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1
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Najafipour H, Rostamzadeh F, Jafarinejad-Farsangi S, Bagheri-Hosseinabadi Z, Jafari E, Farsinejad A, Bagheri MM. Human platelet lysate combined with mesenchymal stem cells pretreated with platelet lysate improved cardiac function in rats with myocardial infarction. Sci Rep 2024; 14:27701. [PMID: 39533052 PMCID: PMC11557824 DOI: 10.1038/s41598-024-79050-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Accepted: 11/06/2024] [Indexed: 11/16/2024] Open
Abstract
Myocardial infarction (MI) is a leading cause of heart failure, disability and mortality worldwide. In this study, the effects of intramyocardial injection of human platelet lysate (HPL), bone marrow mesenchymal stem cells pretreated with HPL (PMSCs), and PMSC lysate (lys), alone and in combination were investigated on MI-induced by LAD ligation in male Wistar rats. The experiment was carried out on sham, vehicle (Veh), HPL, PMSCs, PMSC lysate (PMSC lys), HPL + PMSCs, and HPL + PMSC lys groups. SBP, DBP, and ± dp/dt max were monitored by the PowerLab physiograph. The MSC characteristics and CD31, NKX2.5, and cardiac troponin I (cTnI) contents were determined by flow cytometry, immunohistochemistry, and immunofluorescence, respectively. SBP, DBP, and ± dp/dt max that decreased in the MI group were recovered by HPL, PMSC, PMSC lys, HPL + PMSC, and HPL + PMSC lys treatments. CD31 density was higher in all treated groups compared to the Veh group. CD31 density in the HPL + PMSCs and HPL + PMSC lys groups was higher than in the PMSCs group. The number of Dil+/NKX2.5 + and Dil+/cTnI + cells was higher in the HPL + PMSCs group compared to the PMSCs group. The HPL and PMSCs mitigates heart injuries and cardiac dysfunction after MI. HPL provides an appropriate environment for cardiomyocyte differentiation from PMSCs.
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Affiliation(s)
- Hamid Najafipour
- Cardiovascular Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Kerman, Iran
| | - Farzaneh Rostamzadeh
- Physiology Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Boulevard Jihad, Ebne-Sina Avenue, 7619813159, Kerman, Iran.
| | - Seedieh Jafarinejad-Farsangi
- Endocrinology and Metabolism Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Kerman, Iran
| | - Zahra Bagheri-Hosseinabadi
- Physiology-Pharmacology Research Center, Research Institute of Basic Medical Sciences, and Department of Clinical Biochemistry, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Elham Jafari
- Pathology and Stem Cell Research Center, Kerman University of Medical Sciences, Kerman, Iran
| | - Alireza Farsinejad
- Stem Cell and Regenerative Medicine Research Center, Kerman University of Medical Sciences, Kerman, Iran
| | - Mohmmad Mehdi Bagheri
- Gastroenterology and Hepatology Research Center, Kerman University of Medical Sciences, Kerman, Iran
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2
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Yahyazadeh R, Baradaran Rahimi V, Askari VR. Stem cell and exosome therapies for regenerating damaged myocardium in heart failure. Life Sci 2024; 351:122858. [PMID: 38909681 DOI: 10.1016/j.lfs.2024.122858] [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: 05/09/2024] [Revised: 06/13/2024] [Accepted: 06/18/2024] [Indexed: 06/25/2024]
Abstract
Finding novel treatments for cardiovascular diseases (CVDs) is a hot topic in medicine; cell-based therapies have reported promising news for controlling dangerous complications of heart disease such as myocardial infarction (MI) and heart failure (HF). Various progenitor/stem cells were tested in various in-vivo, in-vitro, and clinical studies for regeneration or repairing the injured tissue in the myocardial to accelerate the healing. Fetal, adult, embryonic, and induced pluripotent stem cells (iPSC) have revealed the proper potency for cardiac tissue repair. As an essential communicator among cells, exosomes with specific contacts (proteins, lncRNAs, and miRNAs) greatly promote cardiac rehabilitation. Interestingly, stem cell-derived exosomes have more efficiency than stem cell transplantation. Therefore, stem cells induced pluripotent stem cells (iPSCs), embryonic stem cells (ESCs), cardiac stem cells (CDC), and skeletal myoblasts) and their-derived exosomes will probably be considered an alternative therapy for CVDs remedy. In addition, stem cell-derived exosomes have been used in the diagnosis/prognosis of heart diseases. In this review, we explained the advances of stem cells/exosome-based treatment, their beneficial effects, and underlying mechanisms, which will present new insights in the clinical field in the future.
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Affiliation(s)
- Roghayeh Yahyazadeh
- Pharmacological Research Center of Medicinal Plants, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Vafa Baradaran Rahimi
- Department of Cardiovascular Diseases, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Vahid Reza Askari
- Pharmacological Research Center of Medicinal Plants, Mashhad University of Medical Sciences, Mashhad, Iran.
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3
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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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4
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Clavellina D, Balkan W, Hare JM. Stem cell therapy for acute myocardial infarction: Mesenchymal Stem Cells and induced Pluripotent Stem Cells. Expert Opin Biol Ther 2023; 23:951-967. [PMID: 37542462 PMCID: PMC10837765 DOI: 10.1080/14712598.2023.2245329] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Revised: 08/01/2023] [Accepted: 08/03/2023] [Indexed: 08/07/2023]
Abstract
INTRODUCTION Acute myocardial infarction (AMI) remains a leading cause of death in the United States. The limited capacity of cardiomyocytes to regenerate and the restricted contractility of scar tissue after AMI are not addressed by current pharmacologic interventions. Mesenchymal stem/stromal cells (MSCs) have emerged as a promising therapeutic approach due to their low antigenicity, ease of harvesting, and efficacy and safety in preclinical and clinical studies, despite their low survival and engraftment rates. Other stem cell types, such as induced pluripotent stem cells (iPSCs) also show promise, and optimizing cardiac repair requires integrating emerging technologies and strategies. AREAS COVERED This review offers insights into advancing cell-based therapies for AMI, emphasizing meticulously planned trials with a standardized definition of AMI, for a bench-to-bedside approach. We critically evaluate fundamental studies and clinical trials to provide a comprehensive overview of the advances, limitations and prospects for cell-based therapy in AMI. EXPERT OPINION MSCs continue to show potential promise for treating AMI and its sequelae, but addressing their low survival and engraftment rates is crucial for clinical success. Integrating emerging technologies such as pluripotent stem cells and conducting well-designed trials will harness the full potential of cell-based therapy in AMI management. Collaborative efforts are vital to developing effective stem cell therapies for AMI patients.
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Affiliation(s)
- Diana Clavellina
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Wayne Balkan
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA
- Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Joshua M Hare
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA
- Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA
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5
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Development of an injectable alginate-collagen hydrogel for cardiac delivery of extracellular vesicles. Int J Pharm 2022; 629:122356. [DOI: 10.1016/j.ijpharm.2022.122356] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Revised: 10/07/2022] [Accepted: 10/27/2022] [Indexed: 11/07/2022]
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6
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Zhang Y, Mu W, Zhang Y, He X, Wang Y, Ma H, Zhu T, Li A, Hou Q, Yang W, Ding Y, Ramakrishna S, Li H. Recent Advances in Cardiac Patches: Materials, Preparations, and Properties. ACS Biomater Sci Eng 2022; 8:3659-3675. [PMID: 36037313 DOI: 10.1021/acsbiomaterials.2c00348] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Cardiac patches are biomaterials that can be used for transplantation and repair of damaged myocardium by combining seed cells with the ability to form cardiomyocytes and suitable scaffold materials. On the one hand, they provide temporary support to the infarcted area, and on the other hand, they repair the damaged myocardium by delivering cells or bioactive factors to integrate with the host, which have gradually become a hot research topic in recent years. This paper summarizes the structural properties of natural myocardium and reviews the recent research progress of cardiac patches, including the seed cells and scaffold materials used in patch preparation, as well as the main methods of scaffold preparation and the structure properties of various scaffolds. In addition, a comprehensive analysis of the problems faced in the clinical implementation of cardiac patches is presented. Finally, we look forward to the development of cardiac patches and point out that precisely tunable anisotropic tissue engineering scaffolds close to natural myocardial tissue will become an important direction for future research.
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Affiliation(s)
- Yi Zhang
- College of Mechanical and Electrical Engineering, Beijing University of Chemical Technology, Beijing, 100029, China.,Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing, 100029, China
| | - Wenying Mu
- Beijing Anzhen Hospital, Capital Medical University, Beijing, 100000, China
| | - Yanping Zhang
- Interdisciplinary Nanoscience Center, Aarhus University, Aarhus, DK-8000, Denmark
| | - Xuetao He
- College of Mechanical and Electrical Engineering, Beijing University of Chemical Technology, Beijing, 100029, China
| | - Yiming Wang
- College of Mechanical and Electrical Engineering, Beijing University of Chemical Technology, Beijing, 100029, China
| | - Hongyu Ma
- College of Mechanical and Electrical Engineering, Beijing University of Chemical Technology, Beijing, 100029, China
| | - Tianyang Zhu
- College of Mechanical and Electrical Engineering, Beijing University of Chemical Technology, Beijing, 100029, China
| | - Aoyuan Li
- College of Mechanical and Electrical Engineering, Beijing University of Chemical Technology, Beijing, 100029, China
| | - Qinzheng Hou
- College of Mechanical and Electrical Engineering, Beijing University of Chemical Technology, Beijing, 100029, China
| | - Weimin Yang
- College of Mechanical and Electrical Engineering, Beijing University of Chemical Technology, Beijing, 100029, China.,Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing, 100029, China.,State Key Laboratory of Organic-Inorganic Composites, Beijing University of Chemical Technology, Beijing, 100029, China
| | - Yumei Ding
- College of Mechanical and Electrical Engineering, Beijing University of Chemical Technology, Beijing, 100029, China
| | - Seeram Ramakrishna
- Center for Nanofibers & Nanotechnology, National University of Singapore, Singapore, 119077, Singapore
| | - Haoyi Li
- College of Mechanical and Electrical Engineering, Beijing University of Chemical Technology, Beijing, 100029, China.,Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing, 100029, China.,State Key Laboratory of Organic-Inorganic Composites, Beijing University of Chemical Technology, Beijing, 100029, China
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7
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Spadaccio C, Nenna A, Rose D, Piccirillo F, Nusca A, Grigioni F, Chello M, Vlahakes GJ. The Role of Angiogenesis and Arteriogenesisin Myocardial Infarction and Coronary Revascularization. J Cardiovasc Transl Res 2022; 15:1024-1048. [PMID: 35357670 DOI: 10.1007/s12265-022-10241-0] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/25/2021] [Accepted: 03/18/2022] [Indexed: 12/25/2022]
Abstract
Surgical myocardial revascularization is associated with long-term survival benefit in patients with multivessel coronary artery disease. However, the exact biological mechanisms underlying the clinical benefits of myocardial revascularization have not been elucidated yet. Angiogenesis and arteriogenesis biologically leading to vascular collateralization are considered one of the endogenous mechanisms to preserve myocardial viability during ischemia, and the presence of coronary collateralization has been regarded as one of the predictors of long-term survival in patients with coronary artery disease (CAD). Some experimental studies and indirect clinical evidence on chronic CAD confirmed an angiogenetic response induced by myocardial revascularization and suggested that revascularization procedures could constitute an angiogenetic trigger per se. In this review, the clinical and basic science evidence regarding arteriogenesis and angiogenesis in both CAD and coronary revascularization is analyzed with the aim to better elucidate their significance in the clinical arena and potential therapeutic use.
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Affiliation(s)
- Cristiano Spadaccio
- Cardiac Surgery, Massachusetts General Hospital & Harvard Medical School, Boston, USA. .,Cardiac Surgery, Golden Jubilee National Hospital & University of Glasgow, Glasgow, UK.
| | - Antonio Nenna
- Cardiac Surgery, Università Campus Bio-Medico di Roma, Rome, Italy
| | - David Rose
- Cardiac Surgery, Lancashire Cardiac Centre, Blackpool Victoria Hospital, Blackpool, UK
| | | | | | | | - Massimo Chello
- Cardiac Surgery, Università Campus Bio-Medico di Roma, Rome, Italy
| | - Gus J Vlahakes
- Cardiac Surgery, Massachusetts General Hospital & Harvard Medical School, Boston, USA
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8
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Effects of adipose-derived stromal cells and endothelial progenitor cells on adipose transplant survival and angiogenesis. PLoS One 2022; 17:e0261498. [PMID: 35025920 PMCID: PMC8758088 DOI: 10.1371/journal.pone.0261498] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Accepted: 12/03/2021] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND A paracrine mechanism is thought to mediate the proangiogenic capacity of adipose-derived stromal/stem cells (ASCs). However, the precise mechanism by which ASCs promote the formation of blood vessels by endothelial progenitor cells (EPCs) is unclear. METHODS The EPCs-ASCs cocultures prepared in different ratios were subjected to tube formations assay to verify whether ASCs could directly participate in the tube genesis. The supernatant from cultured ASCs was used to stimulate EPCs to evaluate the effects on the angiogenic property of EPCs, as well as capacity for migration and invasion. A coculture model with transwell chamber were used to explore the regulation of angiogenesis markers expression in EPCs by ASCs. We then mixed ASCs with EPCs and transplanted them with adipose tissue into nude mice to evaluate the effects on angiogenesis in adipose tissue grafts. RESULTS In the EPCs-ASCs cocultures, the tube formation was significantly decreased as the relative abundance of ASCs increased, while the ASCs was found to migrate and integrated into the agglomerates formed by EPCs. The supernatant from ASCs cultures promoted the migration and invasion of EPCs and the ability to form capillary-like structures. The expression of multiple angiogenesis markers in EPCs were significantly increased when cocultured with ASCs. In vivo, ASCs combined with EPC promoted vascularization in the fat transplant. Immunofluorescence straining of Edu and CD31 indicated that the Edu labeled EPC did not directly participate in the vascularization inside the fat tissue. CONCLUSIONS ADSC can participate in the tube formation of EPC although it cannot form canonical capillary structures. Meanwhile, Soluble factors secreted by ASCs promotes the angiogenic potential of EPCs. ASCs paracrine signaling appears to promote angiogenesis by increasing the migration and invasion of EPCs and simultaneously upregulating the expression of angiogenesis markers in EPCs. The results of in vivo experiments showed that ASCs combined with EPCs significantly promote the formation of blood vessels in the fat implant. Remarkably, EPCs may promote angiogenesis by paracrine regulation of endogenous endothelial cells (ECs) rather than direct participation in the formation of blood vessels.
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9
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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: 38] [Impact Index Per Article: 9.5] [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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10
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Yogi A, Rukhlova M, Charlebois C, Tian G, Stanimirovic DB, Moreno MJ. Differentiation of Adipose-Derived Stem Cells into Vascular Smooth Muscle Cells for Tissue Engineering Applications. Biomedicines 2021; 9:biomedicines9070797. [PMID: 34356861 PMCID: PMC8301460 DOI: 10.3390/biomedicines9070797] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 06/15/2021] [Accepted: 06/25/2021] [Indexed: 11/20/2022] Open
Abstract
Synthetic grafts have been developed for vascular bypass surgery, however, the risks of thrombosis and neointimal hyperplasia still limit their use. Tissue engineering with the use of adipose-derived stem cells (ASCs) has shown promise in addressing these limitations. Here we further characterized and optimized the ASC differentiation into smooth muscle cells (VSMCs) induced by TGF-β and BMP-4. TGF-β and BMP-4 induced a time-dependent expression of SMC markers in ASC. Shortening the differentiation period from 7 to 4 days did not impair the functional property of contraction in these cells. Stability of the process was demonstrated by switching cells to regular growth media for up to 14 days. The role of IGFBP7, a downstream effector of TGF-β, was also examined. Finally, topographic and surface patterning of a substrate is recognized as a powerful tool for regulating cell differentiation. Here we provide evidence that a non-woven PET structure does not affect the differentiation of ASC. Taken together, our results indicate that VSMCs differentiated from ASCs are a suitable candidate to populate a PET-based vascular scaffolds. By employing an autologous source of cells we provide a novel alternative to address major issues that reduces long-term patency of currently vascular grafts.
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Affiliation(s)
- Alvaro Yogi
- Human Health Therapeutics, National Research Council of Canada, 1200 Montreal Road, Ottawa, ON K1A0R6, Canada; (M.R.); (C.C.); (D.B.S.)
- Correspondence: (A.Y.); (M.J.M.); Tel.: +1-613-990-0891 (A.Y.); +1-613-990-0829 (M.J.M.)
| | - Marina Rukhlova
- Human Health Therapeutics, National Research Council of Canada, 1200 Montreal Road, Ottawa, ON K1A0R6, Canada; (M.R.); (C.C.); (D.B.S.)
| | - Claudie Charlebois
- Human Health Therapeutics, National Research Council of Canada, 1200 Montreal Road, Ottawa, ON K1A0R6, Canada; (M.R.); (C.C.); (D.B.S.)
| | - Ganghong Tian
- Medical Devices Research Centre, National Research Council of Canada, 435 Ellice Ave, Winnipeg, MB R3B 1Y6, Canada;
| | - Danica B. Stanimirovic
- Human Health Therapeutics, National Research Council of Canada, 1200 Montreal Road, Ottawa, ON K1A0R6, Canada; (M.R.); (C.C.); (D.B.S.)
| | - Maria J. Moreno
- Human Health Therapeutics, National Research Council of Canada, 1200 Montreal Road, Ottawa, ON K1A0R6, Canada; (M.R.); (C.C.); (D.B.S.)
- Correspondence: (A.Y.); (M.J.M.); Tel.: +1-613-990-0891 (A.Y.); +1-613-990-0829 (M.J.M.)
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11
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Qin F, Zhang W, Zhang M, Long X, Si L, Li Z, Huang J, Wang X. Adipose-Derived Stem Cells Improve the Aging Skin of Nude Mice by Promoting Angiogenesis and Reducing Local Tissue Water. Aesthet Surg J 2021; 41:NP905-NP913. [PMID: 33428732 DOI: 10.1093/asj/sjab001] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Adipose-derived stem cells (ASCs) are considered promising cells for skin rejuvenation. However, whether the angiogenetic effect of ASCs plays an important role in the treatment of aging skin and its influence on skin tissue remain elusive. OBJECTIVES The aim of this study was to evaluate the effect of ASCs on angiogenesis and local tissue water (LTW) in the aging skin of nude mice. METHODS Twelve nude mice were randomly divided into a UVB-induced photoaging group and a natural aging group. After the mouse model had been established, ASCs and phosphate-buffered saline (PBS) were then each injected into different sides of the dorsal skin of the mice. Blood perfusion and LTW content were measured. After 7 weeks, mice were killed, and skin samples were collected to measure the thickness of the dermis, the density of the capillaries, and the expression of angiogenic growth factors. RESULTS ASC therapy significantly increased the thickness of the dermis, the number of capillaries, and the expression of some angiogenic growth factors (vascular endothelial growth factor, insulin-like growth factor 1, and epidermal growth factor). At 7 weeks after injection, blood perfusion was significantly higher on the side injected with ASCs than on the side injected with PBS. LTW content was increased in the PBS-injected side, but the ASC-injected side showed no significant changes over time. CONCLUSIONS ASCs increased dermal thickness, promoted angiogenesis, and reduced LTW content in the skin of photoaging mice, providing a potential clinical therapy for skin rejuvenation.
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Affiliation(s)
- Feng Qin
- Department of Plastic Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Beijing, China
| | - Wenchao Zhang
- Department of Plastic Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Beijing, China
| | - Mingzi Zhang
- Department of Plastic Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Beijing, China
| | - Xiao Long
- Department of Plastic Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Beijing, China
| | - Loubin Si
- Department of Plastic Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Beijing, China
| | - Zhenjiang Li
- Department of Vascular Surgery, First Affiliated Hospital of the Medical School of Zhejiang University, Hangzhou, China
| | - Jiuzuo Huang
- Department of Plastic Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Beijing, China
| | - Xiaojun Wang
- Department of Plastic Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Beijing, China
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12
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Ghodrat S, Hoseini SJ, Asadpour S, Nazarnezhad S, Alizadeh Eghtedar F, Kargozar S. Stem cell-based therapies for cardiac diseases: The critical role of angiogenic exosomes. Biofactors 2021; 47:270-291. [PMID: 33606893 DOI: 10.1002/biof.1717] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2020] [Accepted: 01/25/2021] [Indexed: 12/26/2022]
Abstract
Finding effective treatments for cardiac diseases is among the hottest subjects in medicine; cell-based therapies have brought great promises for managing a broad range of life-threatening heart complications such as myocardial infarction. After clarifying the critical role of angiogenesis in tissue repair and regeneration, various stem/progenitor cell were utilized to accelerate the healing of injured cardiac tissue. Embryonic, fetal, adult, and induced pluripotent stem cells have shown the appropriate proangiogenic potential for tissue repair strategies. The capability of stem cells for differentiating into endothelial lineages was initially introduced as the primary mechanism involved in improving angiogenesis and accelerated heart tissue repair. However, recent studies have demonstrated the leading role of paracrine factors secreted by stem cells in advancing neo-vessel formation. Genetically modified stem cells are also being applied for promoting angiogenesis regarding their ability to considerably overexpress and secrete angiogenic bioactive molecules. Yet, conducting further research seems necessary to precisely identify molecular mechanisms behind the proangiogenic potential of stem cells, including the signaling pathways and regulatory molecules such as microRNAs. In conclusion, stem cells' pivotal roles in promoting angiogenesis and consequent improved cardiac healing and remodeling processes should not be ignored, especially in the case of stem cell-derived extracellular vesicles.
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Affiliation(s)
- Sara Ghodrat
- Department of Nutrition, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyed Javad Hoseini
- Department of Medical Biotechnology and Nanotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Shiva Asadpour
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Simin Nazarnezhad
- Tissue Engineering Research Group (TERG), Department of Anatomy and Cell Biology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Fariba Alizadeh Eghtedar
- Tissue Engineering Research Group (TERG), Department of Anatomy and Cell Biology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Saeid Kargozar
- Tissue Engineering Research Group (TERG), Department of Anatomy and Cell Biology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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Functional Recovery after Intramyocardial Injection of Adipose-Derived Stromal Cells Assessed by Cardiac Magnetic Resonance Imaging. Stem Cells Int 2021; 2021:5556800. [PMID: 33976700 PMCID: PMC8087467 DOI: 10.1155/2021/5556800] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Revised: 04/02/2021] [Accepted: 04/15/2021] [Indexed: 12/22/2022] Open
Abstract
Aims A major clinical concern is the continuous increase in the number of patients diagnosed with advanced coronary artery disease, ischemic heart failure, and refractory angina, and one of the most promising treatment options for these conditions is stem cell-based therapy. The aim of this study was to assess the functional improvement following intramyocardial injection of adipose-derived stromal cells, using cardiac magnetic resonance. Methods and Results Thirteen patients with ischemic heart failure, reduced left ventricular ejection fraction, refractory angina, and who have been disqualified from any form of direct revascularization were enrolled in the study with transthoracic autologous adipose-derived stromal cell implantation. All patients underwent cardiac magnetic resonance prior to the procedure and after 12 months of follow-up. A significant increase in stroke volume (83.1 ± 8.5 mL vs 93.8 ± 13.8 mL, p = 0.025) and stroke volume index (43.3 ± 7.6 mL/m2 vs 48.7 ± 9.1 mL/m2, p = 0.019), a statistical trend toward an increase in left ventricle ejection fraction (36.7 ± 13.2 vs 39.7 ± 14.9, p = 0.052), and cardiac output improvement (5.0 ± 0.7 vs 5.5 ± 0.9, p = 0.073) was observed in the patient postprocedure. Enhanced relative regional thickening was noted in the segments with adipose-derived stromal cell implantation. Conclusions Intramyocardial adipose-derived stromal cell implantation is a promising therapeutic option for selected, symptomatic patients with ischemic heart failure, who have preserved myocardial viability despite being unsuitable for direct revascularization.
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14
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Nammian P, Asadi-Yousefabad SL, Daneshi S, Sheikhha MH, Tabei SMB, Razban V. Comparative analysis of mouse bone marrow and adipose tissue mesenchymal stem cells for critical limb ischemia cell therapy. Stem Cell Res Ther 2021; 12:58. [PMID: 33436054 PMCID: PMC7805174 DOI: 10.1186/s13287-020-02110-x] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Accepted: 12/21/2020] [Indexed: 02/08/2023] Open
Abstract
INTRODUCTION Critical limb ischemia (CLI) is the most advanced form of peripheral arterial disease (PAD) characterized by ischemic rest pain and non-healing ulcers. Currently, the standard therapy for CLI is the surgical reconstruction and endovascular therapy or limb amputation for patients with no treatment options. Neovasculogenesis induced by mesenchymal stem cells (MSCs) therapy is a promising approach to improve CLI. Owing to their angiogenic and immunomodulatory potential, MSCs are perfect candidates for the treatment of CLI. The purpose of this study was to determine and compare the in vitro and in vivo effects of allogeneic bone marrow mesenchymal stem cells (BM-MSCs) and adipose tissue mesenchymal stem cells (AT-MSCs) on CLI treatment. METHODS For the first step, BM-MSCs and AT-MSCs were isolated and characterized for the characteristic MSC phenotypes. Then, femoral artery ligation and total excision of the femoral artery were performed on C57BL/6 mice to create a CLI model. The cells were evaluated for their in vitro and in vivo biological characteristics for CLI cell therapy. In order to determine these characteristics, the following tests were performed: morphology, flow cytometry, differentiation to osteocyte and adipocyte, wound healing assay, and behavioral tests including Tarlov, Ischemia, Modified ischemia, Function and the grade of limb necrosis scores, donor cell survival assay, and histological analysis. RESULTS Our cellular and functional tests indicated that during 28 days after cell transplantation, BM-MSCs had a great effect on endothelial cell migration, muscle restructure, functional improvements, and neovascularization in ischemic tissues compared with AT-MSCs and control groups. CONCLUSIONS Allogeneic BM-MSC transplantation resulted in a more effective recovery from critical limb ischemia compared to AT-MSCs transplantation. In fact, BM-MSC transplantation could be considered as a promising therapy for diseases with insufficient angiogenesis including hindlimb ischemia.
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Affiliation(s)
- Pegah Nammian
- Department of Molecular Medicine, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | | | - Sajad Daneshi
- Postdoctoral Researcher, Stem Cells Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohammad Hasan Sheikhha
- Biotechnology Research Center, International Campus, Shahid Sadoughi University of MedicalSciences, Yazd, Iran
- Research and Clinical Center for Infertility, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Seyed Mohammad Bagher Tabei
- Department of Genetics, Shiraz University of Medical Science, Shiraz, Iran.
- Maternal-fetal Medicine Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
| | - Vahid Razban
- Department of Molecular Medicine, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran.
- Stem Cells Technology Research center, Shiraz University of Medical Sciences, Shiraz, Iran.
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15
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Fang J, Chen F, Liu D, Gu F, Wang Y. Adipose tissue-derived stem cells in breast reconstruction: a brief review on biology and translation. Stem Cell Res Ther 2021; 12:8. [PMID: 33407902 PMCID: PMC7789635 DOI: 10.1186/s13287-020-01955-6] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Accepted: 09/27/2020] [Indexed: 02/07/2023] Open
Abstract
Recent developments in adipose-derived stromal/stem cell (ADSC) biology provide new hopes for tissue engineering and regeneration medicine. Due to their pluripotent activity, paracrine activity, and immunomodulatory function, ADSCs have been widely administrated and exhibited significant therapeutic effects in the treatment for autoimmune disorders, neurodegenerative diseases, and ischemic conditions both in animals and human clinical trials. Cell-assisted lipotransfer (CAL) based on ADSCs has emerged as a promising cell therapy technology and significantly improved the fat graft retention. Initially applied for cosmetic breast and facial enhancement, CAL has found a potential use for breast reconstruction in breast cancer patients. However, more challenges emerge related to CAL including lack of a standardized surgical procedure, the controversy in the effectiveness of CAL, and the potential oncogenic risk of ADSCs in cancer patients. In this review, we summarized the latest research and intended to give an outline involving the biological characteristics of ADSCs as well as the preclinical and clinical application of ADSCs.
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Affiliation(s)
- Jun Fang
- Zhejiang Key Laboratory of Radiation Oncology, Hangzhou, China.,Department of Radiation Therapy, Zhejiang Cancer Hospital, Hangzhou, China.,Radiotherapy, Institute of Cancer and Basic Medicine (ICBM), Chinese Academy of Sciences, Cancer Hospital of the University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou, China
| | - Feng Chen
- Department of Breast Tumor Surgery, Institute of Cancer Research and Basic Medical Sciences of Chinese Academy of Sciences, Cancer Hospital of University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou, China
| | - Dong Liu
- Zhejiang Key Laboratory of Radiation Oncology, Hangzhou, China.,Department of Radiation Therapy, Zhejiang Cancer Hospital, Hangzhou, China.,Radiotherapy, Institute of Cancer and Basic Medicine (ICBM), Chinese Academy of Sciences, Cancer Hospital of the University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou, China
| | - Feiying Gu
- Zhejiang Key Laboratory of Radiation Oncology, Hangzhou, China.,Department of Radiation Therapy, Zhejiang Cancer Hospital, Hangzhou, China.,Radiotherapy, Institute of Cancer and Basic Medicine (ICBM), Chinese Academy of Sciences, Cancer Hospital of the University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou, China
| | - Yuezhen Wang
- Zhejiang Key Laboratory of Radiation Oncology, Hangzhou, China. .,Department of Radiation Therapy, Zhejiang Cancer Hospital, Hangzhou, China. .,Radiotherapy, Institute of Cancer and Basic Medicine (ICBM), Chinese Academy of Sciences, Cancer Hospital of the University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou, China.
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16
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Capin L, Abbassi N, Lachat M, Calteau M, Barratier C, Mojallal A, Bourgeois S, Auxenfans C. Encapsulation of Adipose-Derived Mesenchymal Stem Cells in Calcium Alginate Maintains Clonogenicity and Enhances their Secretory Profile. Int J Mol Sci 2020; 21:E6316. [PMID: 32878250 PMCID: PMC7504546 DOI: 10.3390/ijms21176316] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Revised: 08/18/2020] [Accepted: 08/28/2020] [Indexed: 12/11/2022] Open
Abstract
Adipose-derived mesenchymal stem cells (ASCs) are well known for their secretory potential, which confers them useful properties in cell therapy. Nevertheless, this therapeutic potential is reduced after transplantation due to their short survival in the human body and their migration property. This study proposes a method to protect cells during and after injection by encapsulation in microparticles of calcium alginate. Besides, the consequences of encapsulation on ASC proliferation, pluripotential, and secretome were studied. Spherical particles with a mean diameter of 500 µm could be obtained in a reproducible manner with a viability of 70% after 16 days in vitro. Moreover, encapsulation did not alter the proliferative properties of ASCs upon return to culture nor their differentiation potential in adipocytes, chondrocytes, and osteocytes. Concerning their secretome, encapsulated ASCs consistently produced greater amounts of interleukin-6 (IL-6), interleukin-8 (IL-8), and vascular endothelial growth factor (VEGF) compared to monolayer cultures. Encapsulation therefore appears to enrich the secretome with transforming growth factor β1 (TGF-β1) and macrophage inflammatory protein-1β (MIP-1β) not detectable in monolayer cultures. Alginate microparticles seem sufficiently porous to allow diffusion of the cytokines of interest. With all these cytokines playing an important role in wound healing, it appears relevant to investigate the impact of using encapsulated ASCs on the wound healing process.
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Affiliation(s)
- Lucille Capin
- Banque de Tissus et de Cellules des Hospices Civils de Lyon, Hôpital Edouard Herriot, Place d’Arsonval, 69003 Lyon, France; (N.A.); (M.L.); (M.C.)
| | - Nacira Abbassi
- Banque de Tissus et de Cellules des Hospices Civils de Lyon, Hôpital Edouard Herriot, Place d’Arsonval, 69003 Lyon, France; (N.A.); (M.L.); (M.C.)
| | - Maëlle Lachat
- Banque de Tissus et de Cellules des Hospices Civils de Lyon, Hôpital Edouard Herriot, Place d’Arsonval, 69003 Lyon, France; (N.A.); (M.L.); (M.C.)
| | - Marie Calteau
- Banque de Tissus et de Cellules des Hospices Civils de Lyon, Hôpital Edouard Herriot, Place d’Arsonval, 69003 Lyon, France; (N.A.); (M.L.); (M.C.)
| | - Cynthia Barratier
- Univ Lyon, Université Claude Bernard Lyon 1, LAGEPP UMR 5007 CNRS, F-69100 Villeurbanne, France; (C.B.); (S.B.)
- Univ Lyon, Université Claude Bernard Lyon 1, ISPB-Faculté de Pharmacie, F-69008 Lyon, France
| | - Ali Mojallal
- Service de chirurgie plastique, reconstructrice et esthétique, Hôpital de la Croix Rousse, Hospices Civils de Lyon, 69004 Lyon, France;
- Univ Lyon, Université Claude Bernard-Lyon 1, 8 avenue Rockefeller, 69008 Lyon, France
| | - Sandrine Bourgeois
- Univ Lyon, Université Claude Bernard Lyon 1, LAGEPP UMR 5007 CNRS, F-69100 Villeurbanne, France; (C.B.); (S.B.)
- Univ Lyon, Université Claude Bernard Lyon 1, ISPB-Faculté de Pharmacie, F-69008 Lyon, France
| | - Céline Auxenfans
- Banque de Tissus et de Cellules des Hospices Civils de Lyon, Hôpital Edouard Herriot, Place d’Arsonval, 69003 Lyon, France; (N.A.); (M.L.); (M.C.)
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17
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Hutchings G, Janowicz K, Moncrieff L, Dompe C, Strauss E, Kocherova I, Nawrocki MJ, Kruszyna Ł, Wąsiatycz G, Antosik P, Shibli JA, Mozdziak P, Perek B, Krasiński Z, Kempisty B, Nowicki M. The Proliferation and Differentiation of Adipose-Derived Stem Cells in Neovascularization and Angiogenesis. Int J Mol Sci 2020; 21:ijms21113790. [PMID: 32471255 PMCID: PMC7312564 DOI: 10.3390/ijms21113790] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Accepted: 05/25/2020] [Indexed: 12/13/2022] Open
Abstract
Neovascularization and angiogenesis are vital processes in the repair of damaged tissue, creating new blood vessel networks and increasing oxygen and nutrient supply for regeneration. The importance of Adipose-derived Mesenchymal Stem Cells (ASCs) contained in the adipose tissue surrounding blood vessel networks to these processes remains unknown and the exact mechanisms responsible for directing adipogenic cell fate remain to be discovered. As adipose tissue contains a heterogenous population of partially differentiated cells of adipocyte lineage; tissue repair, angiogenesis and neovascularization may be closely linked to the function of ASCs in a complex relationship. This review aims to investigate the link between ASCs and angiogenesis/neovascularization, with references to current studies. The molecular mechanisms of these processes, as well as ASC differentiation and proliferation are described in detail. ASCs may differentiate into endothelial cells during neovascularization; however, recent clinical trials have suggested that ASCs may also stimulate angiogenesis and neovascularization indirectly through the release of paracrine factors.
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Affiliation(s)
- Greg Hutchings
- The School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen AB25 2ZD, UK; (G.H.); (K.J.); (L.M.)
- Department of Anatomy, Poznan University of Medical Sciences, 60-781 Poznan, Poland; (I.K.); (M.J.N.); (B.K.)
| | - Krzysztof Janowicz
- The School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen AB25 2ZD, UK; (G.H.); (K.J.); (L.M.)
- Department of Anatomy, Poznan University of Medical Sciences, 60-781 Poznan, Poland; (I.K.); (M.J.N.); (B.K.)
| | - Lisa Moncrieff
- The School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen AB25 2ZD, UK; (G.H.); (K.J.); (L.M.)
- Department of Histology and Embryology, Poznan University of Medical Sciences, 60-781 Poznan, Poland;
| | - Claudia Dompe
- The School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen AB25 2ZD, UK; (G.H.); (K.J.); (L.M.)
- Department of Histology and Embryology, Poznan University of Medical Sciences, 60-781 Poznan, Poland;
- Correspondence:
| | - Ewa Strauss
- Institute of Human Genetics, Polish Academy of Sciences, 60-479 Poznan, Poland;
- Department of Vascular, Endovascular Surgery, Angiology and Phlebology Poznan University of Medical Sciences, 61-701 Poznan, Poland; (L.K.); (Z.K.)
| | - Ievgeniia Kocherova
- Department of Anatomy, Poznan University of Medical Sciences, 60-781 Poznan, Poland; (I.K.); (M.J.N.); (B.K.)
| | - Mariusz J. Nawrocki
- Department of Anatomy, Poznan University of Medical Sciences, 60-781 Poznan, Poland; (I.K.); (M.J.N.); (B.K.)
| | - Łukasz Kruszyna
- Department of Vascular, Endovascular Surgery, Angiology and Phlebology Poznan University of Medical Sciences, 61-701 Poznan, Poland; (L.K.); (Z.K.)
| | - Grzegorz Wąsiatycz
- Department of Veterinary Surgery, Institute of Veterinary Medicine, Nicolaus Copernicus University in Toruń, 87-100 Toruń, Poland; (G.W.); (P.A.)
| | - Paweł Antosik
- Department of Veterinary Surgery, Institute of Veterinary Medicine, Nicolaus Copernicus University in Toruń, 87-100 Toruń, Poland; (G.W.); (P.A.)
| | - Jamil A. Shibli
- Department of Periodontology and Oral Implantology, Dental Research Division, University of Guarulhos, São Paulo 07023-070, Brazil;
| | - Paul Mozdziak
- Physiology Graduate Program, North Carolina State University, Raleigh, NC 27695, USA;
| | - Bartłomiej Perek
- Department of Cardiac Surgery and Transplantology, Poznan University of Medical Sciences, 61-848 Poznań, Poland;
| | - Zbigniew Krasiński
- Department of Vascular, Endovascular Surgery, Angiology and Phlebology Poznan University of Medical Sciences, 61-701 Poznan, Poland; (L.K.); (Z.K.)
| | - Bartosz Kempisty
- Department of Anatomy, Poznan University of Medical Sciences, 60-781 Poznan, Poland; (I.K.); (M.J.N.); (B.K.)
- Department of Histology and Embryology, Poznan University of Medical Sciences, 60-781 Poznan, Poland;
- Department of Veterinary Surgery, Institute of Veterinary Medicine, Nicolaus Copernicus University in Toruń, 87-100 Toruń, Poland; (G.W.); (P.A.)
- Department of Obstetrics and Gynecology, University Hospital and Masaryk University, 601 77 Brno, Czech Republic
| | - Michał Nowicki
- Department of Histology and Embryology, Poznan University of Medical Sciences, 60-781 Poznan, Poland;
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18
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Mesenchymal and Induced Pluripotent Stem Cells-Derived Extracellular Vesicles: The New Frontier for Regenerative Medicine? Cells 2020; 9:cells9051163. [PMID: 32397132 PMCID: PMC7290733 DOI: 10.3390/cells9051163] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Revised: 05/02/2020] [Accepted: 05/04/2020] [Indexed: 12/13/2022] Open
Abstract
Regenerative medicine aims to repair damaged, tissues or organs for the treatment of various diseases, which have been poorly managed with conventional drugs and medical procedures. To date, multimodal regenerative methods include transplant of healthy organs, tissues, or cells, body stimulation to activate a self-healing response in damaged tissues, as well as the combined use of cells and bio-degradable scaffold to obtain functional tissues. Certainly, stem cells are promising tools in regenerative medicine due to their ability to induce de novo tissue formation and/or promote organ repair and regeneration. Currently, several studies have shown that the beneficial stem cell effects, especially for mesenchymal stem cells (MSCs) and induced pluripotent stem cells (iPSCs) in damaged tissue restore are not dependent on their engraftment and differentiation on the injury site, but rather to their paracrine activity. It is now well known that paracrine action of stem cells is due to their ability to release extracellular vesicles (EVs). EVs play a fundamental role in cell-to-cell communication and are directly involved in tissue regeneration. In the present review, we tried to summarize the molecular mechanisms through which MSCs and iPSCs-derived EVs carry out their therapeutic action and their possible application for the treatment of several diseases.
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19
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Lin Y, Li X, Fan C, Yang F, Hao D, Ge W, Gao Y. Cardioprotective effects of rat adipose‑derived stem cells differ under normoxic/physioxic conditions and are associated with paracrine factor secretion. Int J Mol Med 2020; 45:1591-1600. [PMID: 32323745 DOI: 10.3892/ijmm.2020.4524] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Accepted: 02/13/2020] [Indexed: 11/06/2022] Open
Abstract
Adipose tissue‑derived stem cells (ASCs) are beneficial for myocardial regeneration. The physiological oxygen content of human organs is estimated to range between 1 and 11%. However, in the majority of previous in vitro studies with cultured ASCs, the O2 concentration was artificially set to 21%. The present study aimed to compare the protective effects of rat ASCs on neonatal rat ventricular myocytes (NRVMs) under normoxic (21% O2) and physioxic (5% O2) conditions. Rat NRVMs cultured under normoxia or physioxia were treated with H2O2 or left untreated, and further co‑cultured with ASCs in 21% or 5% O2. The apoptosis of NRVMs was evaluated by Annexin V staining and quantitating the protein levels of Bcl‑2 and Bax by western blotting. The oxidative stress of NRVMs was determined by a glutathione/oxidized glutathione assay kit. The concentrations of secreted vascular endothelium growth factor (VEGF), insulin like growth factor‑1 (IGF‑1) and basic fibroblast growth factor (bFGF) in the culture medium were quantified by enzyme‑linked immunosorbent assay. Under both normoxia and physioxia, co‑culture with ASCs protected H2O2‑exposed NRVMs from apoptosis and significantly alleviated the oxidative stress in NRVMs. The protective effects of ASCs were associated with increased secretion of VEGF, IGF‑1 and bFGF. ASCs cultured in 5% O2 exhibited certain cardioprotective effects against H2O2 stress. The results of the present study suggested that O2 concentrations influenced the cardioprotective effects of ASCs. VEGF, IGF‑1 and bFGF may serve a role in the myocardial regeneration mediated by transplanted ASCs.
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Affiliation(s)
- Yuanyuan Lin
- Department of Cardiology, Shanxi Bethune Hospital, Taiyuan, Shanxi 030032, P.R. China
| | - Xuewen Li
- Department of Cardiology, Shanxi Bethune Hospital, Taiyuan, Shanxi 030032, P.R. China
| | - Chunhui Fan
- Department of Information, Shanxi Bethune Hospital, Taiyuan, Shanxi 030032, P.R. China
| | - Fan Yang
- Department of Cardiology, Shanxi Bethune Hospital, Taiyuan, Shanxi 030032, P.R. China
| | - Dajie Hao
- Department of Cardiology, Shanxi Bethune Hospital, Taiyuan, Shanxi 030032, P.R. China
| | - Wenjia Ge
- Department of Science Research and Education, Shanxi Bethune Hospital, Taiyuan, Shanxi 030032, P.R. China
| | - Yuping Gao
- Department of Cardiology, Shanxi Bethune Hospital, Taiyuan, Shanxi 030032, P.R. China
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Qayyum AA, Mathiasen AB, Mygind ND, Vejlstrup NG, Kastrup J. Cardiac Magnetic Resonance Imaging used for Evaluation of Adipose-Derived Stromal Cell Therapy in Patients with Chronic Ischemic Heart Disease. Cell Transplant 2019; 28:1700-1708. [PMID: 31698917 PMCID: PMC6923551 DOI: 10.1177/0963689719883592] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Adipose-derived stromal cell (ASC) therapy is currently investigated as a new treatment
option for patients with ischemic heart disease (IHD). The aim of this study was to
evaluate the effect of ASC therapy in patients with chronic IHD measuring myocardial
perfusion and cardiac function using cardiac magnetic resonance imaging (CMRI). Patients
were included in MyStromalCell trial, a phase II, randomized, double-blinded,
placebo-controlled study investigated the effect of ASCs in patients with chronic IHD with
preserved left ventricular ejection fraction (LVEF). In total, 41 of 60 patients underwent
cine, late enhancement, rest and stress imaging with CMRI. There was a non-significant
difference between stress and rest values in maximal signal intensity, a measure of
myocardial perfusion, from baseline to follow-up comparing placebo with ASC group (–52.52
± 88.61 and 3.05 ± 63.17, p = 0.061, respectively). LVEF, myocardial
mass, stroke volume, left ventricle end-diastolic volume and end-systolic volume changed
non-significantly (–0.5 ± 4.7%, –3.5 ± 13.1 g, –0.7 ± 8.6 mL, 1.9 ± 25.1 mL and 2.6 ± 16.5
mL, respectively) in the placebo group and in the ASC group (0.7 ± 8.6%, 0.9 ± 10.8 g,
–0.3 ± 26.1 mL, –3.0 ± 31.5 mL and –2.7 ± 20.4 mL, respectively) from baseline to 6 months
follow-up. The amount of scar tissue was unchanged in the placebo group by 0.0 ± 1.6 g,
p = 1.0 and in the ASC group with –0.3 ± 2.3 g, p =
0.540. There was no difference between the groups. There was a non-significant trend
toward increased myocardial perfusion but no significant changes in functional parameters
or amount of scar tissue in patients treated with ASCs compared with patients allocated
into the placebo group.
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Affiliation(s)
- Abbas Ali Qayyum
- Department of Cardiology & Cardiac Catheterization Laboratory 2014, Rigshospitalet University of Copenhagen, Copenhagen, Denmark
| | - Anders Bruun Mathiasen
- Department of Cardiology & Cardiac Catheterization Laboratory 2014, Rigshospitalet University of Copenhagen, Copenhagen, Denmark
| | - Naja Dam Mygind
- Department of Cardiology & Cardiac Catheterization Laboratory 2014, Rigshospitalet University of Copenhagen, Copenhagen, Denmark
| | - Niels Groove Vejlstrup
- Department of Cardiology & Cardiac Catheterization Laboratory 2014, Rigshospitalet University of Copenhagen, Copenhagen, Denmark
| | - Jens Kastrup
- Department of Cardiology & Cardiac Catheterization Laboratory 2014, Rigshospitalet University of Copenhagen, Copenhagen, Denmark.,Cardiology Stem Cell Centre 9302, Rigshospitalet University of Copenhagen, Copenhagen, Denmark
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Choi JW, Moon H, Jung SE, Lim S, Lee S, Kim IK, Lee HB, Lee J, Song BW, Kim SW, Hwang KC. Hypoxia Rapidly Induces the Expression of Cardiomyogenic Factors in Human Adipose-Derived Adherent Stromal Cells. J Clin Med 2019; 8:1231. [PMID: 31443313 PMCID: PMC6723458 DOI: 10.3390/jcm8081231] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Revised: 08/12/2019] [Accepted: 08/15/2019] [Indexed: 11/27/2022] Open
Abstract
BACKGROUND The efficacy of interstitial vascular fraction (SVF) transplantation in the treatment of heart disease has been proven in a variety of in vivo studies. In a previous study, we found that bone marrow-derived mesenchymal stem cells (BM-MSCs) altered their expression of several cardiomyogenic factors under hypoxic conditions. METHODS We hypothesized that hypoxia may also induce obtained adipose-derived adherent stromal cells (ADASs) from SVFs and adipose-derived stem cells (ASCs) to differentiate into cardiomyocytes and/or cells with comparable phenotypes. We examined the differentiation markers of cell lineages in ADASs and ASCs according to time by hypoxic stress and found that only ADASs expressed cardiomyogenic markers within 24 h under hypoxic conditions in association with the expression of hypoxia-inducible factor 1-α (HIF-1α). RESULTS Differentially secreted proteins in a conditioned medium (CM) from ASCs and ADASs under normoxic or hypoxic conditions were detected using an antibody assay and may be associated with a dramatic increase in the expression of cardiomyogenic markers in only ADASs. Furthermore, the cardiomyogenic factors were expressed more rapidly in ADASs than in ASCs under hypoxic conditions in association with the expression of HIF-1α, and angiogenin, fibroblast growth factor-19 (FGF-19) and/or macrophage inhibitory factor (MIF) are related. CONCLUSIONS These results provide new insights into the applicability of ADASs preconditioned by hypoxic stress in cardiac diseases.
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Affiliation(s)
- Jung-Won Choi
- Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung-si, Gangwon-do 210-701, Korea
| | - Hanbyeol Moon
- Department of Integrated Omics for Biomedical Sciences, Graduate School, Yonsei University, Seoul 03722, Korea
| | - Seung Eun Jung
- Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung-si, Gangwon-do 210-701, Korea
| | - Soyeon Lim
- Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung-si, Gangwon-do 210-701, Korea
- International St. Mary's Hospital, Catholic Kwandong University, Incheon Metropolitan City 22711, Korea
| | - Seahyoung Lee
- Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung-si, Gangwon-do 210-701, Korea
- International St. Mary's Hospital, Catholic Kwandong University, Incheon Metropolitan City 22711, Korea
| | - Il-Kwon Kim
- Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung-si, Gangwon-do 210-701, Korea
- International St. Mary's Hospital, Catholic Kwandong University, Incheon Metropolitan City 22711, Korea
| | - Hoon-Bum Lee
- Department of Plastic and Reconstructive Surgery, International St. Mary's Hospital, Catholic Kwandong University, Incheon Metropolitan City 22711, Korea
| | - Jiyun Lee
- Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung-si, Gangwon-do 210-701, Korea
| | - Byeong-Wook Song
- Department of Medical Science, College of Medicine, Catholic Kwandong University, Gangneung-si, Gangwon-do 25601, Korea
| | - Sang Woo Kim
- Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung-si, Gangwon-do 210-701, Korea.
- International St. Mary's Hospital, Catholic Kwandong University, Incheon Metropolitan City 22711, Korea.
| | - Ki-Chul Hwang
- Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung-si, Gangwon-do 210-701, Korea.
- International St. Mary's Hospital, Catholic Kwandong University, Incheon Metropolitan City 22711, Korea.
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22
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Li X, Ma T, Sun J, Shen M, Xue X, Chen Y, Zhang Z. Harnessing the secretome of adipose-derived stem cells in the treatment of ischemic heart diseases. Stem Cell Res Ther 2019; 10:196. [PMID: 31248452 PMCID: PMC6598280 DOI: 10.1186/s13287-019-1289-7] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Adipose-derived stem cells (ASCs) are promising therapeutic cells for ischemic heart diseases, due to the ease and efficiency of acquisition, the potential of myocardial lineage differentiation, and the paracrine effects. Recently, many researchers have claimed that the ASC-based myocardial repair is mainly attributed to its paracrine effects, including the anti-apoptosis, pro-angiogenesis, anti-inflammation effects, and the inhibition of fibrosis, rather than the direct differentiation into cardiovascular lineage cells. However, the usage of ASCs comes with the problems of low cardiac retention and survival after transplantation, like other stem cells, which compromises the effectiveness of the therapy. To overcome these drawbacks, researchers have proposed various strategies for improving survival rate and ensuring sustained paracrine secretion. They also investigated the safety and efficacy of phase I and II clinical trials of ASC-based therapy for cardiovascular diseases. In this review, we will discuss the characterization and paracrine effects of ASCs on myocardial repair, followed by the strategies for stimulating the paracrine secretion of ASCs, and finally their clinical usage.
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Affiliation(s)
- Xiaoting Li
- Department of Cardiology, The Second Affiliated Hospital of Soochow University, No.1055, Sanxiang Road, Suzhou, 215004, China
| | - Teng Ma
- Department of Cardiovascular Surgery, The First Affiliated Hospital & Institute for Cardiovascular Science, Soochow University, No.899, Pinghai Road, Suzhou, 215006, China
| | - Jiacheng Sun
- Department of Cardiovascular Surgery, The First Affiliated Hospital & Institute for Cardiovascular Science, Soochow University, No.899, Pinghai Road, Suzhou, 215006, China
| | - Mingjing Shen
- Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Soochow University, No.1055, Sanxiang Road, Suzhou, 215004, China
| | - Xiang Xue
- Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Soochow University, No.1055, Sanxiang Road, Suzhou, 215004, China
| | - Yongbing Chen
- Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Soochow University, No.1055, Sanxiang Road, Suzhou, 215004, China.
| | - Zhiwei Zhang
- Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Soochow University, No.1055, Sanxiang Road, Suzhou, 215004, China.
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23
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Induction of Macrophage M2b/c Polarization by Adipose Tissue-Derived Mesenchymal Stem Cells. J Immunol Res 2019; 2019:7059680. [PMID: 31321244 PMCID: PMC6607735 DOI: 10.1155/2019/7059680] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Accepted: 04/30/2019] [Indexed: 01/22/2023] Open
Abstract
Background Adipose-derived mesenchymal stem cells (ADMSCs) can promote healing and inhibit inflammation/immune response in local tissues, while the detailed mechanism remains unknown. Results ADMSCs and peritoneal macrophages were collected from C57BL/6 mice. The culture medium (CM) from ADMSCs (24 hours cultured) was collected. The CM was added to the Mφ culture system with lipopolysaccharide (LPS) or IL-4/IL-13 or blank. And those Mφ cultures without adding CM were used as controls. A series of classification markers and signaling pathways for Mφ polarization were detected by using flow cytometry, RT-PCR, and western blotting. Furthermore, the cell viability of all the groups was detected by CCK8 assay. After CM induction in different groups, M1-Mφ markers and M2a-Mφ were decreased; however, M2b/c-Mφ markers increased. STAT3/SOCS3 and STAT6/IRF4 were suppressed in all 3 CM-treated groups. Moreover, the cell viability of all 3 groups which were induced by CM significantly increased as compared to that of the control groups without adding CM. Conclusion ADMSCs can induce nonactivated macrophage and M1-Mφ into M2b/c-Mφ. Downregulation of the STAT3 and STAT6 pathway may involve in this process. This data shows that the anti-inflammatory role of ADMSC in local tissues may be partly due to their effect on Mφ to M2b/c-Mφ.
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24
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Stem cell therapy in heart failure: Where do we stand today? Biochim Biophys Acta Mol Basis Dis 2019; 1866:165489. [PMID: 31199998 DOI: 10.1016/j.bbadis.2019.06.003] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2019] [Revised: 05/30/2019] [Accepted: 06/01/2019] [Indexed: 02/06/2023]
Abstract
Heart failure is a global epidemic that drastically cuts short longevity and compromises quality of life. Approximately 6 million Americans ≥20 years of age carry a diagnosis of heart failure. Worldwide, about 40 million adults are affected. The treatment of HF depends on the etiology. If left untreated it rapidly progresses and compromises quality of life. One of the newer technologies still in its infancy is stem cell therapy for heart failure. This review attempts to highlight the clinical studies done in ischemic cardiomyopathy, dilated cardiomyopathy and restrictive cardiomyopathy. A combined approach of simultaneous revascularization and stem cell therapy appears to produce maximum benefit in ischemic cardiomyopathy. Treatment of dilated cardiomyopathy with stem cells also holds promise but needs more definition with regards to timing, route of cell delivery and type of cell used to achieve reproducible results. The variability noted in response to stem cell therapy in patients could also be secondary to their co-morbidities. Abnormalities of glucose metabolism and diabetes in particular impair stem cell and angiogenic cell mobilization. This opens up a whole new area of investigation into exploring the biochemical microenvironment which could influence the efficacy of stem cell therapy. This article is part of a Special Issue entitled: Stem Cells and Their Applications to Human Diseases edited by Hemachandra Reddy.
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25
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Yu Z, Cai Y, Deng M, Li D, Wang X, Zheng H, Xu Y, Li W, Zhang W. Fat extract promotes angiogenesis in a murine model of limb ischemia: a novel cell-free therapeutic strategy. Stem Cell Res Ther 2018; 9:294. [PMID: 30409190 PMCID: PMC6225561 DOI: 10.1186/s13287-018-1014-y] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2018] [Revised: 09/10/2018] [Accepted: 09/21/2018] [Indexed: 12/22/2022] Open
Abstract
Background The proangiogenic capacity of adipose tissue and its derivatives has been demonstrated in a variety of studies. The paracrine mechanism of the cellular component is considered to play a critical role in the regenerative properties of these tissues. However, cell-based therapy for clinical application has been hindered by limitations such as safety, immunogenicity issues, and difficulties in cell preservation, transportation, and phenotype control. In the current study, we aimed to produce a cell-free extract directly from human fat tissue and evaluate its potential therapeutic efficacy. Methods We developed a novel physical approach to produce a cell-free aqueous extract from human fat tissue (fat extract (FE)). The therapeutic potential of FE was investigated in the ischemic hindlimb model of nude mice. After establishment of hindlimb ischemia with ligation of the left femoral artery and intramuscular injection of FE, blood perfusion was monitored at days 0, 7, 14, 21, and 28. Tissue necrosis and capillary density were evaluated. Enzyme-linked immunosorbent assay was used to analyze the growth factors contained in FE. Moreover, the proliferation, migration, and tube formation ability were tested on human umbilical vein endothelial cells (HUVECs) in vitro when treated with FE. The proangiogenic ability of FE was further assessed in an in-vivo Matrigel plug assay. Results FE was prepared and characterized. The intramuscular injection of FE into the ischemic hindlimb of mice attenuated severe limb loss and increased blood flow and capillary density of the ischemic tissue. Enzyme-linked immunosorbent assay showed that FE contained high levels of various growth factors. When added as a cell culture supplement, FE promoted HUVEC proliferation, migration, and tube formation ability in a dose-dependent manner. The subcutaneous injection of Matrigel infused with FE enhanced vascular formation. Conclusions We developed a novel cell-free therapeutic agent, FE, produced from human adipose tissue. FE was able to attenuate ischemic injury and stimulate angiogenesis in ischemic tissues. This study indicates that FE may represent a novel cell-free therapeutic agent in the treatment of ischemic disorders.
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Affiliation(s)
- Ziyou Yu
- Department of Plastic and Reconstructive Surgery, Shanghai Key Laboratory of Tissue Engineering, Shanghai 9th People's Hospital, Shanghai Jiao Tong University, 639 Zhi Zao Ju Road, Shanghai, 200011, China
| | - Yizuo Cai
- Department of Plastic and Reconstructive Surgery, Shanghai Key Laboratory of Tissue Engineering, Shanghai 9th People's Hospital, Shanghai Jiao Tong University, 639 Zhi Zao Ju Road, Shanghai, 200011, China
| | - Mingwu Deng
- Department of Plastic and Reconstructive Surgery, Shanghai Key Laboratory of Tissue Engineering, Shanghai 9th People's Hospital, Shanghai Jiao Tong University, 639 Zhi Zao Ju Road, Shanghai, 200011, China
| | - Dong Li
- Department of Plastic and Reconstructive Surgery, Shanghai Key Laboratory of Tissue Engineering, Shanghai 9th People's Hospital, Shanghai Jiao Tong University, 639 Zhi Zao Ju Road, Shanghai, 200011, China
| | - Xiangsheng Wang
- Department of Plastic and Reconstructive Surgery, Shanghai Key Laboratory of Tissue Engineering, Shanghai 9th People's Hospital, Shanghai Jiao Tong University, 639 Zhi Zao Ju Road, Shanghai, 200011, China
| | - Hongjie Zheng
- Department of Plastic and Reconstructive Surgery, Shanghai Key Laboratory of Tissue Engineering, Shanghai 9th People's Hospital, Shanghai Jiao Tong University, 639 Zhi Zao Ju Road, Shanghai, 200011, China
| | - Yuda Xu
- Department of Plastic and Reconstructive Surgery, Shanghai Key Laboratory of Tissue Engineering, Shanghai 9th People's Hospital, Shanghai Jiao Tong University, 639 Zhi Zao Ju Road, Shanghai, 200011, China
| | - Wei Li
- Department of Plastic and Reconstructive Surgery, Shanghai Key Laboratory of Tissue Engineering, Shanghai 9th People's Hospital, Shanghai Jiao Tong University, 639 Zhi Zao Ju Road, Shanghai, 200011, China.
| | - Wenjie Zhang
- Department of Plastic and Reconstructive Surgery, Shanghai Key Laboratory of Tissue Engineering, Shanghai 9th People's Hospital, Shanghai Jiao Tong University, 639 Zhi Zao Ju Road, Shanghai, 200011, China.
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26
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The use of stem cells in ischemic heart disease treatment. POLISH JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY 2018; 15:196-199. [PMID: 30310400 PMCID: PMC6180025 DOI: 10.5114/kitp.2018.78446] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/10/2018] [Accepted: 06/12/2018] [Indexed: 11/22/2022]
Abstract
Ischemic heart disease is a major cause of death and disabilities worldwide. Unfortunately, not all patients are suitable for direct revascularization. Cell-based therapies may be alternative options because of their potential to promote neovascularisation and endothelial repair, improving myocardial perfusion. The success of cell-based therapies depends on the type of implanted stem cells, delivery method and underlying disease. Several different cell populations including bone marrow-derived mononuclear cells (MNCs), mesenchymal stromal cells (MSCs), CD34+, CD133+, endothelial progenitor cells, adipose-derived mesenchymal stromal cells (ASCs) and stem cells from placenta and umbilical cord have been investigated. Presently, no consensus exists about the best cell type for clinical regenerative therapy. Because the system of coronary arteries in the ischemic area is poor and most of the coronary artery is significantly narrowed or closed, direct implantation of stem cells in the ischemic area of the heart muscle appears an attractive method.
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27
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Dolati S, Yousefi M, Mahdipour M, Afrasiabi Rad A, Pishgahi A, Nouri M, Jodati AR. Mesenchymal stem cell and bone marrow mononuclear cell therapy for cardiomyopathy: From bench to bedside. J Cell Biochem 2018; 120:45-55. [DOI: 10.1002/jcb.27531] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Accepted: 08/01/2018] [Indexed: 12/19/2022]
Affiliation(s)
- Sanam Dolati
- Aging Research Institute, Tabriz University of Medical Sciences Tabriz Iran
- Drug Applied Research Center, Tabriz University of Medical Sciences Tabriz Iran
- Student’s Research Committee, Tabriz University of Medical Sciences Tabriz Iran
| | - Mehdi Yousefi
- Drug Applied Research Center, Tabriz University of Medical Sciences Tabriz Iran
- Stem Cell Research Center, Tabriz University of Medical Sciences Tabriz Iran
- Department of Immunology Tabriz University of Medical Sciences Tabriz Iran
| | - Mahdi Mahdipour
- Stem Cell Research Center, Tabriz University of Medical Sciences Tabriz Iran
- Department of Reproductive Biology Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences Tabriz Iran
| | - Abbas Afrasiabi Rad
- Cardiovascular Research Center, Tabriz University of Medical Sciences Tabriz Iran
- Department of Cardiac Surgery Tabriz University of Medical Tabriz Iran
| | - Alireza Pishgahi
- Department of Physical Medicine and Rehabilitation Physical Medicine and Rehabilitation Research Center, Tabriz University of Medical Science Tabriz Iran
| | - Mohammad Nouri
- Stem Cell Research Center, Tabriz University of Medical Sciences Tabriz Iran
- Department of Reproductive Biology Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences Tabriz Iran
| | - Ahmad Reza Jodati
- Cardiovascular Research Center, Tabriz University of Medical Sciences Tabriz Iran
- Department of Cardiac Surgery Tabriz University of Medical Tabriz Iran
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28
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Shaik S, Wu X, Gimble J, Devireddy R. Effects of Decade Long Freezing Storage on Adipose Derived Stem Cells Functionality. Sci Rep 2018; 8:8162. [PMID: 29802353 PMCID: PMC5970158 DOI: 10.1038/s41598-018-26546-7] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2018] [Accepted: 05/10/2018] [Indexed: 12/21/2022] Open
Abstract
Over the last decade and half, the optimization of cryopreservation for adipose tissue derived stromal/stem cells (ASCs) especially in determining the optimal combination of cryoprotectant type, cooling rate, and thawing rate have been extensively studied. In this study, we examined the functionality of ASCs that have been frozen-stored for more than 10 years denoted as long-term freezing, frozen within the last 3 to 7 years denoted as short-term freezing and compared their response with fresh ASCs. The mean post-thaw viability for long-term frozen group was 78% whereas for short-term frozen group 79% with no significant differences between the two groups. The flow cytometry evaluation of stromal surface markers, CD29, CD90, CD105, CD44, and CD73 indicated the expression (above 95%) in passages P1-P4 in all of the frozen-thawed ASC groups and fresh ASCs whereas the hematopoietic markers CD31, CD34, CD45, and CD146 were expressed extremely low (below 2%) within both the frozen-thawed and fresh cell groups. Quantitative real time polymerase chain reaction (qPCR) analysis revealed some differences between the osteogenic gene expression of long-term frozen group in comparison to fresh ASCs. Intriguingly, one group of cells from the short-term frozen group exhibited remarkably higher expression of osteogenic genes in comparison to fresh ASCs. The adipogenic differentiation potential remained virtually unchanged between all of the frozen-thawed groups and the fresh ASCs. Long-term cryopreservation of ASCs, in general, has a somewhat negative impact on the osteogenic potential of ASCs, especially as it relates to the decrease in osteopontin gene expression but not significantly so with respect to RUNX2 and osteonectin gene expressions. However, the adipogenic potential, post thaw viability, and immunophenotype characteristics remain relatively intact between all the groups.
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Affiliation(s)
- Shahensha Shaik
- Bioengineering Laboratory, Department of Mechanical Engineering, Louisiana State University, Baton Rouge, LA, USA
| | - Xiying Wu
- La Cell LLC, Tulane University School of Medicine, New Orleans, LA, USA
| | - Jeffrey Gimble
- La Cell LLC, Tulane University School of Medicine, New Orleans, LA, USA
- Center for Stem Cell Research & Regenerative Medicine and Departments of Medicine, Structural & Cellular Biology, and Surgery, Tulane University School of Medicine, New Orleans, LA, USA
| | - Ram Devireddy
- Bioengineering Laboratory, Department of Mechanical Engineering, Louisiana State University, Baton Rouge, LA, USA.
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29
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Muñoz MF, Argüelles S, Guzman-Chozas M, Guillén-Sanz R, Franco JM, Pintor-Toro JA, Cano M, Ayala A. Cell tracking, survival, and differentiation capacity of adipose-derived stem cells after engraftment in rat tissue. J Cell Physiol 2018; 233:6317-6328. [PMID: 29319169 DOI: 10.1002/jcp.26439] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2017] [Accepted: 01/05/2018] [Indexed: 12/30/2022]
Abstract
Adipose tissue is an important source of adipose derived stem cells (ADSCs). These cells have the potential of being used for certain therapies, in which the main objective is to recover the function of a tissue/organ affected by a disease. In order to contribute to repair of the tissue, these cells should be able to survive and carry out their functions in unfavorable conditions after being transplanted. This process requires a better understanding of the biology involved: such as the time cells remain in the implant site, how long they stay there, and whether or not they differentiate into host tissue cells. This report focuses on these questions. ADSC were injected into three different tissues (substantia nigra, ventricle, liver) and they were tracked in vivo with a dual GFP-Luc reporter system. The results show that ADSCs were able to survive up to 4 months after the engraftment and some of them started showing resident cell tissue phenotype. These results demonstrate their long-term capacity of survival and differentiation when injected in vivo.
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Affiliation(s)
- Mario F Muñoz
- Departamento de Bioquímica y Biología Molecular, Universidad de Sevilla, Sevilla, Spain
| | - Sandro Argüelles
- Departamento de Fisiología, Universidad de Sevilla, Sevilla, Spain
| | - Matias Guzman-Chozas
- Departamento de Nutrición, Bromatología, Toxicología y Medicina Legal, . Facultad de Farmacia, Universidad de Sevilla, Sevilla, Spain
| | - Remedios Guillén-Sanz
- Departamento de Nutrición, Bromatología, Toxicología y Medicina Legal, . Facultad de Farmacia, Universidad de Sevilla, Sevilla, Spain
| | - Jaime M Franco
- Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), Departamento de Señalización Celular, Universidad de Sevilla, Sevilla, Spain
| | - José A Pintor-Toro
- Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), Departamento de Señalización Celular, Universidad de Sevilla, Sevilla, Spain
| | - Mercedes Cano
- Departamento de Fisiología, Universidad de Sevilla, Sevilla, Spain
| | - Antonio Ayala
- Departamento de Bioquímica y Biología Molecular, Universidad de Sevilla, Sevilla, Spain
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Adipose-Derived Stromal Cells for Treatment of Patients with Chronic Ischemic Heart Disease (MyStromalCell Trial): A Randomized Placebo-Controlled Study. Stem Cells Int 2017; 2017:5237063. [PMID: 29333165 PMCID: PMC5733128 DOI: 10.1155/2017/5237063] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2017] [Revised: 09/21/2017] [Accepted: 10/12/2017] [Indexed: 12/20/2022] Open
Abstract
We aimed to evaluate the effect of intramyocardial injections of autologous VEGF-A165-stimulated adipose-derived stromal cells (ASCs) in patients with refractory angina. MyStromalCell trial is a randomized double-blind placebo-controlled study including sixty patients with CCS/NYHA class II-III, left ventricular ejection fraction > 40%, and at least one significant coronary artery stenosis. Patients were treated with ASC or placebo in a 2 : 1 ratio. ASCs from the abdomen were culture expanded and stimulated with VEGF-A165. At 6 months follow-up, bicycle exercise tolerance increased significantly in time duration 22 s (95%CI −164 to 208 s) (P = 0.034), in watt 4 (95%CI −33 to 41, 0.048), and in METs 0.2 (95%CI −1.4 to 1.8) (P = 0.048) in the ASC group while there was a nonsignificant increase in the placebo group in time duration 9 s (95%CI −203 to 221 s) (P = 0.053), in watt 7 (95%CI −40 to 54) (P = 0.41), and in METs 0.1 (95%CI −1.7 to 1.9) (P = 0.757). The difference between the groups was not significant (P = 0.680, P = 0.608, and P = 0.720 for time duration, watt, and METs, resp.). Intramyocardial delivered VEGF-A165-stimulated ASC treatment was safe but did not improve exercise capacity compared to placebo. However, exercise capacity increased in the ASC but not in the placebo group. This trial is registered with ClinicalTrials.gov NCT01449032.
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31
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Steinhoff G, Nesteruk J, Wolfien M, Große J, Ruch U, Vasudevan P, Müller P. Stem cells and heart disease - Brake or accelerator? Adv Drug Deliv Rev 2017; 120:2-24. [PMID: 29054357 DOI: 10.1016/j.addr.2017.10.007] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2017] [Revised: 10/12/2017] [Accepted: 10/13/2017] [Indexed: 12/11/2022]
Abstract
After two decades of intensive research and attempts of clinical translation, stem cell based therapies for cardiac diseases are not getting closer to clinical success. This review tries to unravel the obstacles and focuses on underlying mechanisms as the target for regenerative therapies. At present, the principal outcome in clinical therapy does not reflect experimental evidence. It seems that the scientific obstacle is a lack of integration of knowledge from tissue repair and disease mechanisms. Recent insights from clinical trials delineate mechanisms of stem cell dysfunction and gene defects in repair mechanisms as cause of atherosclerosis and heart disease. These findings require a redirection of current practice of stem cell therapy and a reset using more detailed analysis of stem cell function interfering with disease mechanisms. To accelerate scientific development the authors suggest intensifying unified computational data analysis and shared data knowledge by using open-access data platforms.
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Affiliation(s)
- Gustav Steinhoff
- University Medicine Rostock, Department of Cardiac Surgery, Reference and Translation Center for Cardiac Stem Cell Therapy, University Medical Center Rostock, Schillingallee 35, 18055 Rostock, Germany.
| | - Julia Nesteruk
- University Medicine Rostock, Department of Cardiac Surgery, Reference and Translation Center for Cardiac Stem Cell Therapy, University Medical Center Rostock, Schillingallee 35, 18055 Rostock, Germany.
| | - Markus Wolfien
- University Rostock, Institute of Computer Science, Department of Systems Biology and Bioinformatics, Ulmenstraße 69, 18057 Rostock, Germany.
| | - Jana Große
- University Medicine Rostock, Department of Cardiac Surgery, Reference and Translation Center for Cardiac Stem Cell Therapy, University Medical Center Rostock, Schillingallee 35, 18055 Rostock, Germany.
| | - Ulrike Ruch
- University Medicine Rostock, Department of Cardiac Surgery, Reference and Translation Center for Cardiac Stem Cell Therapy, University Medical Center Rostock, Schillingallee 35, 18055 Rostock, Germany.
| | - Praveen Vasudevan
- University Medicine Rostock, Department of Cardiac Surgery, Reference and Translation Center for Cardiac Stem Cell Therapy, University Medical Center Rostock, Schillingallee 35, 18055 Rostock, Germany.
| | - Paula Müller
- University Medicine Rostock, Department of Cardiac Surgery, Reference and Translation Center for Cardiac Stem Cell Therapy, University Medical Center Rostock, Schillingallee 35, 18055 Rostock, Germany.
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Morisaki T, Kishimoto Y, Tateya I, Kawai Y, Suzuki R, Tsuji T, Hiwatashi N, Nakamura T, Omori K, Kitano H, Takeuchi H, Hirano S. Adipose-derived mesenchymal stromal cells prevented rat vocal fold scarring. Laryngoscope 2017; 128:E33-E40. [DOI: 10.1002/lary.26855] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2017] [Revised: 06/30/2017] [Accepted: 07/24/2017] [Indexed: 12/22/2022]
Affiliation(s)
- Tsuyoshi Morisaki
- Department of Otolaryngology-Head and Neck Surgery; Faculty of Medicine, Tottori University; Tottori Japan
| | - Yo Kishimoto
- Department of Otolaryngology-Head and Neck Surgery Graduate School of Medicine; Kyoto University; Kyoto Japan
| | - Ichiro Tateya
- Department of Otolaryngology-Head and Neck Surgery Graduate School of Medicine; Kyoto University; Kyoto Japan
| | - Yoshitaka Kawai
- Department of Otolaryngology-Head and Neck Surgery Graduate School of Medicine; Kyoto University; Kyoto Japan
| | - Ryo Suzuki
- Department of Otolaryngology-Head and Neck Surgery Graduate School of Medicine; Kyoto University; Kyoto Japan
| | - Takuya Tsuji
- Department of Otolaryngology-Head and Neck Surgery Graduate School of Medicine; Kyoto University; Kyoto Japan
| | - Nao Hiwatashi
- Department of Otolaryngology-Head and Neck Surgery Graduate School of Medicine; Kyoto University; Kyoto Japan
- Department of Otolaryngology-Head and Neck Surgery; NYU Voice Center, New York University School of Medicine; New York New York U.S.A
| | - Tatsuo Nakamura
- Department of Bioartificial Organs; Institute for Frontier Medical Science, Kyoto University; Kyoto Japan
| | - Koichi Omori
- Department of Otolaryngology-Head and Neck Surgery Graduate School of Medicine; Kyoto University; Kyoto Japan
| | - Hiroya Kitano
- Department of Otolaryngology-Head and Neck Surgery; Faculty of Medicine, Tottori University; Tottori Japan
| | - Hiromi Takeuchi
- Department of Otolaryngology-Head and Neck Surgery; Faculty of Medicine, Tottori University; Tottori Japan
| | - Shigeru Hirano
- Department of Otolaryngology-Head and Neck Surgery; Kyoto Prefectural University of Medicine; Kyoto Japan
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Wang J, Xiang B, Deng JX, Lin HY, Freed DH, Arora RC, Tian GH. Hypoxia enhances the therapeutic potential of superparamagnetic iron oxide-labeled adipose-derived stem cells for myocardial infarction. ACTA ACUST UNITED AC 2017; 37:516-522. [PMID: 28786062 DOI: 10.1007/s11596-017-1766-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2016] [Revised: 03/23/2017] [Indexed: 12/26/2022]
Abstract
Adipose-derived stem cells (ASCs) induce therapeutic angiogenesis due to pro-angiogenic cytokines secretion. Superparamagnetic iron oxide (SPIO) nanoparticles are critical for magnetic resonance (MR) tracking of implanted cells. Hypoxia is a powerful stimulus for angiogenic activity of ASCs. In this study, we investigated whether therapeutic potency could be enhanced by implantation of hypoxia-preconditioned SPIO-labeled ASCs (SPIOASCs) into the infarcted myocardium. ASCs and SPIOASCs were cultured under 2% O2 (hypoxia) or 95% air (normoxia). Cells were intramyocardially injected into the infarcted myocardium after 48-h culture. We found that hypoxia culture increased the mRNA expression of hypoxia-inducible factor-1 alpha (HIF-1α) and vascular endothelial growth factor (VEGF) in ASCs and SPIOASCs. The VEGF protein in the conditioned medium was significantly higher in hypoxic ASCs and SPIOASCs than in normoxic ASCs and SPIOASCs. The capillary density and left ventricular contractile function in the infarcted myocardium were significantly higher 4 weeks after implantation with hypoxic ASCs and SPIOASCs than with normoxic ASCs and SPIOASCs. Improvement in the capillary density and left ventricle function didn't differ between hypoxic ASCs-transplanted rats and hypoxic SPIOASCs-transplanted rats. Hypoxic culture enhanced the angiogenic efficiency of ASCs. It was concluded that implantation of hypoxic ASCs or SPIOASCs promotes therapeutic angiogenesis and cardiac function recovery in the infarcted myocardium. SPIO labeling does not impact the beneficial effect of hypoxic ASCs.
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Affiliation(s)
- Jian Wang
- Department of Vascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. .,National Research Council of Canada, Winnipeg, R3B 1Y6, Canada. .,Department of Physiology, Faculty of Medicine, University of Manitoba, Winnipeg, R3E 3P5, Canada.
| | - Bo Xiang
- National Research Council of Canada, Winnipeg, R3B 1Y6, Canada.,Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Manitoba, Winnipeg, R3E 0T6, Canada
| | - Ji-Xian Deng
- National Research Council of Canada, Winnipeg, R3B 1Y6, Canada.,Department of Physiology, Faculty of Medicine, University of Manitoba, Winnipeg, R3E 3P5, Canada
| | - Hung-Yu Lin
- National Research Council of Canada, Winnipeg, R3B 1Y6, Canada
| | - Darren H Freed
- National Research Council of Canada, Winnipeg, R3B 1Y6, Canada.,Department of Physiology, Faculty of Medicine, University of Manitoba, Winnipeg, R3E 3P5, Canada.,Division of Cardiac Surgery, University of Alberta Hospital, Edmonton, T6G 2B7, Canada
| | - Rakesh C Arora
- National Research Council of Canada, Winnipeg, R3B 1Y6, Canada.,Department of Physiology, Faculty of Medicine, University of Manitoba, Winnipeg, R3E 3P5, Canada.,Cardiac Science Program, Institute of Cardiovascular Science, St. Boniface General Hospital, Winnipeg, R2H 2A6, Canada
| | - Gang-Hong Tian
- National Research Council of Canada, Winnipeg, R3B 1Y6, Canada. .,Department of Physiology, Faculty of Medicine, University of Manitoba, Winnipeg, R3E 3P5, Canada.
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Zhao L, Johnson T, Liu D. Therapeutic angiogenesis of adipose-derived stem cells for ischemic diseases. Stem Cell Res Ther 2017; 8:125. [PMID: 28583178 PMCID: PMC5460534 DOI: 10.1186/s13287-017-0578-2] [Citation(s) in RCA: 139] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Ischemic diseases, the leading cause of disability and death, are caused by the stenosis or obstruction of arterioles/capillaries that is not compensated for by vessel dilatation or collateral circulation. Angiogenesis is a complex process leading to new blood vessel formation and is triggered by ischemic conditions. Adequate angiogenesis, as a compensatory mechanism in response to ischemia, may increase oxygen and nutrient supplies to tissues and protect their function. Therapeutic angiogenesis has been the most promising therapy for treating ischemic diseases. In recent years, stem cell transplantation has been recognized as a new technique with therapeutic angiogenic effects on ischemic diseases. Adipose-derived stem cells, characterized by their ease of acquisition, high yields, proliferative growth, and low immunogenicity, are an ideal cell source. In this review, the characterization of adipose-derived stem cells and the role of angiogenesis in ischemic attack are summarized. The angiogenic effects of adipose-derived stem cells are discussed from the perspectives of in-vitro, in-vivo, and clinical trial studies for the treatment of ischemic diseases, including ischemic cardiac, cerebral, and peripheral vascular diseases and wound healing. The microvesicles/exosomes released from adipose-derived stem cells are also presented as a novel therapeutic prospect for treating ischemic diseases.
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Affiliation(s)
- Lina Zhao
- Cardiovascular Research Institute, Morehouse School of Medicine, 720 Westview Drive SW, Atlanta, GA, 30310, USA
| | - Takerra Johnson
- Cardiovascular Research Institute, Morehouse School of Medicine, 720 Westview Drive SW, Atlanta, GA, 30310, USA
| | - Dong Liu
- Cardiovascular Research Institute, Morehouse School of Medicine, 720 Westview Drive SW, Atlanta, GA, 30310, USA.
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Bobi J, Solanes N, Fernández-Jiménez R, Galán-Arriola C, Dantas AP, Fernández-Friera L, Gálvez-Montón C, Rigol-Monzó E, Agüero J, Ramírez J, Roqué M, Bayés-Genís A, Sánchez-González J, García-Álvarez A, Sabaté M, Roura S, Ibáñez B, Rigol M. Intracoronary Administration of Allogeneic Adipose Tissue-Derived Mesenchymal Stem Cells Improves Myocardial Perfusion But Not Left Ventricle Function, in a Translational Model of Acute Myocardial Infarction. J Am Heart Assoc 2017; 6:e005771. [PMID: 28468789 PMCID: PMC5524109 DOI: 10.1161/jaha.117.005771] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2017] [Accepted: 03/30/2017] [Indexed: 11/16/2022]
Abstract
BACKGROUND Autologous adipose tissue-derived mesenchymal stem cells (ATMSCs) therapy is a promising strategy to improve post-myocardial infarction outcomes. In a porcine model of acute myocardial infarction, we studied the long-term effects and the mechanisms involved in allogeneic ATMSCs administration on myocardial performance. METHODS AND RESULTS Thirty-eight pigs underwent 50 minutes of coronary occlusion; the study was completed in 33 pigs. After reperfusion, allogeneic ATMSCs or culture medium (vehicle) were intracoronarily administered. Follow-ups were performed at short (2 days after acute myocardial infarction vehicle-treated, n=10; ATMSCs-treated, n=9) or long term (60 days after acute myocardial infarction vehicle-treated, n=7; ATMSCs-treated, n=7). At short term, infarcted myocardium analysis showed reduced apoptosis in the ATMSCs-treated animals (48.6±6% versus 55.9±5.7% in vehicle; P=0.017); enhancement of the reparative process with up-regulated vascular endothelial growth factor, granulocyte macrophage colony-stimulating factor, and stromal-derived factor-1α gene expression; and increased M2 macrophages (67.2±10% versus 54.7±10.2% in vehicle; P=0.016). In long-term groups, increase in myocardial perfusion at the anterior infarct border was observed both on day-7 and day-60 cardiac magnetic resonance studies in ATMSCs-treated animals, compared to vehicle (87.9±28.7 versus 57.4±17.7 mL/min per gram at 7 days; P=0.034 and 99±22.6 versus 43.3±14.7 22.6 mL/min per gram at 60 days; P=0.0001, respectively). At day 60, higher vascular density was detected at the border zone in the ATMSCs-treated animals (118±18 versus 92.4±24.3 vessels/mm2 in vehicle; P=0.045). Cardiac magnetic resonance-measured left ventricular ejection fraction of left ventricular volumes was not different between groups at any time point. CONCLUSIONS In this porcine acute myocardial infarction model, allogeneic ATMSCs-based therapy was associated with increased cardioprotective and reparative mechanisms and with better cardiac magnetic resonance-measured perfusion. No effect on left ventricular volumes or ejection fraction was observed.
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Affiliation(s)
- Joaquim Bobi
- August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Institut de Malalties Cardiovasculars, Hospital Clínic de Barcelona, Universitat de Barcelona, Spain
| | - Núria Solanes
- August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Institut de Malalties Cardiovasculars, Hospital Clínic de Barcelona, Universitat de Barcelona, Spain
| | - Rodrigo Fernández-Jiménez
- Centro Nacional de Investigaciones Cardiovasculares Carlos III, CNIC, Madrid, Spain
- Icahn School of Medicine at Mount Sinai, New York, NY
- CIBER de enfermedades CardioVasculares (CIBERCV), Madrid, Spain
| | - Carlos Galán-Arriola
- Centro Nacional de Investigaciones Cardiovasculares Carlos III, CNIC, Madrid, Spain
- CIBER de enfermedades CardioVasculares (CIBERCV), Madrid, Spain
| | - Ana Paula Dantas
- August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Institut de Malalties Cardiovasculars, Hospital Clínic de Barcelona, Universitat de Barcelona, Spain
| | - Leticia Fernández-Friera
- Centro Nacional de Investigaciones Cardiovasculares Carlos III, CNIC, Madrid, Spain
- Hospital Universitario HM Montepríncipe, Madrid, Spain
- CIBER de enfermedades CardioVasculares (CIBERCV), Madrid, Spain
| | - Carolina Gálvez-Montón
- ICREC Research Program, Health Science Research Institute Germans Trias i Pujol, Badalona, Spain
- CIBER de enfermedades CardioVasculares (CIBERCV), Madrid, Spain
| | | | - Jaume Agüero
- Centro Nacional de Investigaciones Cardiovasculares Carlos III, CNIC, Madrid, Spain
- CIBER de enfermedades CardioVasculares (CIBERCV), Madrid, Spain
- Cardiology Department, Hospital Universitari i Politecnic La Fe, Valencia, Spain
| | - José Ramírez
- Servei d'Anatomia Patològica, Hospital Clínic de Barcelona, Barcelona, Spain
| | - Mercè Roqué
- August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Institut de Malalties Cardiovasculars, Hospital Clínic de Barcelona, Universitat de Barcelona, Spain
| | - Antoni Bayés-Genís
- ICREC Research Program, Health Science Research Institute Germans Trias i Pujol, Badalona, Spain
- Cardiology Service, Germans Trias i Pujol University Hospital, Badalona, Spain
- Department of Medicine, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain
- CIBER de enfermedades CardioVasculares (CIBERCV), Madrid, Spain
| | | | - Ana García-Álvarez
- August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Institut de Malalties Cardiovasculars, Hospital Clínic de Barcelona, Universitat de Barcelona, Spain
- Centro Nacional de Investigaciones Cardiovasculares Carlos III, CNIC, Madrid, Spain
| | - Manel Sabaté
- August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Institut de Malalties Cardiovasculars, Hospital Clínic de Barcelona, Universitat de Barcelona, Spain
| | - Santiago Roura
- ICREC Research Program, Health Science Research Institute Germans Trias i Pujol, Badalona, Spain
- Center of Regenerative Medicine in Barcelona, Barcelona, Spain
- CIBER de enfermedades CardioVasculares (CIBERCV), Madrid, Spain
| | - Borja Ibáñez
- Centro Nacional de Investigaciones Cardiovasculares Carlos III, CNIC, Madrid, Spain
- IIS- Fundación Jiménez Díaz Hospital, Madrid, Spain
- CIBER de enfermedades CardioVasculares (CIBERCV), Madrid, Spain
| | - Montserrat Rigol
- August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Institut de Malalties Cardiovasculars, Hospital Clínic de Barcelona, Universitat de Barcelona, Spain
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Lee JH, Han YS, Lee SH. Potentiation of biological effects of mesenchymal stem cells in ischemic conditions by melatonin via upregulation of cellular prion protein expression. J Pineal Res 2017; 62. [PMID: 28095625 DOI: 10.1111/jpi.12385] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2016] [Accepted: 01/11/2017] [Indexed: 12/18/2022]
Abstract
Mesenchymal stem cells (MSCs) are promising candidates for stem cell-based therapy in ischemic diseases. However, ischemic injury induces pathophysiological conditions, such as oxidative stress and inflammation, which diminish therapeutic efficacy of MSC-based therapy by reducing survival and functionality of transplanted MSCs. To overcome this problem, we explored the effects of melatonin on the proliferation, resistance to oxidative stress, and immunomodulatory properties of MSCs. Treatment with melatonin enhanced MSC proliferation and self-renewal via upregulation of cellular prion protein (PrPC ) expression. Melatonin diminished the extent of MSC apoptosis in oxidative stress conditions by regulating the levels of apoptosis-associated proteins, such as BCL-2, BAX, PARP-1, and caspase-3, in a PrPC -dependent manner. In addition, melatonin regulated the immunomodulatory effects of MSCs via the PrPC -IDO axis. In a murine hind-limb ischemia model, melatonin-stimulated MSCs improved the blood flow perfusion, limb salvage, and vessel regeneration by lowering the extent of apoptosis of affected local cells and transplanted MSCs as well as by reducing infiltration of macrophages. These melatonin-mediated therapeutic effects were inhibited by silencing of PrPC expression. Our findings for the first time indicate that melatonin promotes MSC functionality and enhances MSC-mediated neovascularization in ischemic tissues through the upregulation of PrPC expression. In conclusion, melatonin-treated MSCs could provide a therapeutic strategy for vessel regeneration in ischemic disease, and the targeting of PrPC levels may prove instrumental for MSC-based therapies.
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Affiliation(s)
- Jun Hee Lee
- Department of Pharmacology and Toxicology, University of Alabama at Birmingham School of Medicine, Birmingham, AL, USA
| | - Yong-Seok Han
- Medical Science Research Institute, Soonchunhyang University Seoul Hospital, Seoul, Korea
| | - Sang Hun Lee
- Medical Science Research Institute, Soonchunhyang University Seoul Hospital, Seoul, Korea
- Departments of Biochemistry, Soonchunhyang University College of Medicine, Cheonan, Korea
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Joo HJ, Kim JH, Hong SJ. Adipose Tissue-Derived Stem Cells for Myocardial Regeneration. Korean Circ J 2017; 47:151-159. [PMID: 28382066 PMCID: PMC5378017 DOI: 10.4070/kcj.2016.0207] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2016] [Revised: 07/09/2016] [Accepted: 07/15/2016] [Indexed: 12/14/2022] Open
Abstract
Over the past decade, stem cell therapy has been extensively studied for clinical application for heart diseases. Among various stem cells, adipose tissue-derived stem cell (ADSC) is still an attractive stem cell resource due to its abundance and easy accessibility. In vitro studies showed the multipotent differentiation potentials of ADSC, even differentiation into cardiomyocytes. Many pre-clinical animal studies have also demonstrated promising therapeutic results of ADSC. Furthermore, there were several clinical trials showing the positive results in acute myocardial infarction using ADSC. The present article covers the brief introduction, the suggested therapeutic mechanisms, application methods including cell dose and delivery, and human clinical trials of ADSC for myocardial regeneration.
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Affiliation(s)
- Hyung Joon Joo
- Department of Cardiology, Cardiovascular Center, Korea University Anam Hospital, Seoul, Korea
| | - Jong-Ho Kim
- Department of Cardiology, Cardiovascular Center, Korea University Anam Hospital, Seoul, Korea
| | - Soon Jun Hong
- Department of Cardiology, Cardiovascular Center, Korea University Anam Hospital, Seoul, Korea
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38
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Mesenchymal stromal cell therapy to promote cardiac tissue regeneration and repair. Curr Opin Organ Transplant 2017; 22:86-96. [DOI: 10.1097/mot.0000000000000379] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Hao M, Wang R, Wang W. Cell Therapies in Cardiomyopathy: Current Status of Clinical Trials. Anal Cell Pathol (Amst) 2017; 2017:9404057. [PMID: 28194324 PMCID: PMC5282433 DOI: 10.1155/2017/9404057] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2016] [Revised: 12/06/2016] [Accepted: 12/08/2016] [Indexed: 12/28/2022] Open
Abstract
Because the human heart has limited potential for regeneration, the loss of cardiomyocytes during cardiac myopathy and ischaemic injury can result in heart failure and death. Stem cell therapy has emerged as a promising strategy for the treatment of dead myocardium, directly or indirectly, and seems to offer functional benefits to patients. The ideal candidate donor cell for myocardial reconstitution is a stem-like cell that can be easily obtained, has a robust proliferation capacity and a low risk of tumour formation and immune rejection, differentiates into functionally normal cardiomyocytes, and is suitable for minimally invasive clinical transplantation. The ultimate goal of cardiac repair is to regenerate functionally viable myocardium after myocardial infarction (MI) to prevent or heal heart failure. This review provides a comprehensive overview of treatment with stem-like cells in preclinical and clinical studies to assess the feasibility and efficacy of this novel therapeutic strategy in ischaemic cardiomyopathy.
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Affiliation(s)
- Ming Hao
- Cellular Biomedicine Group, 333 Guiping Road, Shanghai 200233, China
- Cellular Biomedicine Group, 19925 Stevens Creek Blvd, Suite 100, Cupertino, CA 95014, USA
| | - Richard Wang
- Cellular Biomedicine Group, 333 Guiping Road, Shanghai 200233, China
- Cellular Biomedicine Group, 19925 Stevens Creek Blvd, Suite 100, Cupertino, CA 95014, USA
| | - Wen Wang
- Cellular Biomedicine Group, 333 Guiping Road, Shanghai 200233, China
- Cellular Biomedicine Group, 19925 Stevens Creek Blvd, Suite 100, Cupertino, CA 95014, USA
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40
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Riccobono D, Agay D, François S, Scherthan H, Drouet M, Forcheron F. Contribution of INTRAMUSCULAR Autologous Adipose Tissue-Derived Stem Cell Injections to Treat Cutaneous Radiation Syndrome: Preliminary Results. HEALTH PHYSICS 2016; 111:117-126. [PMID: 27356055 DOI: 10.1097/hp.0000000000000515] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/06/2023]
Abstract
Cutaneous radiation syndrome caused by high dose located irradiation is characterized by delayed symptoms, incomplete wound healing, and poor revascularization. Subcutaneous adipose tissue derived stromal/stem cells have been shown to improve skin repair in a minipig model of cutaneous radiation syndrome despite a subcutaneous defect being a consequence of radio-induced muscular fibrosis. Based on the pro-myogenic potential of stromal/stem cells, a new protocol combining subcutaneous and intramuscular injections was evaluated in a preliminary study. Six female minipigs were locally irradiated at the dose of 50 Gy using a Co source (0.6 Gy min) and randomly divided into two groups. Three animals received the vehicle (phosphate-buffer-saline solution) and three animals received three injections of 75 × 10 adipose tissue derived stromal/stem cells each time (day 25, 46, and 66 post-irradiation). Pigs were euthanized on day 76 post-irradiation before development of clinical skin symptoms. All minipigs exhibited a homogeneous skin evolution. Macroscopic observation of irradiated muscles showed prominent fibrosis and necrosis areas in controls as opposed to adipose tissue-derived stromal/stem cells injected animals. Moreover, muscle biopsy analysis highlighted a recruitment of myofibroblasts (Immune Reactive Score: p < 0.01), an interleukin 10 secretion and a muscle regeneration pathway activation after intramuscular injections of adipose tissue-derived stromal/stem cells (western-blot: respectively, 200-fold change difference and twofold higher in treated animals). Globally, these preliminary data suggest that intramuscular injections of adipose tissue-derived stromal/stem cells improve muscle regeneration in the cutaneous-radiation syndrome. Further work is ongoing to evaluate this therapeutic strategy on a larger animal number with a longer clinical follow-up.
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Affiliation(s)
- Diane Riccobono
- *Institut de Recherche Biomédicale des Armées (IRBA), Département des Effets Biologiques des Rayonnements, BP 73, Brétigny sur Orge Cedex, France; †Clinatec, 17 rue des Martyrs 38054, Grenoble cedex, France; ‡Institut für Radiobiologie der Bundeswehr, Neuherbergstraße 11, 80937 München, Germany
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Wang J, Xiang B, Deng J, Lin HY, Zheng D, Freed DH, Arora RC, Tian G. Externally Applied Static Magnetic Field Enhances Cardiac Retention and Functional Benefit of Magnetically Iron-Labeled Adipose-Derived Stem Cells in Infarcted Hearts. Stem Cells Transl Med 2016; 5:1380-1393. [PMID: 27400797 DOI: 10.5966/sctm.2015-0220] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2015] [Accepted: 01/25/2016] [Indexed: 01/22/2023] Open
Abstract
: Although adipose-derived stem cells (ASCs) hold the promise of effective therapy for myocardial infarction, low cardiac retention of implanted ASCs has hindered their therapeutic efficiency. We investigated whether an externally applied static magnetic field (SMF) enhances cardiac localization of "magnetic" cells and promotes heart function recovery when ASCs are preloaded with superparamagnetic iron oxide (SPIO) nanoparticles. The influence of SMF (0.1 Tesla) on the biological activities of SPIO-labeled ASCs (SPIOASCs) was investigated first. Fifty-six female rats with myocardial infarction underwent intramyocardial injection of cell culture medium (CCM) or male SPIOASCs with or without the subcutaneous implantable magnet (CCM-magnet or SPIOASC-magnet). Four weeks later, endothelial differentiation, angiogenic cytokine secretion, angiogenesis, cardiomyocyte apoptosis, cell retention, and cardiac performance were examined. The 0.1-Tsela SMF did not adversely affect the viability, proliferation, angiogenic cytokine secretion, and DNA integrity of SPIOASCs. The implanted SPIOASCs could differentiate into endothelial cell, incorporate into newly formed vessels, and secrete multiple angiogenic cytokines. Four weeks after cell transplantation, the number of cardiac SPIOASCs was significantly increased, vascular density was markedly enlarged, fewer apoptotic cardiomyocytes were present, and heart contractile function was substantially improved in the SPIOASC-magnet treated rats in comparison with the SPIOASC-treated rats. The SPIOASCs could differentiate into endothelial cells, incorporate into vessels, promote angiogenesis, and inhibit ischemic cardiomyocyte apoptosis. An externally applied SMF offered a secure environment for biological properties of SPIOASCs, increased the cardiac retention of implanted magnetic SPIOASCs, and further enhanced heart function recovery after myocardial infarction. SIGNIFICANCE This pilot proof-of-concept study suggests that a 0.1-Tesla static magnetic field does not adversely affect the viability, proliferation, angiogenic cytokine secretion, or DNA integrity of the superparamagnetic iron oxide-labeled adipose-derived stem cells (SPIOASCs). Implantation of adipose-derived stem cells promotes myocardial neovascularization and inhibits ischemic cardiomyocyte apoptosis through endothelial differentiation, incorporation into vessels, and paracrine factor secretion. An externally applied static magnetic field enhanced myocardial retention of intramyocardially injected "magnetic" SPIOASCs and promoted cardiac function recovery after myocardial infarction. With further preclinical optimization, this approach may improve the outcome of current stem cell therapy for ischemic myocardial infarction.
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Affiliation(s)
- Jian Wang
- Department of Vascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China National Research Council of Canada, Winnipeg, Manitoba, Canada Department of Physiology, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Bo Xiang
- National Research Council of Canada, Winnipeg, Manitoba, Canada Department of Pharmacology and Therapeutics Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Jixian Deng
- National Research Council of Canada, Winnipeg, Manitoba, Canada Department of Physiology, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Hung-Yu Lin
- National Research Council of Canada, Winnipeg, Manitoba, Canada
| | - Dayang Zheng
- National Research Council of Canada, Winnipeg, Manitoba, Canada Department of Physiology, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada Department of Cardiothoracic Surgery, The Second Affiliated Hospital of University of South China, Hengyang, Hunan, People's Republic of China
| | - Darren H Freed
- National Research Council of Canada, Winnipeg, Manitoba, Canada Department of Physiology, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada Division of Cardiac Surgery, University of Alberta Hospital, Edmonton, Alberta, Canada
| | - Rakesh C Arora
- National Research Council of Canada, Winnipeg, Manitoba, Canada Department of Physiology, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada Cardiac Science Program, Institute of Cardiovascular Science, St. Boniface General Hospital, Winnipeg, Manitoba, Canada
| | - Ganghong Tian
- National Research Council of Canada, Winnipeg, Manitoba, Canada Department of Physiology, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada
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Inhibition of Viability, Proliferation, Cytokines Secretion, Surface Antigen Expression, and Adipogenic and Osteogenic Differentiation of Adipose-Derived Stem Cells by Seven-Day Exposure to 0.5 T Static Magnetic Fields. Stem Cells Int 2016; 2016:7168175. [PMID: 26880984 PMCID: PMC4736570 DOI: 10.1155/2016/7168175] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2015] [Revised: 11/24/2015] [Accepted: 11/26/2015] [Indexed: 01/12/2023] Open
Abstract
After seven-day exposure to 0.5-Tesla Static Magnetic Field (SMF), Adipose-derived Stem Cells (ASCs) and those labeled by superparamagnetic iron oxide (SPIO) nanoparticles were examined for viability by methyl thiazol tetrazolium (MTT) assay, proliferation by cell counting and bromodeoxyuridine (BrdU) incorporation, DNA integrity by single cell gel electrophoresis, surface antigen by flow cytometry analysis, and the expression of cytokines and genetic markers by reverse transcription-PCR and underwent adipogenic and osteogenic differentiation assessed by quantifying related specific genes expression. The SMF slightly reduced cell viability and proliferation and inhibited the expression of CD49d, CD54, and CD73 but did not damage DNA integrity. The SMF slightly downregulated the expression of cytokines including Vascular Endothelial Growth Factor (VEGF), Insulin-like Growth Factor-1 (IGF-1), Transforming Growth Factor Beta 1 (TGF-β1), genetic markers comprising Stem Cell Antigen-1 (Sca1), Octamer-4 (Oct-4), ATP-binding Cassette Subfamily B Member 1 (ABCB1), adipogenic marker genes containing Lipoprotein Lipase (LPL), Peroxisome Proliferator-Activated Receptor Gamma (PPAR-γ), and osteogenic marker genes including Secreted Phosphor-protein 1 (SPP1) and Osterix (OSX). Exposure to 0.5 T SMF for seven days inhibited viability, proliferation, surface antigen expression, cytokine secretion, stem cell genetic marker expression, and adipogenic and osteogenic differentiation but did not affect the DNA integrity in ASCs with or without SPIO labeling.
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Puig-Sanvicens VAC, Semino CE, Zur Nieden NI. Cardiac differentiation potential of human induced pluripotent stem cells in a 3D self-assembling peptide scaffold. Differentiation 2015; 90:101-10. [PMID: 26707885 DOI: 10.1016/j.diff.2015.11.002] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2015] [Revised: 11/19/2015] [Accepted: 11/20/2015] [Indexed: 01/01/2023]
Abstract
In the past decade, various strategies for cardiac reparative medicine involving stem cells from multiple sources have been investigated. However, the intra-cardiac implantation of cells with contractile ability may seriously disrupt the cardiac syncytium and de-synchronize cardiac rhythm. For this reason, bioactive cardiac implants, consisting of stem cells embedded in biomaterials that act like band aids, have been exploited to repair the cardiac wall after myocardial infarction. For such bioactive implants to function properly after transplantation, the choice of biomaterial is equally important as the selection of the stem cell source. While adult stem cells have shown promising results, they have various disadvantages including low proliferative potential in vitro, which make their successful usage in human transplants difficult. As a first step towards the development of a bioactive cardiac patch, we investigate here the cardiac differentiation properties of human induced pluripotent stem cells (hiPSCs) when cultured with and without ascorbic acid (AA) and when embedded in RAD16-I, a biomaterial commonly used to develop cardiac implants. In adherent cultures and in the absence of RAD16-I, AA promotes the cardiac differentiation of hiPSCs by enhancing the expression of specific cardiac genes and proteins and by increasing the number of contracting clusters. In turn, embedding in peptide hydrogel based on RAD16-I interferes with the normal cardiac differentiation progression. Embedded hiPSCs up-regulate genes associated with early cardiogenesis by up to 105 times independently of the presence of AA. However, neither connexin 43 nor troponin I proteins, which are related with mature cardiomyocytes, were detected and no contraction was noted in the constructs. Future experiments will need to focus on characterizing the mature cardiac phenotype of these cells when implanted into infarcted myocardia and assess their regenerative potential in vivo.
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Affiliation(s)
- Veronica A C Puig-Sanvicens
- Department of Cell Biology & Neuroscience and Stem Cell Center, College of Natural and Agricultural Sciences, University of California Riverside, United States; Laboratory of Tissue Engineering, Department of Bioengineering, Institut Químic de Sarrià, School of Engineering, Universitat Ramon Llull, Barcelona, Spain.
| | - Carlos E Semino
- Laboratory of Tissue Engineering, Department of Bioengineering, Institut Químic de Sarrià, School of Engineering, Universitat Ramon Llull, Barcelona, Spain.
| | - Nicole I Zur Nieden
- Department of Cell Biology & Neuroscience and Stem Cell Center, College of Natural and Agricultural Sciences, University of California Riverside, United States.
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Bagno LL, Carvalho D, Mesquita F, Louzada RA, Andrade B, Kasai-Brunswick TH, Lago VM, Suhet G, Cipitelli D, Werneck-de-Castro JP, Campos-de-Carvalho AC. Sustained IGF-1 Secretion by Adipose-Derived Stem Cells Improves Infarcted Heart Function. Cell Transplant 2015; 25:1609-1622. [PMID: 26624235 DOI: 10.3727/096368915x690215] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
The mechanism by which stem cell-based therapy improves heart function is still unknown, but paracrine mechanisms seem to be involved. Adipose-derived stem cells (ADSCs) secrete several factors, including insulin-like growth factor-1 (IGF-1), which may contribute to myocardial regeneration. Our aim was to investigate whether the overexpression of IGF-1 in ADSCs (IGF-1-ADSCs) improves treatment of chronically infarcted rat hearts. ADSCs were transduced with a lentiviral vector to induce IGF-1 overexpression. IGF-1-ADSCs transcribe100- to 200-fold more IGF-1 mRNA levels compared to nontransduced ADSCs. IGF-1 transduction did not alter ADSC immunophenotypic characteristics even under hypoxic conditions. However, IGF-1-ADSCs proliferate at higher rates and release greater amounts of growth factors such as IGF-1, vascular endothelial growth factor (VEGF), and hepatocyte growth factor (HGF) under normoxic and hypoxic conditions. Importantly, IGF-1 secreted by IGF-1-ADSCs is functional given that Akt-1 phosphorylation was remarkably induced in neonatal cardiomyocytes cocultured with IGF-1-ADSCs, and this increase was prevented with phosphatidylinositol 3-kinase (PI3K) inhibitor treatment. Next, we tested IGF-1-ADSCs in a rat myocardial infarction (MI) model. MI was performed by coronary ligation, and 4 weeks after MI, animals received intramyocardial injections of either ADSCs (n = 7), IGF-1-ADSCs (n = 7), or vehicle (n = 7) into the infarcted border zone. Left ventricular function was evaluated by echocardiography before and after 6 weeks of treatment, and left ventricular hemodynamics were assessed 7 weeks after cell injection. Notably, IGF-1-ADSCs improved left ventricular ejection fraction and cardiac contractility index, but did not reduce scar size when compared to the ADSC-treated group. In summary, transplantation of ADSCs transduced with IGF-1 is a superior therapeutic approach to treat MI compared to nontransduced ADSCs, suggesting that gene and cell therapy may bring additional benefits to the treatment of MI.
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Affiliation(s)
- Luiza L Bagno
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
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45
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Bakermans AJ, Abdurrachim D, Moonen RPM, Motaal AG, Prompers JJ, Strijkers GJ, Vandoorne K, Nicolay K. Small animal cardiovascular MR imaging and spectroscopy. PROGRESS IN NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY 2015; 88-89:1-47. [PMID: 26282195 DOI: 10.1016/j.pnmrs.2015.03.001] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/12/2014] [Revised: 03/09/2015] [Accepted: 03/09/2015] [Indexed: 06/04/2023]
Abstract
The use of MR imaging and spectroscopy for studying cardiovascular disease processes in small animals has increased tremendously over the past decade. This is the result of the remarkable advances in MR technologies and the increased availability of genetically modified mice. MR techniques provide a window on the entire timeline of cardiovascular disease development, ranging from subtle early changes in myocardial metabolism that often mark disease onset to severe myocardial dysfunction associated with end-stage heart failure. MR imaging and spectroscopy techniques play an important role in basic cardiovascular research and in cardiovascular disease diagnosis and therapy follow-up. This is due to the broad range of functional, structural and metabolic parameters that can be quantified by MR under in vivo conditions non-invasively. This review describes the spectrum of MR techniques that are employed in small animal cardiovascular disease research and how the technological challenges resulting from the small dimensions of heart and blood vessels as well as high heart and respiratory rates, particularly in mice, are tackled.
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Affiliation(s)
- Adrianus J Bakermans
- Biomedical NMR, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands; Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Desiree Abdurrachim
- Biomedical NMR, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands
| | - Rik P M Moonen
- Biomedical NMR, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands
| | - Abdallah G Motaal
- Biomedical NMR, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands; Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Jeanine J Prompers
- Biomedical NMR, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands
| | - Gustav J Strijkers
- Biomedical NMR, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands; Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Katrien Vandoorne
- Biomedical NMR, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands
| | - Klaas Nicolay
- Biomedical NMR, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands.
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46
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Merfeld-Clauss S, Lupov IP, Lu H, March KL, Traktuev DO. Adipose Stromal Cell Contact with Endothelial Cells Results in Loss of Complementary Vasculogenic Activity Mediated by Induction of Activin A. Stem Cells 2015; 33:3039-51. [PMID: 26037810 DOI: 10.1002/stem.2074] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2015] [Accepted: 05/07/2015] [Indexed: 12/30/2022]
Abstract
Adipose stem/stromal cells (ASCs) after isolation produce numerous angiogenic growth factors. This justifies their use to promote angiogenesis per transplantation. In parallel, local coimplantation of ASC with endothelial cells (ECs) leading to formation of functional vessels by the donor cells suggests the existence of a mechanism responsible for fine-tuning ASC paracrine activity essential for vasculogenesis. As expected, conditioned media (CM) from ASC promoted ECs survival, proliferation, migration, and vasculogenesis. In contrast, media from EC-ASC cocultures had neutral effects upon EC responses. Media from cocultures exhibited lower levels of vascular endothelial growth factor (VEGF), hepatic growth factor, angiopoietin-1, and stromal cell-derived factor-1 compared with those in ASC CM. Activin A was induced in ASC in response to EC exposure and was responsible for overall antivasculogenic activity of EC-ASC CM. Except for VEGF, activin A diminished secretion of all tested factors by ASC. Activin A mediated induction of VEGF expression in ASC, but also upregulated expression of VEGF scavenger receptor FLT-1 in EC in EC-ASC cocultures. Blocking the FLT-1 expression in EC led to an increase in VEGF concentration in CM. In vitro pre-exposure of ASC to low number of EC before subcutaneous coimplantation with EC resulted in decrease in vessel density in the implants. In vitro tests suggested that activin A was partially responsible for this diminished ASC activity. This study shows that neovessel formation is associated with induction of activin A expression in ASC; this factor, by affecting the bioactivity of both ASC and EC, directs the crosstalk between these complementary cell types to establish stable vessels.
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Affiliation(s)
- Stephanie Merfeld-Clauss
- Department of Medicine, Indiana Center for Vascular Biology and Medicine, Krannert Institute of Cardiology, Indianapolis, Indiana, USA.,Department of Medicine, Indiana Center for Vascular Biology and Medicine, Krannert Institute of Cardiology, Indianapolis, Indiana, USA.,VA Center for Regenerative Medicine, R.L. Roudebush VA Medical Center, Indianapolis, Indiana, USA
| | - Ivan P Lupov
- Department of Medicine, Indiana Center for Vascular Biology and Medicine, Krannert Institute of Cardiology, Indianapolis, Indiana, USA.,Department of Medicine, Indiana Center for Vascular Biology and Medicine, Krannert Institute of Cardiology, Indianapolis, Indiana, USA.,VA Center for Regenerative Medicine, R.L. Roudebush VA Medical Center, Indianapolis, Indiana, USA
| | - Hongyan Lu
- Department of Medicine, Indiana Center for Vascular Biology and Medicine, Krannert Institute of Cardiology, Indianapolis, Indiana, USA.,Department of Medicine, Indiana Center for Vascular Biology and Medicine, Krannert Institute of Cardiology, Indianapolis, Indiana, USA.,VA Center for Regenerative Medicine, R.L. Roudebush VA Medical Center, Indianapolis, Indiana, USA
| | - Keith L March
- Department of Medicine, Indiana Center for Vascular Biology and Medicine, Krannert Institute of Cardiology, Indianapolis, Indiana, USA.,Department of Medicine, Indiana Center for Vascular Biology and Medicine, Krannert Institute of Cardiology, Indianapolis, Indiana, USA.,VA Center for Regenerative Medicine, R.L. Roudebush VA Medical Center, Indianapolis, Indiana, USA.,Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Dmitry O Traktuev
- Department of Medicine, Indiana Center for Vascular Biology and Medicine, Krannert Institute of Cardiology, Indianapolis, Indiana, USA.,Department of Medicine, Indiana Center for Vascular Biology and Medicine, Krannert Institute of Cardiology, Indianapolis, Indiana, USA.,VA Center for Regenerative Medicine, R.L. Roudebush VA Medical Center, Indianapolis, Indiana, USA
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47
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Adipose-derived Mesenchymal Stem Cells and Their Reparative Potential in Ischemic Heart Disease. ACTA ACUST UNITED AC 2015; 68:599-611. [DOI: 10.1016/j.rec.2015.02.025] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2015] [Accepted: 02/23/2015] [Indexed: 12/21/2022]
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48
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Badimon L, Oñate B, Vilahur G. Células madre mesenquimales derivadas de tejido adiposo y su potencial reparador en la enfermedad isquémica coronaria. Rev Esp Cardiol 2015. [DOI: 10.1016/j.recesp.2015.02.025] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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49
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Exosomes Derived from Human Umbilical Cord Mesenchymal Stem Cells Relieve Acute Myocardial Ischemic Injury. Stem Cells Int 2015; 2015:761643. [PMID: 26106430 PMCID: PMC4461782 DOI: 10.1155/2015/761643] [Citation(s) in RCA: 187] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2015] [Revised: 04/23/2015] [Accepted: 05/10/2015] [Indexed: 12/13/2022] Open
Abstract
This study is aimed at investigating whether human umbilical cord mesenchymal stem cell- (hucMSC-) derived exosomes (hucMSC-exosomes) have a protective effect on acute myocardial infarction (AMI). Exosomes were characterized under transmission electron microscopy and the particles of exosomes were further examined through nanoparticle tracking analysis. Exosomes (400 μg protein) were intravenously administrated immediately following ligation of the left anterior descending (LAD) coronary artery in rats. Cardiac function was evaluated by echocardiography and apoptotic cells were counted using TUNEL staining. The cardiac fibrosis was assessed using Masson's trichrome staining. The Ki67 positive cells in ischemic myocardium were determined using immunohistochemistry. The effect of hucMSC-exosomes on blood vessel formation was evaluated through tube formation and migration of human umbilical vein endothelial cells (EA.hy926 cells). The results indicated that ligation of the LAD coronary artery reduced cardiac function and induced cardiomyocyte apoptosis. Administration of hucMSC-exosomes significantly improved cardiac systolic function and reduced cardiac fibrosis. Moreover, hucMSC-exosomes protected myocardial cells from apoptosis and promoted the tube formation and migration of EA.hy926 cells. It is concluded that hucMSC-exosomes improved cardiac systolic function by protecting myocardial cells from apoptosis and promoting angiogenesis. These effects of hucMSC-exosomes might be associated with regulating the expression of Bcl-2 family.
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50
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Alrefai MT, Murali D, Paul A, Ridwan KM, Connell JM, Shum-Tim D. Cardiac tissue engineering and regeneration using cell-based therapy. STEM CELLS AND CLONING-ADVANCES AND APPLICATIONS 2015; 8:81-101. [PMID: 25999743 PMCID: PMC4437607 DOI: 10.2147/sccaa.s54204] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Stem cell therapy and tissue engineering represent a forefront of current research in the treatment of heart disease. With these technologies, advancements are being made into therapies for acute ischemic myocardial injury and chronic, otherwise nonreversible, myocardial failure. The current clinical management of cardiac ischemia deals with reestablishing perfusion to the heart but not dealing with the irreversible damage caused by the occlusion or stenosis of the supplying vessels. The applications of these new technologies are not yet fully established as part of the management of cardiac diseases but will become so in the near future. The discussion presented here reviews some of the pioneering works at this new frontier. Key results of allogeneic and autologous stem cell trials are presented, including the use of embryonic, bone marrow-derived, adipose-derived, and resident cardiac stem cells.
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Affiliation(s)
- Mohammad T Alrefai
- Division of Cardiac Surgery, McGill University Health Center, Montreal, QC, Canada ; Division of Surgical Research, McGill University Health Center, Montreal, QC, Canada ; King Faisal Specialist Hospital and Research Center, Jeddah, Saudi Arabia
| | - Divya Murali
- Department of Chemical and Petroleum Engineering, School of Engineering, University of Kansas, Lawrence, KS, USA
| | - Arghya Paul
- Department of Chemical and Petroleum Engineering, School of Engineering, University of Kansas, Lawrence, KS, USA
| | - Khalid M Ridwan
- Division of Cardiac Surgery, McGill University Health Center, Montreal, QC, Canada ; Division of Surgical Research, McGill University Health Center, Montreal, QC, Canada
| | - John M Connell
- Division of Cardiac Surgery, McGill University Health Center, Montreal, QC, Canada ; Division of Surgical Research, McGill University Health Center, Montreal, QC, Canada
| | - Dominique Shum-Tim
- Division of Cardiac Surgery, McGill University Health Center, Montreal, QC, Canada ; Division of Surgical Research, McGill University Health Center, Montreal, QC, Canada
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