubkova
- National Medical Research Center for Cardiology of the Ministry of Health of the Russian Federation, Moscow, Russia
| | - I B Beloglazova
- National Medical Research Center for Cardiology of the Ministry of Health of the Russian Federation, Moscow, Russia
| | - М Yu Menshikov
- National Medical Research Center for Cardiology of the Ministry of Health of the Russian Federation, Moscow, Russia
| | - Е V Parfyonova
- National Medical Research Center for Cardiology of the Ministry of Health of the Russian Federation, Moscow, Russia.,M.V. Lomonosov Moscow State University, Moscow, Russia
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28
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Alpinate Oxyphyllae
extracts enhance the longevity and homing of mesenchymal stem cells and augment their protection against senescence in H9c2 cells. J Cell Physiol 2018; 234:12042-12050. [DOI: 10.1002/jcp.27867] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2018] [Accepted: 11/13/2018] [Indexed: 12/19/2022]
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29
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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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30
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Bollini S, Smits AM, Balbi C, Lazzarini E, Ameri P. Triggering Endogenous Cardiac Repair and Regeneration via Extracellular Vesicle-Mediated Communication. Front Physiol 2018; 9:1497. [PMID: 30405446 PMCID: PMC6206049 DOI: 10.3389/fphys.2018.01497] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2018] [Accepted: 10/03/2018] [Indexed: 12/15/2022] Open
Abstract
A variety of paracrine signals create networks within the myocardium and mediate intercellular communications. Indeed, paracrine stimulation of the endogenous regenerative program of the heart, mainly based on resident cardiac progenitor cell (CPC) activation together with cardiomyocyte proliferation, has become increasingly relevant for future cardiac medicine. In the last years, it has been shown that extracellular vesicles (EV), including exosomes (Ex), are powerful conveyors of relevant biological effects. EV have been proposed not only as promising therapeutic tool for triggering cardiac regeneration and improving repair, but also as means of better understanding the physiological and pathological relationships between specific cardiac components, including cardiomyocytes and fibroblasts. Actually, EV from different kinds of exogenous stem cells have been shown to mediate beneficial effects on the injured myocardium. Moreover, endogenous cells, like CPC can instruct cardiovascular cell types, including cardiomyocytes, while cardiac stromal cells, especially fibroblasts, secrete EV that modulate relevant aspects of cardiomyocyte biology, such as hypertrophy and electrophysiological properties. Finally, cardiomyocytes too may release EV influencing the function of other cardiac cell types. Therefore, EV-based crosstalk is thought to be important in both physiology and pathology, being involved in the responses of the heart to noxious stimuli. In this review we will discuss the role of EV in both regulating cardiac homeostasis and driving heart regeneration. In particular, we will address their role in: (i) providing cardio-protection and enhancing cardiac repair mechanisms; (ii) CPC biology; and (iii) influencing adult cardiomyocyte behavior.
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Affiliation(s)
- Sveva Bollini
- Regenerative Medicine Laboratory, Department of Experimental Medicine, University of Genova, Genoa, Italy
| | - Anke M Smits
- Laboratory of Cardiovascular Cell Biology, Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, Netherlands
| | - Carolina Balbi
- Laboratory of Molecular and Cellular Cardiology, CardioCentro Ticino, Lugano, Switzerland
| | - Edoardo Lazzarini
- Laboratory of Cardiovascular Biology, Department of Internal Medicine, University of Genova, Genoa, Italy
| | - Pietro Ameri
- Laboratory of Cardiovascular Biology, Department of Internal Medicine, University of Genova, Genoa, Italy.,Cardiovascular Disease Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
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31
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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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32
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Jara Avaca M, Gruh I. Bioengineered Cardiac Tissue Based on Human Stem Cells for Clinical Application. ADVANCES IN BIOCHEMICAL ENGINEERING/BIOTECHNOLOGY 2018; 163:117-146. [PMID: 29218360 DOI: 10.1007/10_2017_24] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Engineered cardiac tissue might enable novel therapeutic strategies for the human heart in a number of acquired and congenital diseases. With recent advances in stem cell technologies, namely the availability of pluripotent stem cells, the generation of potentially autologous tissue grafts has become a realistic option. Nevertheless, a number of limitations still have to be addressed before clinical application of engineered cardiac tissue based on human stem cells can be realized. We summarize current progress and pending challenges regarding the optimal cell source, cardiomyogenic lineage specification, purification, safety of genetic cell engineering, and genomic stability. Cardiac cells should be combined with clinical grade scaffold materials for generation of functional myocardial tissue in vitro. Scale-up to clinically relevant dimensions is mandatory, and tissue vascularization is most probably required both for preclinical in vivo testing in suitable large animal models and for clinical application. Graphical Abstract.
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Affiliation(s)
- Monica Jara Avaca
- Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Department for Cardiothoracic, Vascular and Transplantation Surgery (HTTG), Hannover Medical School (MHH) & Cluster of Excellence REBIRTH, Hannover, Germany
| | - Ina Gruh
- Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Department for Cardiothoracic, Vascular and Transplantation Surgery (HTTG), Hannover Medical School (MHH) & Cluster of Excellence REBIRTH, Hannover, Germany.
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33
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Gurusamy N, Alsayari A, Rajasingh S, Rajasingh J. Adult Stem Cells for Regenerative Therapy. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2018; 160:1-22. [PMID: 30470288 DOI: 10.1016/bs.pmbts.2018.07.009] [Citation(s) in RCA: 61] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Cell therapy has been identified as an effective method to regenerate damaged tissue. Adult stem cells, also known as somatic stem cells or resident stem cells, are a rare population of undifferentiated cells, located within a differentiated organ, in a specialized structure, called a niche, which maintains the microenvironments that regulate the growth and development of adult stem cells. The adult stem cells are self-renewing, clonogenic, and multipotent in nature, and their main role is to maintain the tissue homeostasis. They can be activated to proliferate and differentiate into the required type of cells, upon the loss of cells or injury to the tissue. Adult stem cells have been identified in many tissues including blood, intestine, skin, muscle, brain, and heart. Extensive preclinical and clinical studies have demonstrated the structural and functional regeneration capabilities of these adult stem cells, such as bone marrow-derived mononuclear cells, hematopoietic stem cells, mesenchymal stromal/stem cells, resident adult stem cells, induced pluripotent stem cells, and umbilical cord stem cells. In this review, we focus on the human therapies, utilizing adult stem cells for their regenerative capabilities in the treatment of cardiac, brain, pancreatic, and eye disorders.
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Affiliation(s)
- Narasimman Gurusamy
- Department of Pharmacology, College of Pharmacy, King Khalid University, Abha, Saudi Arabia
| | - Abdulrhman Alsayari
- Department of Pharmacognosy, College of Pharmacy, King Khalid University, Abha, Saudi Arabia
| | - Sheeja Rajasingh
- Department of Internal Medicine, University of Kansas Medical Center, Kansas, KS, United States
| | - Johnson Rajasingh
- Department of Internal Medicine, University of Kansas Medical Center, Kansas, KS, United States.
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34
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Cianflone E, Aquila I, Scalise M, Marotta P, Torella M, Nadal-Ginard B, Torella D. Molecular basis of functional myogenic specification of Bona Fide multipotent adult cardiac stem cells. Cell Cycle 2018; 17:927-946. [PMID: 29862928 PMCID: PMC6103696 DOI: 10.1080/15384101.2018.1464852] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2018] [Revised: 06/01/2018] [Accepted: 04/08/2018] [Indexed: 01/14/2023] Open
Abstract
Ischemic Heart Disease (IHD) remains the developed world's number one killer. The improved survival from Acute Myocardial Infarction (AMI) and the progressive aging of western population brought to an increased incidence of chronic Heart Failure (HF), which assumed epidemic proportions nowadays. Except for heart transplantation, all treatments for HF should be considered palliative because none of the current therapies can reverse myocardial degeneration responsible for HF syndrome. To stop the HF epidemic will ultimately require protocols to reduce the progressive cardiomyocyte (CM) loss and to foster their regeneration. It is now generally accepted that mammalian CMs renew throughout life. However, this endogenous regenerative reservoir is insufficient to repair the extensive damage produced by AMI/IHD while the source and degree of CM turnover remains strongly disputed. Independent groups have convincingly shown that the adult myocardium harbors bona-fide tissue specific cardiac stem cells (CSCs). Unfortunately, recent reports have challenged the identity and the endogenous myogenic capacity of the c-kit expressing CSCs. This has hampered progress and unless this conflict is settled, clinical tests of repair/regenerative protocols are unlikely to provide convincing answers about their clinical potential. Here we review recent data that have eventually clarified the specific phenotypic identity of true multipotent CSCs. These cells when coaxed by embryonic cardiac morphogens undergo a precisely orchestrated myogenic commitment process robustly generating bona-fide functional cardiomyocytes. These data should set the path for the revival of further investigation untangling the regenerative biology of adult CSCs to harness their potential for HF prevention and treatment.
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Affiliation(s)
- Eleonora Cianflone
- Molecular and Cellular Cardiology, Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy
| | - Iolanda Aquila
- Molecular and Cellular Cardiology, Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy
| | - Mariangela Scalise
- Molecular and Cellular Cardiology, Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy
| | - Pina Marotta
- Molecular and Cellular Cardiology, Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy
| | - Michele Torella
- Department of Cardiothoracic Sciences, University of Campania Campus “Salvatore Venuta” Viale Europa- Loc. Germaneto “L. Vanvitelli”, Naples, Italy
| | - Bernardo Nadal-Ginard
- Molecular and Cellular Cardiology, Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy
| | - Daniele Torella
- Molecular and Cellular Cardiology, Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy
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Abstract
Congenital heart disease (CHD) is the most common birth defect, affecting 1 in 100 babies. Among CHDs, single ventricle (SV) physiologies, such as hypoplastic left heart syndrome and tricuspid atresia, are particularly severe conditions that require multiple palliative surgeries, including the Fontan procedure. Although the management strategies for SV patients have markedly improved, the prevalence of ventricular dysfunction continues to increase over time, especially after the Fontan procedure. At present, the final treatment for SV patients who develop heart failure is heart transplantation; however, transplantation is difficult to achieve because of severe donor shortages. Recently, various regenerative therapies for heart failure have been developed that increase cardiomyocytes and restore cardiac function, with promising results in adults. The clinical application of various forms of regenerative medicine for CHD patients with heart failure is highly anticipated, and the latest research in this field is reviewed here. In addition, regenerative therapy is important for children with CHD because of their natural growth. The ideal pediatric cardiovascular device would have the potential to adapt to a child's growth. Therefore, if a device that increases in size in accordance with the patient's growth could be developed using regenerative medicine, it would be highly beneficial. This review provides an overview of the available regenerative technologies for CHD patients.
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36
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Docshin PM, Karpov AA, Eyvazova SD, Puzanov MV, Kostareva AA, Galagudza MM, Malashicheva AB. Activation of Cardiac Stem Cells in Myocardial Infarction. ACTA ACUST UNITED AC 2018. [DOI: 10.1134/s1990519x18030045] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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Vigneault P, Naud P, Qi X, Xiao J, Villeneuve L, Davis DR, Nattel S. Calcium-dependent potassium channels control proliferation of cardiac progenitor cells and bone marrow-derived mesenchymal stem cells. J Physiol 2018; 596:2359-2379. [PMID: 29574723 DOI: 10.1113/jp275388] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2018] [Accepted: 02/26/2018] [Indexed: 12/26/2022] Open
Abstract
KEY POINTS Ex vivo proliferated c-Kit+ endogenous cardiac progenitor cells (eCPCs) obtained from mouse and human cardiac tissues have been reported to express a wide range of functional ion channels. In contrast to previous reports in cultured c-Kit+ eCPCs, we found that ion currents were minimal in freshly isolated cells. However, inclusion of free Ca2+ intracellularly revealed a prominent inwardly rectifying current identified as the intermediate conductance Ca2+ -activated K+ current (KCa3.1) Electrical function of both c-Kit+ eCPCs and bone marrow-derived mesenchymal stem cells is critically governed by KCa3.1 calcium-dependent potassium channels. Ca2+ -induced increases in KCa3.1 conductance are necessary to optimize membrane potential during Ca2+ entry. Membrane hyperpolarization due to KCa3.1 activation maintains the driving force for Ca2+ entry that activates stem cell proliferation. Cardiac disease downregulates KCa3.1 channels in resident cardiac progenitor cells. Alterations in KCa3.1 may have pathophysiological and therapeutic significance in regenerative medicine. ABSTRACT Endogenous c-Kit+ cardiac progenitor cells (eCPCs) and bone marrow (BM)-derived mesenchymal stem cells (MSCs) are being developed for cardiac regenerative therapy, but a better understanding of their physiology is needed. Here, we addressed the unknown functional role of ion channels in freshly isolated eCPCs and expanded BM-MSCs using patch-clamp, microfluorometry and confocal microscopy. Isolated c-Kit+ eCPCs were purified from dog hearts by immunomagnetic selection. Ion currents were barely detectable in freshly isolated c-Kit+ eCPCs with buffering of intracellular calcium (Ca2+i ). Under conditions allowing free intracellular Ca2+ , freshly isolated c-Kit+ eCPCs and ex vivo proliferated BM-MSCs showed prominent voltage-independent conductances that were sensitive to intermediate-conductance K+ -channel (KCa3.1 current, IKCa3.1 ) blockers and corresponding gene (KCNN4)-expression knockdown. Depletion of Ca2+i induced membrane-potential (Vmem ) depolarization, while store-operated Ca2+ entry (SOCE) hyperpolarized Vmem in both cell types. The hyperpolarizing SOCE effect was substantially reduced by IKCa3.1 or SOCE blockade (TRAM-34, 2-APB), and IKCa3.1 blockade (TRAM-34) or KCNN4-knockdown decreased the Ca2+ entry resulting from SOCE. IKCa3.1 suppression reduced c-Kit+ eCPC and BM-MSC proliferation, while significantly altering the profile of cyclin expression. IKCa3.1 was reduced in c-Kit+ eCPCs isolated from dogs with congestive heart failure (CHF), along with corresponding KCNN4 mRNA. Under perforated-patch conditions to maintain physiological [Ca2+ ]i , c-Kit+ eCPCs from CHF dogs had less negative resting membrane potentials (-58 ± 7 mV) versus c-Kit+ eCPCs from control dogs (-73 ± 3 mV, P < 0.05), along with slower proliferation. Our study suggests that Ca2+ -induced increases in IKCa3.1 are necessary to optimize membrane potential during the Ca2+ entry that activates progenitor cell proliferation, and that alterations in KCa3.1 may have pathophysiological and therapeutic significance in regenerative medicine.
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Affiliation(s)
- Patrick Vigneault
- Research Center and Department of Medicine, Montreal Heart Institute, Université de Montréal, Montreal, Quebec, Canada
| | - Patrice Naud
- Research Center and Department of Medicine, Montreal Heart Institute, Université de Montréal, Montreal, Quebec, Canada
| | - Xiaoyan Qi
- Research Center and Department of Medicine, Montreal Heart Institute, Université de Montréal, Montreal, Quebec, Canada
| | - Jiening Xiao
- Research Center and Department of Medicine, Montreal Heart Institute, Université de Montréal, Montreal, Quebec, Canada
| | - Louis Villeneuve
- Research Center and Department of Medicine, Montreal Heart Institute, Université de Montréal, Montreal, Quebec, Canada
| | - Darryl R Davis
- University of Ottawa Heart Institute, Ottawa, Ontario, Canada
| | - Stanley Nattel
- Research Center and Department of Medicine, Montreal Heart Institute, Université de Montréal, Montreal, Quebec, Canada.,Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada.,Institute of Pharmacology, West German Heart and Vascular Center, Faculty of Medicine, University Duisburg-Essen, Essen, Germany
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38
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Broughton KM, Wang BJ, Firouzi F, Khalafalla F, Dimmeler S, Fernandez-Aviles F, Sussman MA. Mechanisms of Cardiac Repair and Regeneration. Circ Res 2018; 122:1151-1163. [PMID: 29650632 PMCID: PMC6191043 DOI: 10.1161/circresaha.117.312586] [Citation(s) in RCA: 126] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Cardiovascular regenerative therapies are pursued on both basic and translational levels. Although efficacy and value of cell therapy for myocardial regeneration can be debated, there is a consensus that profound deficits in mechanistic understanding limit advances, optimization, and implementation. In collaboration with the TACTICS (Transnational Alliance for Regenerative Therapies in Cardiovascular Syndromes), this review overviews several pivotal aspects of biological processes impinging on cardiac maintenance, repair, and regeneration. The goal of summarizing current mechanistic understanding is to prompt innovative directions for fundamental studies delineating cellular reparative and regenerative processes. Empowering myocardial regenerative interventions, whether dependent on endogenous processes or exogenously delivered repair agents, ultimately depends on mastering mechanisms and novel strategies that take advantage of rather than being limited by inherent myocardial biology.
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Affiliation(s)
- Kathleen M Broughton
- From the Department of Biology, San Diego State University Heart Institute and the Integrated Regenerative Research Institute, CA (K.M.B., B.J.W., F.F., F.K., M.A.S.); Institute for Cardiovascular Regeneration, Center of Molecular Medicine, Frankfurt, Germany (S.D.); and Department of Cardiology, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), CIBERCV and Universidad Complutense de Madrid, Spain (F.F.-A.)
| | - Bingyan J Wang
- From the Department of Biology, San Diego State University Heart Institute and the Integrated Regenerative Research Institute, CA (K.M.B., B.J.W., F.F., F.K., M.A.S.); Institute for Cardiovascular Regeneration, Center of Molecular Medicine, Frankfurt, Germany (S.D.); and Department of Cardiology, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), CIBERCV and Universidad Complutense de Madrid, Spain (F.F.-A.)
| | - Fareheh Firouzi
- From the Department of Biology, San Diego State University Heart Institute and the Integrated Regenerative Research Institute, CA (K.M.B., B.J.W., F.F., F.K., M.A.S.); Institute for Cardiovascular Regeneration, Center of Molecular Medicine, Frankfurt, Germany (S.D.); and Department of Cardiology, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), CIBERCV and Universidad Complutense de Madrid, Spain (F.F.-A.)
| | - Farid Khalafalla
- From the Department of Biology, San Diego State University Heart Institute and the Integrated Regenerative Research Institute, CA (K.M.B., B.J.W., F.F., F.K., M.A.S.); Institute for Cardiovascular Regeneration, Center of Molecular Medicine, Frankfurt, Germany (S.D.); and Department of Cardiology, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), CIBERCV and Universidad Complutense de Madrid, Spain (F.F.-A.)
| | - Stefanie Dimmeler
- From the Department of Biology, San Diego State University Heart Institute and the Integrated Regenerative Research Institute, CA (K.M.B., B.J.W., F.F., F.K., M.A.S.); Institute for Cardiovascular Regeneration, Center of Molecular Medicine, Frankfurt, Germany (S.D.); and Department of Cardiology, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), CIBERCV and Universidad Complutense de Madrid, Spain (F.F.-A.)
| | - Francisco Fernandez-Aviles
- From the Department of Biology, San Diego State University Heart Institute and the Integrated Regenerative Research Institute, CA (K.M.B., B.J.W., F.F., F.K., M.A.S.); Institute for Cardiovascular Regeneration, Center of Molecular Medicine, Frankfurt, Germany (S.D.); and Department of Cardiology, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), CIBERCV and Universidad Complutense de Madrid, Spain (F.F.-A.)
| | - Mark A Sussman
- From the Department of Biology, San Diego State University Heart Institute and the Integrated Regenerative Research Institute, CA (K.M.B., B.J.W., F.F., F.K., M.A.S.); Institute for Cardiovascular Regeneration, Center of Molecular Medicine, Frankfurt, Germany (S.D.); and Department of Cardiology, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), CIBERCV and Universidad Complutense de Madrid, Spain (F.F.-A.).
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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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Saheera S, Potnuri AG, Nair RR. Modulation of cardiac stem cell characteristics by metoprolol in hypertensive heart disease. Hypertens Res 2018; 41:253-262. [PMID: 29449707 DOI: 10.1038/s41440-018-0015-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2017] [Revised: 06/19/2017] [Accepted: 08/04/2017] [Indexed: 11/09/2022]
Abstract
Cardiac stem cells (CSCs) play a vital role in cardiac remodeling. Uncontrolled hypertension leads to cardiac hypertrophy, followed by cardiac failure. Pathological remodeling is associated with enhanced oxidative stress. Decreased cardiac stem cell efficiency is speculated in heart diseases. Maintaining a healthy stem cell population is essential for preventing progressive cardiac remodeling. Some anti-hypertensive drugs are cardioprotective. However, the effect of these drugs on CSCs has not been investigated. Metoprolol is a cardioprotective anti-hypertensive agent. To examine whether metoprolol can prevent the deterioration of CSC efficiency, spontaneously hypertensive rats (SHRs) were treated with this drug, and the effects on stem cell function were evaluated. Six-month-old male SHRs were treated with metoprolol (50 mg × kg-1per day) for 2 months. The effectiveness of the treatment at reducing blood pressure and reducing hypertrophy was ensured, and the animals were killed. Cardiac stem cells were isolated from the atrial tissue, and the effect of metoprolol on stem cell migration, proliferation, differentiation, and survival was evaluated by comparing the treated SHRs with untreated SHRs and normotensive Wistar rats. Compared to the Wistar rats, the SHR rats presented with a decrease in stem cell migration and proliferation and an increase in intracellular oxidative stress and senescence. Treating SHRs with metoprolol increased CSC migration and proliferation potential and stemness retention. Cellular senescence and oxidative stress were reduced. The attributes of stem cells from the metoprolol-treated SHRs were comparable to those of the Wistar rats. The restoration of stem cell efficiency is expected to prevent hypertension-induced progressive cardiac remodeling.
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Affiliation(s)
- Sherin Saheera
- Division of Cellular and Molecular Cardiology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, Thiruvananthapuram, Kerala, 695011, India
| | - Ajay Godwin Potnuri
- Division of Cellular and Molecular Cardiology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, Thiruvananthapuram, Kerala, 695011, India
| | - Renuka R Nair
- Division of Cellular and Molecular Cardiology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, Thiruvananthapuram, Kerala, 695011, India.
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Sterner RM, Sterner RC, Brenes-Salazar JA, Yu Ballard AC. Cellular therapies for chronic ischemic heart failure. Hellenic J Cardiol 2018; 59:78-90. [PMID: 29355725 DOI: 10.1016/j.hjc.2018.01.010] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2017] [Revised: 01/10/2018] [Accepted: 01/12/2018] [Indexed: 12/16/2022] Open
Abstract
The development of stem cell therapies for chronic ischemic heart failure is highly sought after to attempt to improve morbidity and mortality of this prevalent disease. This article reviews clinical trials that investigate stem cell therapy for chronic ischemic heart failure. To generate this review article, PubMed was searched using keywords "stem cell therapy heart failure" with the article type "Clinical Trial" selected on 10/04/2016. The raw search yielded 156 articles; 53 articles were selected for inclusion in the review between the original literature search and manual research/cross-referencing. Additional reviews and original articles were also manually researched and cross-referenced. Cellular-based therapies utilizing peripheral blood progenitor cells, bone marrow cells, mesenchymal stem cells, cells of cardiac origin, and embryonic stem cells have yielded mixed results, but some studies have shown modest efficacy. Skeletal myoblasts raised concerns about safety due to arrhythmias. Optimizing cell type and delivery method will be of critical importance in enhancing efficacy of therapy within various subsets of chronic ischemic heart failure patients. Although much more work needs to be done to optimize treatment strategies, developing stem cell therapies for chronic ischemic heart failure could be of critical importance to lessen the impactful health burden that heart failure has on patients and society.
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Affiliation(s)
- Rosalie M Sterner
- Mayo Clinic Medical Scientist Training Program, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
| | - Robert C Sterner
- University of Wisconsin-Madison Medical Scientist Training Program, 750 Highland Avenue, Madison, WI, 53726, USA.
| | | | - Aimee C Yu Ballard
- Primary Care Internal Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
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Renko O, Tolonen AM, Rysä J, Magga J, Mustonen E, Ruskoaho H, Serpi R. SDF1 gradient associates with the distribution of c-Kit+ cardiac cells in the heart. Sci Rep 2018; 8:1160. [PMID: 29348441 PMCID: PMC5773575 DOI: 10.1038/s41598-018-19417-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2017] [Accepted: 12/29/2017] [Indexed: 12/11/2022] Open
Abstract
Identification of the adult cardiac stem cells (CSCs) has offered new therapeutic possibilities for treating ischemic myocardium. CSCs positive for the cell surface antigen c-Kit are known as the primary source for cardiac regeneration. Accumulating evidence shows that chemokines play important roles in stem cell homing. Here we investigated molecular targets to be utilized in modulating the mobility of endogenous CSCs. In a four week follow-up after experimental acute myocardial infarction (AMI) with ligation of the left anterior descending (LAD) coronary artery of Sprague-Dawley rats c-Kit+ CSCs redistributed in the heart. The number of c-Kit+ CSCs in the atrial c-Kit niche was diminished, whereas increased amount was observed in the left ventricle and apex. This was associated with increased expression of stromal cell-derived factor 1 alpha (SDF1α), and a significant positive correlation was found between c-Kit+ CSCs and SDF1α expression in the heart. Moreover, the migratory capacity of isolated c-Kit+ CSCs was induced by SDF1 treatment in vitro. We conclude that upregulation of SDF1α after AMI associates with increased expression of endogenous c-Kit+ CSCs in the injury area, and show induced migration of c-Kit+ cells by SDF1.
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Affiliation(s)
- Outi Renko
- Research Unit of Biomedicine, Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland
| | - Anna-Maria Tolonen
- Research Unit of Biomedicine, Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland
| | - Jaana Rysä
- School of Pharmacy, University of Eastern Finland, Kuopio, Finland
| | - Johanna Magga
- Research Unit of Biomedicine, Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland
| | - Erja Mustonen
- Research Unit of Biomedicine, Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland
| | - Heikki Ruskoaho
- Division of Pharmacology and Pharmacotherapy, University of Helsinki, Helsinki, Finland
| | - Raisa Serpi
- Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research, University of Oulu, Oulu, Finland.
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Lara-Martínez LA, Gutiérrez-Villegas I, Arenas-Luna VM, Hernández-Gutierrez S. [Stem cells: searching predisposition to cardiac commitment by surface markers expression]. ARCHIVOS DE CARDIOLOGIA DE MEXICO 2018; 88:483-495. [PMID: 29311024 DOI: 10.1016/j.acmx.2017.12.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2017] [Revised: 11/30/2017] [Accepted: 12/01/2017] [Indexed: 11/19/2022] Open
Abstract
It is well-known that cardiovascular diseases are the leading cause of death worldwide, and represent an important economic burden to health systems. In an attempt to solve this problem, stem cell therapy has emerged as a therapeutic option. Within the last 20 years, a great variety of stem cells have been used in different myocardial infarction models. Up until now, the use of cardiac stem cells (CSCs) has seemed to be the best option, but the inaccessibility and scarcity of these cells make their use unreliable. Additionally, there is a high risk as they have to be obtained directly from the heart of the patient. Unlike CSCs, adult stem cells originating from bone marrow or adipose tissue, among others, appear to be an attractive option due to their easier accessibility and abundance, but particularly due to the probable existence of cardiac progenitors among their different sub-populations. In this review an analysis is made of the surface markers present in CSCs compared with other adult stem cells. This suggested the pre-existence of cells sharing specific surface markers with CSCs, a predictable immunophenotype present in some cells, although in low proportions, and with a potential of cardiac differentiation that could be similar to CSCs, thus increasing their therapeutic value. This study highlights new perspectives regarding MSCs that would enable some of these sub-populations to be differentiated at cardiac tissue level.
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Affiliation(s)
- Luis A Lara-Martínez
- Laboratorio de Biología Molecular, Escuela de Medicina, Universidad Panamericana, Ciudad de México, México
| | - Ingrid Gutiérrez-Villegas
- Laboratorio de Biología Molecular, Escuela de Medicina, Universidad Panamericana, Ciudad de México, México
| | - Victor M Arenas-Luna
- Laboratorio de Biología Molecular, Escuela de Medicina, Universidad Panamericana, Ciudad de México, México
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Cappetta D, Rossi F, Piegari E, Quaini F, Berrino L, Urbanek K, De Angelis A. Doxorubicin targets multiple players: A new view of an old problem. Pharmacol Res 2018; 127:4-14. [DOI: 10.1016/j.phrs.2017.03.016] [Citation(s) in RCA: 123] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2017] [Revised: 03/16/2017] [Accepted: 03/16/2017] [Indexed: 01/22/2023]
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Gnecchi M, Danieli P, Malpasso G, Ciuffreda MC. Paracrine Mechanisms of Mesenchymal Stem Cells in Tissue Repair. Methods Mol Biol 2017; 1416:123-46. [PMID: 27236669 DOI: 10.1007/978-1-4939-3584-0_7] [Citation(s) in RCA: 297] [Impact Index Per Article: 37.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Tissue regeneration from transplanted mesenchymal stromal cells (MSC) either through transdifferentiation or cell fusion was originally proposed as the principal mechanism underlying their therapeutic action. However, several studies have now shown that both these mechanisms are very inefficient. The low MSC engraftment rate documented in injured areas also refutes the hypothesis that MSC repair tissue damage by replacing cell loss with newly differentiated cells. Indeed, despite evidence of preferential homing of MSC to the site of myocardial ischemia, exogenously administered MSC show poor survival and do not persist in the infarcted area. Therefore, it has been proposed that the functional benefits observed after MSC transplantation in experimental models of tissue injury might be related to the secretion of soluble factors acting in a paracrine fashion. This hypothesis is supported by pre-clinical studies demonstrating equal or even improved organ function upon infusion of MSC-derived conditioned medium (MSC-CM) compared with MSC transplantation. Identifying key MSC-secreted factors and their functional role seems a reasonable approach for a rational design of nextgeneration MSC-based therapeutics. Here, we summarize the major findings regarding both different MSC-mediated paracrine actions and the identification of paracrine mediators.
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Affiliation(s)
- Massimiliano Gnecchi
- Department of Molecular Medicine, Unit of Cardiology, University of Pavia, Pavia, Italy. .,Department of Cardiothoracic and Vascular Sciences - Coronary Care Unit and Laboratory of Clinical and Experimental Cardiology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy. .,Laboratory of Experimental Cardiology for Cell and Molecular Therapy, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy. .,Department of Medicine, University of Cape Town, Cape Town, South Africa.
| | - Patrizia Danieli
- Department of Molecular Medicine, Unit of Cardiology, University of Pavia, Pavia, Italy.,Department of Cardiothoracic and Vascular Sciences - Coronary Care Unit and Laboratory of Clinical and Experimental Cardiology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.,Laboratory of Experimental Cardiology for Cell and Molecular Therapy, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Giuseppe Malpasso
- Department of Molecular Medicine, Unit of Cardiology, University of Pavia, Pavia, Italy.,Department of Cardiothoracic and Vascular Sciences - Coronary Care Unit and Laboratory of Clinical and Experimental Cardiology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.,Laboratory of Experimental Cardiology for Cell and Molecular Therapy, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Maria Chiara Ciuffreda
- Department of Molecular Medicine, Unit of Cardiology, University of Pavia, Pavia, Italy.,Department of Cardiothoracic and Vascular Sciences - Coronary Care Unit and Laboratory of Clinical and Experimental Cardiology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.,Laboratory of Experimental Cardiology for Cell and Molecular Therapy, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
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Wang Y, Xia Y, Kuang D, Duan Y, Wang G. PP2A regulates SCF-induced cardiac stem cell migration through interaction with p38 MAPK. Life Sci 2017; 191:59-67. [DOI: 10.1016/j.lfs.2017.10.006] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2017] [Revised: 09/22/2017] [Accepted: 10/02/2017] [Indexed: 12/29/2022]
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Ling L, Gu S, Cheng Y, Ding L. bFGF promotes Sca‑1+ cardiac stem cell migration through activation of the PI3K/Akt pathway. Mol Med Rep 2017; 17:2349-2356. [PMID: 29207135 PMCID: PMC5783475 DOI: 10.3892/mmr.2017.8178] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2015] [Accepted: 11/21/2016] [Indexed: 01/19/2023] Open
Abstract
Cardiac stem cells (CSCs) are important for improving cardiac function following myocardial infarction, with CSC migration to infarcted or ischemic myocardium important for cardiac regeneration. Strategies to improve cell migration may improve the efficiency of myocardial regeneration. Basic fibroblast growth factor (bFGF) is an essential molecule in cell migration, but the endogenous bFGF level is too low to be effective. The effect of exogenously delivered bFGF on CSC migration was observed in vitro and in vivo in the present study. The CSC migration index in response to various bFGF concentrations was demonstrated in vitro. In addition, a murine myocardial infarction model was constructed and bFGF protein expression levels and CSC aggregation following myocardial infarction were observed. To study cell migration in vivo, CM-Dil-labeled CSCs or bFGF-CSCs were injected into the peri-infarct myocardium following myocardium infarction and cell migration and maintenance in the peri-infarct/infarct area was observed 1 week later. Protein expression levels of bFGF, CXCR-4 and SDF-1 were assessed, as was myocardium capillary density. The Akt inhibitor deguelin was used to assess the role of the PI3K/Akt pathway in vitro and in vivo. The present study demonstrated that bFGF-promoted Sca-1+ CSC migration, with the highest migration rate occurring at a concentration of 45 ng/ml. The PI3K/Akt pathway inhibitor deguelin attenuated this increase. The phospho-Akt/Akt ratio was elevated significantly after 30 min of bFGF exposure. Transplantation of bFGF-treated Sca-1+ CSCs led to improved cell maintenance in the peri-infarct area and increased cell migration to the infarct area, as well as improved angiogenesis. Protein expression levels of bFGF, CXCR-4 and SDF-1 were upregulated, and this upregulation was partially attenuated by deguelin. Therefore, bFGF was demonstrated to promote Sca-1+ CSC migration both in vitro and in vivo, partially through activation of the PI3K/Akt pathway. This may provide a new method for facilitating CSC therapy for myocardium repair after myocardium injury.
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Affiliation(s)
- Lin Ling
- Department of Cardiology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Shaohua Gu
- Department of Nephrology, The Third People's Hospital of Kunshan, Kunshan, Jiangsu 215300, P.R. China
| | - Yan Cheng
- Department of Cardiology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, Jiangsu 214000, P.R. China
| | - Liucheng Ding
- Department of Urology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210000, P.R. China
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Li C, Matsushita S, Li Z, Guan J, Amano A. c-kit Positive Cardiac Outgrowth Cells Demonstrate Better Ability for Cardiac Recovery Against Ischemic Myopathy. ACTA ACUST UNITED AC 2017; 7. [PMID: 29238626 PMCID: PMC5726283 DOI: 10.4172/2157-7633.1000402] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Objective Resident cardiac stem cells are expected to be a therapeutic option for patients who suffer from severe heart failure. However, uncertainty remains over whether sorting cells for c-kit, a stem cell marker, improves therapeutic outcomes. Materials and methods Cardiac outgrowth cells cultured from explants of rat heart atrium were sorted according to their positivity (+) or negativity (−) for c-kit. These cells were exposed to hypoxia for 3 d, and subsequently harvested for mRNA expression measurement. The cell medium was also collected to assess cytokine secretion. To test for a functional benefit in animals, myocardial infarction (MI) was induced in rats, and c-kit+ or c-kit− cells were injected. The left ventricular ejection fraction (LVEF) was measured for up to 4 weeks, after which the heart was harvested for biological and histological analyses. Results and conclusion Expression of the angiogenesis-related genes, VEGF and ANGPTL2, was significantly higher in c-kit+ cells after 3 d of hypoxic culture, although we found no such difference prior to hypoxia. Secretion of VEGF and ANGPTL2 was greater in the c-kit+ group than in the c-kit− group, while hypoxia tended to increase cytokine expression in both groups. In addition, IGF-1 was significantly increased in the c-kit+ group, consistent with the relatively low expression of cleaved-caspase 3 revealed by western blot assay, and the relatively low count of apoptotic cells revealed by histochemical analysis. Administration of c-kit+cells into the MI heart improved the LVEF and increased neovascularization. These results indicate that c-kit+cells may be useful in cardiac stem cell therapy.
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Affiliation(s)
- Chuan Li
- Department of Cardiovascular Surgery, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Satoshi Matsushita
- Department of Cardiovascular Surgery, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Zhengqing Li
- Department of Materials Science and Engineering, Ohio State University, Columbus, USA
| | - Jianjun Guan
- Department of Materials Science and Engineering, Ohio State University, Columbus, USA
| | - Atsushi Amano
- Department of Cardiovascular Surgery, Juntendo University Faculty of Medicine, Tokyo, Japan
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Cardiac Progenitor Cells and the Interplay with Their Microenvironment. Stem Cells Int 2017; 2017:7471582. [PMID: 29075298 PMCID: PMC5623801 DOI: 10.1155/2017/7471582] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2017] [Accepted: 07/26/2017] [Indexed: 02/06/2023] Open
Abstract
The microenvironment plays a crucial role in the behavior of stem and progenitor cells. In the heart, cardiac progenitor cells (CPCs) reside in specific niches, characterized by key components that are altered in response to a myocardial infarction. To date, there is a lack of knowledge on these niches and on the CPC interplay with the niche components. Insight into these complex interactions and into the influence of microenvironmental factors on CPCs can be used to promote the regenerative potential of these cells. In this review, we discuss cardiac resident progenitor cells and their regenerative potential and provide an overview of the interactions of CPCs with the key elements of their niche. We focus on the interaction between CPCs and supporting cells, extracellular matrix, mechanical stimuli, and soluble factors. Finally, we describe novel approaches to modulate the CPC niche that can represent the next step in recreating an optimal CPC microenvironment and thereby improve their regeneration capacity.
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Bellio MA, Pinto MT, Florea V, Barrios PA, Taylor CN, Brown AB, Lamondin C, Hare JM, Schulman IH, Rodrigues CO. Hypoxic Stress Decreases c-Myc Protein Stability in Cardiac Progenitor Cells Inducing Quiescence and Compromising Their Proliferative and Vasculogenic Potential. Sci Rep 2017; 7:9702. [PMID: 28851980 PMCID: PMC5575078 DOI: 10.1038/s41598-017-09813-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2016] [Accepted: 07/31/2017] [Indexed: 12/27/2022] Open
Abstract
Cardiac progenitor cells (CPCs) have been shown to promote cardiac regeneration and improve heart function. However, evidence suggests that their regenerative capacity may be limited in conditions of severe hypoxia. Elucidating the mechanisms involved in CPC protection against hypoxic stress is essential to maximize their cardioprotective and therapeutic potential. We investigated the effects of hypoxic stress on CPCs and found significant reduction in proliferation and impairment of vasculogenesis, which were associated with induction of quiescence, as indicated by accumulation of cells in the G0-phase of the cell cycle and growth recovery when cells were returned to normoxia. Induction of quiescence was associated with a decrease in the expression of c-Myc through mechanisms involving protein degradation and upregulation of p21. Inhibition of c-Myc mimicked the effects of severe hypoxia on CPC proliferation, also triggering quiescence. Surprisingly, these effects did not involve changes in p21 expression, indicating that other hypoxia-activated factors may induce p21 in CPCs. Our results suggest that hypoxic stress compromises CPC function by inducing quiescence in part through downregulation of c-Myc. In addition, we found that c-Myc is required to preserve CPC growth, suggesting that modulation of pathways downstream of it may re-activate CPC regenerative potential under ischemic conditions.
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Affiliation(s)
- Michael A Bellio
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida, United States of America
| | - Mariana T Pinto
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida, United States of America
| | - Victoria Florea
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida, United States of America
| | - Paola A Barrios
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida, United States of America
| | - Christy N Taylor
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida, United States of America
| | - Ariel B Brown
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida, United States of America
| | - Courtney Lamondin
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida, United States of America
| | - Joshua M Hare
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida, United States of America
- Department of Medicine, Cardiovascular Division, University of Miami Miller School of Medicine, Miami, Florida, United States of America
| | - Ivonne H Schulman
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida, United States of America
- Department of Medicine, Katz Family Division of Nephrology and Hypertension, University of Miami Miller School of Medicine, Miami, Florida, United States of America
| | - Claudia O Rodrigues
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida, United States of America.
- Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, Florida, United States of America.
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