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Yun CW, Lee SH. Enhancement of Functionality and Therapeutic Efficacy of Cell-Based Therapy Using Mesenchymal Stem Cells for Cardiovascular Disease. Int J Mol Sci 2019; 20:ijms20040982. [PMID: 30813471 PMCID: PMC6412804 DOI: 10.3390/ijms20040982] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2019] [Revised: 02/20/2019] [Accepted: 02/21/2019] [Indexed: 12/13/2022] Open
Abstract
Cardiovascular disease usually triggers coronary heart disease, stroke, and ischemic diseases, thus promoting the development of functional failure. Mesenchymal stem cells (MSCs) are cells that can be isolated from various human tissues, with multipotent and immunomodulatory characteristics to help damaged tissue repair and avoidance of immune responses. Much research has proved the feasibility, safety, and efficiency of MSC-based therapy for cardiovascular disease. Despite the fact that the precise mechanism of MSCs remains unclear, their therapeutic capability to treat ischemic diseases has been tested in phase I/II clinical trials. MSCs have the potential to become an effective therapeutic strategy for the treatment of ischemic and non-ischemic cardiovascular disorders. The molecular mechanism underlying the efficacy of MSCs in promoting engraftment and accelerating the functional recovery of injury sites is still unclear. It is hypothesized that the mechanisms of paracrine effects for the cardiac repair, optimization of the niche for cell survival, and cardiac remodeling by inflammatory control are involved in the interaction between MSCs and the damaged myocardial environment. This review focuses on recent experimental and clinical findings related to cardiovascular disease. We focus on MSCs, highlighting their roles in cardiovascular disease repair, differentiation, and MSC niche, and discuss their therapeutic efficacy and the current status of MSC-based cardiovascular disease therapies.
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Affiliation(s)
- Chul Won Yun
- Medical Science Research Institute, Soonchunhyang University Seoul Hospital, Seoul 04401, Korea.
| | - Sang Hun Lee
- Medical Science Research Institute, Soonchunhyang University Seoul Hospital, Seoul 04401, Korea.
- Department of Biochemistry, Soonchunhyang University College of Medicine, Cheonan 34538, Korea.
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Ciuffreda MC, Malpasso G, Chokoza C, Bezuidenhout D, Goetsch KP, Mura M, Pisano F, Davies NH, Gnecchi M. Synthetic extracellular matrix mimic hydrogel improves efficacy of mesenchymal stromal cell therapy for ischemic cardiomyopathy. Acta Biomater 2018; 70:71-83. [PMID: 29341932 DOI: 10.1016/j.actbio.2018.01.005] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2017] [Revised: 12/28/2017] [Accepted: 01/08/2018] [Indexed: 01/09/2023]
Abstract
BACKGROUND Mesenchymal stromal cells (MSC) repair infarcted hearts mainly through paracrine mechanisms. Low cell engraftment limits the release of soluble paracrine factors (SF) over time and, consequently, MSC efficacy. We tested whether a synthetic extracellular matrix mimic, a hydrogel containing heparin (H-HG), could ameliorate MSC engraftment and binding/release of SF, thus improving MSC therapy efficacy. METHODS AND RESULTS In vitro, rat bone-marrow MSC (rBM-MSC) were seeded and grown into H-HG. Under normoxia, the hydrogel did not affect cell survival (rBM-MSC survival >90% at each time point tested); vice versa, under hypoxia the biomaterial resulted to be protective for the cells (p < .001 vs rBM-MSC alone). H-HG or control PEG hydrogels (HG) were incubated with VEGF or bFGF for binding/release quantification. Data showed significantly higher amount of VEGF and bFGF bound by H-HG compared with HG (p < .05) and a constant release over time. In vivo, myocardial infarction (MI) was induced in female Sprague Dawley rats by permanent coronary ligation. One week later, saline, rBM-MSC, H-HG or rBM-MSC/H-HG were injected in the infarct zone. The co-injection of rBM-MSC/H-HG into infarcted hearts significantly increased cardiac function. Importantly, we observed a significant gain in MSC engraftment, reduction of ventricular remodeling and stimulation of neo-vasculogenesis. We also documented higher amounts of several pro-angiogenic factors in hearts treated with rBM-MSC/H-HG. CONCLUSIONS Our data show that H-HG increases MSC engraftment, efficiently fine tunes the paracrine MSC actions and improves cardiac function in infarcted rat hearts. STATEMENT OF SIGNIFICANCE Transplantation of MSC is a promising treatment for ischemic heart disease, but low cell engraftment has so far limited its efficacy. The enzymatically degradable H-HG that we developed is able to increase MSC retention/engraftment and, at the same time, to fine-tune the paracrine effects mediated by the cells. Most importantly, the co-transplantation of MSC and H-HG in a rat model of ischemic cardiomyopathy improved heart function through a significant reduction in ventricular remodeling/scarring and amelioration in neo-vasculogenesis/endogenous cardiac regeneration. These beneficial effects are comparable to those obtained by others using a much greater number of cells, strengthening the efficacy of the biomaterial used in increasing the therapeutic effects of MSC. Given its efficacy and safety, documented by the absence of immunoreaction, our strategy appears readily translatable to clinical scenarios.
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Affiliation(s)
- Maria Chiara Ciuffreda
- Department of Medical Sciences and Infectious Diseases - Coronary Care Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; Laboratory of Experimental Cardiology for Cell and Molecular Therapy, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; Department of Molecular Medicine, Unit of Cardiology, University of Pavia, Italy
| | - Giuseppe Malpasso
- Department of Medical Sciences and Infectious Diseases - Coronary Care Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; Laboratory of Experimental Cardiology for Cell and Molecular Therapy, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; Department of Molecular Medicine, Unit of Cardiology, University of Pavia, Italy
| | - Cindy Chokoza
- Cardiovascular Research Unit, Chris Barnard Division of Cardiothoracic Surgery, University of Cape Town, Department of Health Sciences, Cape Town, South Africa
| | - Deon Bezuidenhout
- Cardiovascular Research Unit, Chris Barnard Division of Cardiothoracic Surgery, University of Cape Town, Department of Health Sciences, Cape Town, South Africa
| | - Kyle P Goetsch
- Cardiovascular Research Unit, Chris Barnard Division of Cardiothoracic Surgery, University of Cape Town, Department of Health Sciences, Cape Town, South Africa
| | - Manuela Mura
- Department of Medical Sciences and Infectious Diseases - Coronary Care Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; Laboratory of Experimental Cardiology for Cell and Molecular Therapy, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; Department of Molecular Medicine, Unit of Cardiology, University of Pavia, Italy
| | - Federica Pisano
- Department of Medical Sciences and Infectious Diseases - Coronary Care Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; Laboratory of Experimental Cardiology for Cell and Molecular Therapy, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; Department of Molecular Medicine, Unit of Cardiology, University of Pavia, Italy
| | - Neil H Davies
- Cardiovascular Research Unit, Chris Barnard Division of Cardiothoracic Surgery, University of Cape Town, Department of Health Sciences, Cape Town, South Africa
| | - Massimiliano Gnecchi
- Department of Medical Sciences and Infectious Diseases - Coronary Care Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; Laboratory of Experimental Cardiology for Cell and Molecular Therapy, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; Department of Molecular Medicine, Unit of Cardiology, University of Pavia, Italy; Department of Medicine, University of Cape Town, Cape Town, South Africa.
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Devetzi M, Goulielmaki M, Khoury N, Spandidos DA, Sotiropoulou G, Christodoulou I, Zoumpourlis V. Genetically‑modified stem cells in treatment of human diseases: Tissue kallikrein (KLK1)‑based targeted therapy (Review). Int J Mol Med 2018; 41:1177-1186. [PMID: 29328364 PMCID: PMC5819898 DOI: 10.3892/ijmm.2018.3361] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2017] [Accepted: 01/02/2018] [Indexed: 12/12/2022] Open
Abstract
The tissue kallikrein-kinin system (KKS) is an endogenous multiprotein metabolic cascade which is implicated in the homeostasis of the cardiovascular, renal and central nervous system. Human tissue kallikrein (KLK1) is a serine protease, component of the KKS that has been demonstrated to exert pleiotropic beneficial effects in protection from tissue injury through its anti-inflammatory, anti-apoptotic, anti-fibrotic and anti-oxidative actions. Mesenchymal stem cells (MSCs) or endothelial progenitor cells (EPCs) constitute populations of well-characterized, readily obtainable multipotent cells with special immunomodulatory, migratory and paracrine properties rendering them appealing potential therapeutics in experimental animal models of various diseases. Genetic modification enhances their inherent properties. MSCs or EPCs are competent cellular vehicles for drug and/or gene delivery in the targeted treatment of diseases. KLK1 gene delivery using adenoviral vectors or KLK1 protein infusion into injured tissues of animal models has provided particularly encouraging results in attenuating or reversing myocardial, renal and cerebrovascular ischemic phenotype and tissue damage, thus paving the way for the administration of genetically modified MSCs or EPCs with the human tissue KLK1 gene. Engraftment of KLK1-modified MSCs and/or KLK1-modified EPCs resulted in advanced beneficial outcome regarding heart and kidney protection and recovery from ischemic insults. Collectively, findings from pre-clinical studies raise the possibility that tissue KLK1 may be a novel future therapeutic target in the treatment of a wide range of cardiovascular, cerebrovascular and renal disorders.
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Affiliation(s)
- Marina Devetzi
- Biomedical Applications Unit, Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, 11635 Athens, Greece
| | - Maria Goulielmaki
- Biomedical Applications Unit, Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, 11635 Athens, Greece
| | - Nicolas Khoury
- Biomedical Applications Unit, Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, 11635 Athens, Greece
| | - Demetrios A Spandidos
- Laboratory of Clinical Virology, Medical School, University of Crete, 71003 Heraklion, Greece
| | | | - Ioannis Christodoulou
- Biomedical Applications Unit, Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, 11635 Athens, Greece
| | - Vassilis Zoumpourlis
- Biomedical Applications Unit, Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, 11635 Athens, Greece
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Optimized lentiviral transduction of human amniotic mesenchymal stromal cells. Pharmacol Res 2017; 127:49-57. [PMID: 29155015 DOI: 10.1016/j.phrs.2017.11.014] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2017] [Revised: 11/03/2017] [Accepted: 11/13/2017] [Indexed: 01/14/2023]
Abstract
Mesenchymal stromal cells are excellent candidates for regenerative medicine since they are multipotent, easy to isolate, can be expanded to obtain clinically relevant numbers and are immunoprivileged. Stable genetic modification with viral vectors can improve mesenchymal stromal cell function and enhance their therapeutic potential. However, standard viral vectors achieve sub-optimal transduction efficiency with a single infection. On the other hand, multiple transduction cycles or antibiotic-based selection methods may alter the stem cell phenotype. We hypothesized that the use of lentiviral vectors containing specific regulatory sequences may result in improved transduction efficiency. Thus, we compared two types of third generation lentiviral vectors, one of which, the pLenti7.3 vector, contains the optimized sequences for Polypurine Tract and Woodchuck Post-transcriptional Regulatory Element. We demonstrated that with the pLenti7.3 it is possible to efficiently transduce human mesenchymal stromal cells with a single transduction cycle. Additionally, we successfully showed that by using the pLenti7.3 vector it is possible to efficiently over-express different growth factors, particularly relevant for cardiac protection and differentiation, in human mesenchymal stromal cells.
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5
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Jin L, Xu Q, Kuddannaya S, Li C, Zhang Y, Wang Z. Fabrication and Characterization of Three-Dimensional (3D) Core-Shell Structure Nanofibers Designed for 3D Dynamic Cell Culture. ACS APPLIED MATERIALS & INTERFACES 2017; 9:17718-17726. [PMID: 28485136 DOI: 10.1021/acsami.7b02126] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Abstract
Three-dimensional elastic nanofibers (3D eNFs) can offer a suitable 3D dynamic microenvironment and sufficient flexibility to regulate cellular behavior and functional protein expression. In this study, we report a novel approach to prepare 3D nanofibers with excellent mechanical properties by solution-assisted electrospinning technology and in situ polymerization. The obtained 3D eNFs demonstrated excellent biocompatible properties to meet cell culture requirements under a dynamic environment in vitro. Moreover, these 3D eNFs also promoted human bone marrow mesenchymal stem cells (hMSCs) adhesion and collagen expression under biomechanical stimulation. The results demonstrated that this dynamic cell culture system could positively impact cellular collagen but has no significant effect on the proliferation of hMSCs grown in the 3D eNFs. This work may give rise to a new approach for constructing a 3D cell culture for tissue engineering.
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Affiliation(s)
- Lin Jin
- The Key Laboratory of Rare Earth Functional Materials and Applications, Zhoukou Normal University , Zhoukou 466001, P. R. China
- School of Mechanical & Aerospace Engineering, Nanyang Technological University , 50 Nanyang Avenue, 639798 Singapore
| | - Qinwei Xu
- School of Mechanical & Aerospace Engineering, Nanyang Technological University , 50 Nanyang Avenue, 639798 Singapore
| | - Shreyas Kuddannaya
- School of Mechanical & Aerospace Engineering, Nanyang Technological University , 50 Nanyang Avenue, 639798 Singapore
| | - Cheng Li
- School of Mechanical & Aerospace Engineering, Nanyang Technological University , 50 Nanyang Avenue, 639798 Singapore
| | - Yilei Zhang
- School of Mechanical & Aerospace Engineering, Nanyang Technological University , 50 Nanyang Avenue, 639798 Singapore
| | - Zhenling Wang
- The Key Laboratory of Rare Earth Functional Materials and Applications, Zhoukou Normal University , Zhoukou 466001, P. R. China
- International Joint Research Laboratory for Biomedical Nanomaterials of Henan , Zhoukou 466001, P. R. China
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Seo HH, Lee SY, Lee CY, Kim R, Kim P, Oh S, Lee H, Lee MY, Kim J, Kim LK, Hwang KC, Chang W. Exogenous miRNA-146a Enhances the Therapeutic Efficacy of Human Mesenchymal Stem Cells by Increasing Vascular Endothelial Growth Factor Secretion in the Ischemia/Reperfusion-Injured Heart. J Vasc Res 2017; 54:100-108. [DOI: 10.1159/000461596] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2016] [Accepted: 02/08/2017] [Indexed: 11/19/2022] Open
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Der Sarkissian S, Lévesque T, Noiseux N. Optimizing stem cells for cardiac repair: Current status and new frontiers in regenerative cardiology. World J Stem Cells 2017; 9:9-25. [PMID: 28154736 PMCID: PMC5253186 DOI: 10.4252/wjsc.v9.i1.9] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2016] [Revised: 09/20/2016] [Accepted: 10/24/2016] [Indexed: 02/06/2023] Open
Abstract
Cell therapy has the potential to improve healing of ischemic heart, repopulate injured myocardium and restore cardiac function. The tremendous hope and potential of stem cell therapy is well understood, yet recent trials involving cell therapy for cardiovascular diseases have yielded mixed results with inconsistent data thereby readdressing controversies and unresolved questions regarding stem cell efficacy for ischemic cardiac disease treatment. These controversies are believed to arise by the lack of uniformity of the clinical trial methodologies, uncertainty regarding the underlying reparative mechanisms of stem cells, questions concerning the most appropriate cell population to use, the proper delivery method and timing in relation to the moment of infarction, as well as the poor stem cell survival and engraftment especially in a diseased microenvironment which is collectively acknowledged as a major hindrance to any form of cell therapy. Indeed, the microenvironment of the failing heart exhibits pathological hypoxic, oxidative and inflammatory stressors impairing the survival of transplanted cells. Therefore, in order to observe any significant therapeutic benefit there is a need to increase resilience of stem cells to death in the transplant microenvironment while preserving or better yet improving their reparative functionality. Although stem cell differentiation into cardiomyocytes has been observed in some instance, the prevailing reparative benefits are afforded through paracrine mechanisms that promote angiogenesis, cell survival, transdifferentiate host cells and modulate immune responses. Therefore, to maximize their reparative functionality, ex vivo manipulation of stem cells through physical, genetic and pharmacological means have shown promise to enable cells to thrive in the post-ischemic transplant microenvironment. In the present work, we will overview the current status of stem cell therapy for ischemic heart disease, discuss the most recurring cell populations employed, the mechanisms by which stem cells deliver a therapeutic benefit and strategies that have been used to optimize and increase survival and functionality of stem cells including ex vivo preconditioning with drugs and a novel “pharmaco-optimizer” as well as genetic modifications.
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8
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Yu H, Lu K, Zhu J, Wang J. Stem cell therapy for ischemic heart diseases. Br Med Bull 2017; 121:135-154. [PMID: 28164211 DOI: 10.1093/bmb/ldw059] [Citation(s) in RCA: 105] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2016] [Accepted: 01/25/2017] [Indexed: 12/15/2022]
Abstract
INTRODUCTION Ischemic heart diseases, especially the myocardial infarction, is a major hazard problem to human health. Despite substantial advances in control of risk factors and therapies with drugs and interventions including bypass surgery and stent placement, the ischemic heart diseases usually result in heart failure (HF), which could aggravate social burden and increase the mortality rate. The current therapeutic methods to treat HF stay at delaying the disease progression without repair and regeneration of the damaged myocardium. While heart transplantation is the only effective therapy for end-stage patients, limited supply of donor heart makes it impossible to meet the substantial demand from patients with HF. Stem cell-based transplantation is one of the most promising treatment for the damaged myocardial tissue. SOURCES OF DATA Key recent published literatures and ClinicalTrials.gov. AREAS OF AGREEMENT Stem cell-based therapy is a promising strategy for the damaged myocardial tissue. Different kinds of stem cells have their advantages for treatment of Ischemic heart diseases. AREAS OF CONTROVERSY The efficacy and potency of cell therapies vary significantly from trial to trial; some clinical trials did not show benefit. Diverged effects of cell therapy could be affected by cell types, sources, delivery methods, dose and their mechanisms by which delivered cells exert their effects. GROWING POINTS Understanding the origin of the regenerated cardiomyocytes, exploring the therapeutic effects of stem cell-derived exosomes and using the cell reprogram technology to improve the efficacy of cell therapy for cardiovascular diseases. AREAS TIMELY FOR DEVELOPING RESEARCH Recently, stem cell-derived exosomes emerge as a critical player in paracrine mechanism of stem cell-based therapy. It is promising to exploit exosomes-based cell-free therapy for ischemic heart diseases in the future.
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Affiliation(s)
- Hong Yu
- Department of Cardiology, Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, 310009, P.R. China.,Cardiovascular Key Laboratory of Zhejiang Province, Hangzhou, Zhejiang Province, 310009, P.R. China
| | - Kai Lu
- Department of Cardiology, Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, 310009, P.R. China.,Cardiovascular Key Laboratory of Zhejiang Province, Hangzhou, Zhejiang Province, 310009, P.R. China.,Department of Cardiology, The First People's Hospital of Huzhou, 158 Guangchanghou Road, Huzhou, Zhejiang Province, 313000, P.R. China
| | - Jinyun Zhu
- Department of Cardiology, Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, 310009, P.R. China.,Cardiovascular Key Laboratory of Zhejiang Province, Hangzhou, Zhejiang Province, 310009, P.R. China
| | - Jian'an Wang
- Department of Cardiology, Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, 310009, P.R. China.,Cardiovascular Key Laboratory of Zhejiang Province, Hangzhou, Zhejiang Province, 310009, P.R. China
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Shafiq M, Jung Y, Kim SH. Insight on stem cell preconditioning and instructive biomaterials to enhance cell adhesion, retention, and engraftment for tissue repair. Biomaterials 2016; 90:85-115. [PMID: 27016619 DOI: 10.1016/j.biomaterials.2016.03.020] [Citation(s) in RCA: 91] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2015] [Revised: 03/09/2016] [Accepted: 03/13/2016] [Indexed: 12/13/2022]
Abstract
Stem cells are a promising solution for the treatment of a variety of diseases. However, the limited survival and engraftment of transplanted cells due to a hostile ischemic environment is a bottleneck for effective utilization and commercialization. Within this environment, the majority of transplanted cells undergo apoptosis prior to participating in lineage differentiation and cellular integration. Therefore, in order to maximize the clinical utility of stem/progenitor cells, strategies must be employed to increase their adhesion, retention, and engraftment in vivo. Here, we reviewed key strategies that are being adopted to enhance the survival, retention, and engraftment of transplanted stem cells through the manipulation of both the stem cells and the surrounding environment. We describe how preconditioning of cells or cell manipulations strategies can enhance stem cell survival and engraftment after transplantation. We also discuss how biomaterials can enhance the function of stem cells for effective tissue regeneration. Biomaterials can incorporate or mimic extracellular function (ECM) function and enhance survival or differentiation of transplanted cells in vivo. Biomaterials can also promote angiogenesis, enhance engraftment and differentiation, and accelerate electromechanical integration of transplanted stem cells. Insight gained from this review may direct the development of future investigations and clinical trials.
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Affiliation(s)
- Muhammad Shafiq
- Korea University of Science and Technology, 176 Gajeong-dong, Yuseong-gu, Daejeon, Republic of Korea; Center for Biomaterials, Biomedical Research Institute, Korea Institute of Science and Technology, Cheongryang, Seoul 130-650, Republic of Korea
| | - Youngmee Jung
- Korea University of Science and Technology, 176 Gajeong-dong, Yuseong-gu, Daejeon, Republic of Korea; Center for Biomaterials, Biomedical Research Institute, Korea Institute of Science and Technology, Cheongryang, Seoul 130-650, Republic of Korea
| | - Soo Hyun Kim
- Korea University of Science and Technology, 176 Gajeong-dong, Yuseong-gu, Daejeon, Republic of Korea; Center for Biomaterials, Biomedical Research Institute, Korea Institute of Science and Technology, Cheongryang, Seoul 130-650, Republic of Korea; KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul 136-701, Republic of Korea.
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Mizukami T, Iso Y, Sato C, Sasai M, Spees JL, Toyoda M, Umezawa A, Miyazaki A, Suzuki H. Priming with erythropoietin enhances cell survival and angiogenic effect of mesenchymal stem cell implantation in rat limb ischemia. Regen Ther 2016; 4:1-8. [PMID: 31245482 PMCID: PMC6581814 DOI: 10.1016/j.reth.2016.01.004] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2015] [Revised: 01/03/2016] [Accepted: 01/07/2016] [Indexed: 11/17/2022] Open
Abstract
Introduction Bone marrow mesenchymal stem cells (BMMSCs) ameliorate tissue damage after ischemic injury. Erythropoietin (Epo) has pleiotropic effects in addition to hematopoietic activity. The aim of this study was to investigate whether Epo enhanced cell survival and angiogenic effect of BMMSC implantation in rat limb ischemia model. Methods and results MSCs were isolated from BM in GFP-transgenic rats. In a culture study, Epo promoted BMMSC proliferation in normoxia and enhanced cell survival under the culture condition mimicking ischemia (1% oxygen and nutrient deprivation). BMMSCs with and without 48 h of pretreatment by Epo (80 IU/ml) were locally administered to rat hindlimb ischemia models in vivo. At 3 days after implantation, BMMSC engraftment in the perivascular area of the injured muscle was significantly higher in the cells preconditioned with Epo than in the cells without preconditioning. Stromal derived factor-1α and fibroblast growth factor-2 expressions were detected in the engrafted BMMSCs. At 14 days after implantation, the Epo-preconditioned BMMSCs significantly promoted blood perfusion and capillary growth compared to the controls in laser Doppler and histological studies. In addition to promoting neovascularization, the Epo-preconditioned BMMSCs significantly inhibited macrophage infiltration in the perivascular area. Conclusion Epo elicited pro-survival potential in the BMMSCs. Pharmacological cell modification with Epo before implantation may become a feasible and promising strategy for improving current therapeutic angiogenesis with BMMSCs.
Erythropoietin rescued the BMMSCs against the culture condition mimicking ischemia. Erythropoietin promoted cellular engraftment of the BMMSCs in rat ischemic limbs. Preconditioning with erythropoietin enhanced angiogenic effects of the BMMSC implantation.
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Affiliation(s)
- Takuya Mizukami
- Division of Cardiology, Showa University Fujigaoka Hospital, Yokohama, Japan.,Department of Biochemistry, Showa University School of Medicine, Tokyo, Japan
| | - Yoshitaka Iso
- Division of Cardiology, Showa University Fujigaoka Hospital, Yokohama, Japan.,Showa University Research Institute for Sport and Exercise Sciences, Yokohama, Japan
| | - Chisato Sato
- Division of Cardiology, Showa University Fujigaoka Hospital, Yokohama, Japan.,Department of Biochemistry, Showa University School of Medicine, Tokyo, Japan
| | - Masahiro Sasai
- Division of Cardiology, Showa University Fujigaoka Hospital, Yokohama, Japan.,Department of Biochemistry, Showa University School of Medicine, Tokyo, Japan
| | - Jeffery L Spees
- Department of Medicine, Stem Cell Core, University of Vermont, VT, USA
| | - Masashi Toyoda
- Research Team for Vascular Medicine, Tokyo, Metropolitan Institute of Gerontology, Tokyo, Japan
| | - Akihiro Umezawa
- Center for Regenerative Medicine, National Research Institute for Child Health and Development, Tokyo, Japan
| | - Akira Miyazaki
- Department of Biochemistry, Showa University School of Medicine, Tokyo, Japan
| | - Hiroshi Suzuki
- Division of Cardiology, Showa University Fujigaoka Hospital, Yokohama, Japan
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Cell Therapy in Ischemic Heart Disease: Interventions That Modulate Cardiac Regeneration. Stem Cells Int 2016; 2016:2171035. [PMID: 26880938 PMCID: PMC4736413 DOI: 10.1155/2016/2171035] [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: 08/14/2015] [Revised: 10/26/2015] [Accepted: 11/10/2015] [Indexed: 12/15/2022] Open
Abstract
The incidence of severe ischemic heart disease caused by coronary obstruction has progressively increased. Alternative forms of treatment have been studied in an attempt to regenerate myocardial tissue, induce angiogenesis, and improve clinical conditions. In this context, cell therapy has emerged as a promising alternative using cells with regenerative potential, focusing on the release of paracrine and autocrine factors that contribute to cell survival, angiogenesis, and tissue remodeling. Evidence of the safety, feasibility, and potential effectiveness of cell therapy has emerged from several clinical trials using different lineages of adult stem cells. The clinical benefit, however, is not yet well established. In this review, we discuss the therapeutic potential of cell therapy in terms of regenerative and angiogenic capacity after myocardial ischemia. In addition, we addressed nonpharmacological interventions that may influence this therapeutic practice, such as diet and physical training. This review brings together current data on pharmacological and nonpharmacological approaches to improve cell homing and cardiac repair.
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12
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Pisano F, Gnecchi M. Transfection of Embryoid Bodies with miRNA Precursors to Induce Cardiac Differentiation. Bio Protoc 2016. [DOI: 10.21769/bioprotoc.1726] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022] Open
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13
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Vu MQ, Der Sarkissian S, Borie M, Bessette PO, Noiseux N. Optimization of Mesenchymal Stem Cells to Increase Their Therapeutic Potential. Methods Mol Biol 2016; 1416:275-88. [PMID: 27236678 DOI: 10.1007/978-1-4939-3584-0_16] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The heart which has limited renewal and regenerative capacity is a prime target for cellular therapy. Stem cell transplantation has emerged as a promising therapeutic strategy to improve healing of the ischemic heart, repopulate the injured myocardium, and restore cardiac function. However, clinical usefulness is impacted by the quality and quantity of delivered cells, the suboptimal manipulations prior to transplantation, and the general poor viability of the cells transferred particularly to an ischemic microenvironment. Focus is now on developing new ways to enhance stem cell renewal and survival capacity before transplant. This can be done by physical, chemical, pharmacological, or genetic manipulation of cells followed by accurate evaluation of conditioning methods by validated tests.This chapter covers the proper handling of mesenchymal stem cells (human and rat lines) and methodologies to evaluate efficacy and the translational potential of conditioning methods. Specifically, we will cover stem cell culture methods, preconditioning protocols, viability assessment in hypoxic and oxidative challenges as encountered in an ischemic microenvironment, and the proliferative capacity of cells.
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Affiliation(s)
- Minh Quan Vu
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, QC, Canada.,Faculté de Médecine, Université de Montréal, Montreal, QC, Canada
| | - Shant Der Sarkissian
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, QC, Canada.,Faculté de Médecine, Université de Montréal, Montreal, QC, Canada
| | - Melanie Borie
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, QC, Canada
| | | | - Nicolas Noiseux
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, QC, Canada. .,Faculté de Médecine, Université de Montréal, Montreal, QC, Canada. .,Division of Cardiac Surgery, Centre Hospitalier de l'Université de Montréal (CHUM), 3840 Saint-Urbain Street, Montreal, QC, Canada, H2W1T8.
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Improving Cell Engraftment in Cardiac Stem Cell Therapy. Stem Cells Int 2015; 2016:7168797. [PMID: 26783405 PMCID: PMC4691492 DOI: 10.1155/2016/7168797] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2015] [Revised: 07/22/2015] [Accepted: 08/11/2015] [Indexed: 12/18/2022] Open
Abstract
Myocardial infarction (MI) affects millions of people worldwide. MI causes massive cardiac cell death and heart function decrease. However, heart tissue cannot effectively regenerate by itself. While stem cell therapy has been considered an effective approach for regeneration, the efficacy of cardiac stem cell therapy remains low due to inferior cell engraftment in the infarcted region. This is mainly a result of low cell retention in the tissue and poor cell survival under ischemic, immune rejection and inflammatory conditions. Various approaches have been explored to improve cell engraftment: increase of cell retention using biomaterials as cell carriers; augmentation of cell survival under ischemic conditions by preconditioning cells, genetic modification of cells, and controlled release of growth factors and oxygen; and enhancement of cell survival by protecting cells from excessive inflammation and immune surveillance. In this paper, we review current progress, advantages, disadvantages, and potential solutions of these approaches.
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15
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Fouladiha H, Marashi SA, Shokrgozar MA. Reconstruction and validation of a constraint-based metabolic network model for bone marrow-derived mesenchymal stem cells. Cell Prolif 2015; 48:475-85. [PMID: 26132591 DOI: 10.1111/cpr.12197] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2015] [Accepted: 04/14/2015] [Indexed: 12/28/2022] Open
Abstract
OBJECTIVES Over recent years, constraint-based modelling of metabolic networks has become increasingly popular; the models are suitable for system-level modelling of cell physiology. The goal of the present work was to reconstruct a constraint-based metabolic network model of bone marrow-derived mesenchymal stem cells (BMMSCs). MATERIALS AND METHODS To reconstruct a BMMSC-specific metabolic model, transcriptomic data of BMMSCs, and additionally, the human generic metabolic network model (Recon1) were used. Then, using the mCADRE algorithm, a draft metabolic network was reconstructed. Literature and proteomic data were subsequently used to refine and improve the draft. From this, iMSC1255 was derived to be the metabolic network model of BMMSCs. RESULTS iMSC1255 has 1255 genes, 1850 metabolites and 2288 reactions. After including additional constraints based on previously reported experimental results, our model successfully predicted BMMSC growth rate and metabolic phenotypes. CONCLUSIONS Here, iMSC1255 is introduced to be the metabolic network model of bone marrow-derived mesenchymal stem cells. Based on current knowledge, this is the first report on genome-scale reconstruction and validation of a stem cell metabolic network model.
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Affiliation(s)
- H Fouladiha
- Department of Biotechnology, College of Science, University of Tehran, Tehran, 1417614411, Iran
| | - S-A Marashi
- Department of Biotechnology, College of Science, University of Tehran, Tehran, 1417614411, Iran
| | - M A Shokrgozar
- National Cell Bank of Iran, Pasteur Institute of Iran, Tehran, 1316943551, Iran
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16
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Pan A, Weintraub NL, Tang Y. Enhancing stem cell survival in an ischemic heart by CRISPR-dCas9-based gene regulation. Med Hypotheses 2014; 83:702-5. [PMID: 25459138 DOI: 10.1016/j.mehy.2014.09.022] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2014] [Accepted: 09/29/2014] [Indexed: 12/18/2022]
Abstract
Ischemic heart disease has remained the number one killer around the world for over the past 20 years. While stem cell therapy has become a promising new frontier to repair the damaged heart, limited stem cell survivability post-transplantation has precluded widespread use of this therapy. Strategies to genetically modify stem cells to activate pro-survival and anti-apoptotic and anti-inflammatory pathways, such as Akt and heme oxygenase-1, have been shown to improve the lifespan of transplanted stem cells within the ischemic myocardium, but constitutive overexpression of these pathways at high levels has been shown to have side effects. Therefore, more specific and controlled gene activation would be necessary. Current techniques used for gene regulation include zinc finger and TALE proteins, but there are still disadvantages to each of these methods, such as ease and cost of use. Also, those methods use synthesized promoters to express synthesized cDNA, which lack regulatory elements, including introns and 3' untranslated regions for microRNA mediated post-transcriptional regulation. A new novel technique, the CRISPR/dCas9 system, was recently developed as a simple and efficient method for endogenous gene regulation. With its use of single guide chimeric RNA's (sgRNA's), this system has been shown to provide a high level of specificity and efficiency. When targeting different loci, past studies have found that the CRISPR/dCas9 system can activate gene expression at varying levels. In addition, this system makes use of the genome's endogenous regulatory elements, such as the aforementioned introns and 3' UTR's, which can help provide a safer method of gene activation. If targeted to a gene promoting cellular survival or decreasing cell death, it could potentially improve stem cell longevity in a more efficient and controllable manner. As a result, our hypothesis is to use the CRISPR/dCas9 system to activate expression of an anti-inflammatory and anti-apoptotic gene, such as heme oxygenase-1 (HO-1), to an optimal level to increase transplanted stem cell survival while also mitigating its cytotoxic effects due to lack of internal regulation, thus prolonging its effects within the ischemic myocardium leading to greater therapeutic benefit.
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Affiliation(s)
- Alexander Pan
- Vascular Biology Center, Department of Medicine, Medical College of Georgia/Georgia Regents University, 1459 Laney Walker Blvd, Augusta, GA 30912, USA
| | - Neal L Weintraub
- Vascular Biology Center, Department of Medicine, Medical College of Georgia/Georgia Regents University, 1459 Laney Walker Blvd, Augusta, GA 30912, USA
| | - Yaoliang Tang
- Vascular Biology Center, Department of Medicine, Medical College of Georgia/Georgia Regents University, 1459 Laney Walker Blvd, Augusta, GA 30912, USA.
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17
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Chao J, Bledsoe G, Chao L. Kallikrein-kinin in stem cell therapy. World J Stem Cells 2014; 6:448-457. [PMID: 25258666 PMCID: PMC4172673 DOI: 10.4252/wjsc.v6.i4.448] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2014] [Revised: 08/27/2014] [Accepted: 09/01/2014] [Indexed: 02/06/2023] Open
Abstract
The tissue kallikrein-kinin system exerts a wide spectrum of biological activities in the cardiovascular, renal and central nervous systems. Tissue kallikrein-kinin modulates the proliferation, viability, mobility and functional activity of certain stem cell populations, namely mesenchymal stem cells (MSCs), endothelial progenitor cells (EPCs), mononuclear cell subsets and neural stem cells. Stimulation of these stem cells by tissue kallikrein-kinin may lead to protection against renal, cardiovascular and neural damage by inhibiting apoptosis, inflammation, fibrosis and oxidative stress and promoting neovascularization. Moreover, MSCs and EPCs genetically modified with tissue kallikrein are resistant to hypoxia- and oxidative stress-induced apoptosis, and offer enhanced protective actions in animal models of heart and kidney injury and hindlimb ischemia. In addition, activation of the plasma kallikrein-kinin system promotes EPC recruitment to the inflamed synovium of arthritic rats. Conversely, cleaved high molecular weight kininogen, a product of plasma kallikrein, reduces the viability and vasculogenic activity of EPCs. Therefore, kallikrein-kinin provides a new approach in enhancing the efficacy of stem cell therapy for human diseases.
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18
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Pankajakshan D, Agrawal DK. Mesenchymal Stem Cell Paracrine Factors in Vascular Repair and Regeneration. ACTA ACUST UNITED AC 2014; 1. [PMID: 28890954 DOI: 10.19104/jbtr.2014.107] [Citation(s) in RCA: 73] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Mesenchymal stem cell therapy show great optimism in the treatment of several diseases. MSCs are attractive candidates for cell therapy because of easy isolation, high expansion potential giving unlimited pool of transplantable cells, low immunogenicity, amenability to ex vivo genetic modification, and multipotency. The stem cells orchestrate the repair process by various mechanisms such as transdifferentiation, cell fusion, microvesicles or exosomes and most importantly by secreting paracrine factors. The MSCs release several angiogenic, mitogenic, anti-apoptotic, anti-inflammatory and anti-oxidative factors that play fundamental role in regulating tissue repair in various vascular and cardiac diseases. The therapeutic release of these factors by the cells can be enhanced by several strategies like genetic modification, physiological and pharmacological preconditioning, improved cell culture and selection methods, and biomaterial based approaches. The current review describes the impact of paracrine factors released by MSCs on vascular repair and regeneration in myocardial infarction, restenosis and peripheral artery disease, and the various strategies adopted to enhance the release of these paracrine factors to enhance organ function.
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Affiliation(s)
- Divya Pankajakshan
- Department of Biomedical Sciences, Creighton University School of Medicine, Omaha, NE, USA
| | - Devendra K Agrawal
- Department of Biomedical Sciences, Creighton University School of Medicine, Omaha, NE, USA
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19
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Escobedo-Uribe CD, Monsiváis-Urenda AE, López-Quijano JM, Carrillo-Calvillo J, Leiva-Pons JL, Peña-Duque MA. [Cell therapy for ischemic heart disease]. ARCHIVOS DE CARDIOLOGIA DE MEXICO 2012; 82:218-29. [PMID: 23021359 DOI: 10.1016/j.acmx.2012.04.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2011] [Revised: 01/02/2012] [Accepted: 04/17/2012] [Indexed: 10/27/2022] Open
Abstract
Ischemic heart disease is the leading cause of death and heart failure worldwide. That is why it is important to develop new therapeutic modalities to decrease mortality and long-term complications in these patients. One of the main lines of research worldwide is myocardial regeneration, using progenitor cells in order to improve systolic and diastolic function in patients with ischemic heart disease, as well as to increase their survival. There have been carried out, with great enthusiasm worldwide, human and animal studies to define the usefulness of stem cells in the management of patients with ischemic heart disease. Today, regenerative therapy in ischemic heart disease is considered a novel therapeutic tool, with substantial theoretical benefits and few side effects. Here we present the scientific principles that support the use of this therapy, discuss the current clinical evidence available; and point out the controversial issues still not clarified on its use and usefulness in the short and long term.
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20
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Cai C, Teng L, Vu D, He JQ, Guo Y, Li Q, Tang XL, Rokosh G, Bhatnagar A, Bolli R. The heme oxygenase 1 inducer (CoPP) protects human cardiac stem cells against apoptosis through activation of the extracellular signal-regulated kinase (ERK)/NRF2 signaling pathway and cytokine release. J Biol Chem 2012; 287:33720-32. [PMID: 22879597 DOI: 10.1074/jbc.m112.385542] [Citation(s) in RCA: 84] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Intracoronary delivery of c-kit-positive human cardiac stem cells (hCSCs) is a promising approach to repair the infarcted heart, but it is severely limited by the poor survival of donor cells. Cobalt protoporphyrin (CoPP), a well known heme oxygenase 1 inducer, has been used to promote endogenous CO generation and protect against ischemia/reperfusion injury. Therefore, we determined whether preconditioning hCSCs with CoPP promotes CSC survival. c-kit-positive, lineage-negative hCSCs were isolated from human heart biopsies. Lactate dehydrogenase release assays demonstrated that preconditioning CSCs with CoPP markedly enhanced cell survival after oxidative stress induced by H(2)O(2), concomitant with up-regulation of heme oxygenase 1, COX-2, and anti-apoptotic proteins (BCL2, BCL2-A1, and MCL-1) and increased phosphorylation of NRF2. Apoptotic cytometric assays showed that pretreatment of CSCs with CoPP enhanced the cells' resistance to apoptosis induced by oxidative stress. Conversely, knocking down HO-1, COX-2, or NRF2 by shRNA gene silencing abrogated the cytoprotective effects of CoPP. Further, preconditioning CSCs with CoPP led to a global increase in release of cytokines, such as EGF, FGFs, colony-stimulating factors, and chemokine ligand. Conditioned medium from cells pretreated with CoPP conferred naive CSCs remarkable resistance to apoptosis, demonstrating that cytokines released by preconditioned cells play a key role in the anti-apoptotic effects of CoPP. Preconditioning CSCs with CoPP also induced an increase in the phosphorylation of Erk1/2, which are known to modulate multiple pro-survival genes. These results potentially provide a simple and effective strategy to enhance survival of CSCs after transplantation and, therefore, their efficacy in repairing infarcted myocardium.
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Affiliation(s)
- Chuanxi Cai
- Department of Medicine, Institute of Molecular Cardiology, University of Louisville, Louisville, Kentucky 40292, USA
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21
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Gnecchi M, Danieli P, Cervio E. Mesenchymal stem cell therapy for heart disease. Vascul Pharmacol 2012; 57:48-55. [PMID: 22521741 DOI: 10.1016/j.vph.2012.04.002] [Citation(s) in RCA: 111] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2012] [Revised: 03/27/2012] [Accepted: 04/04/2012] [Indexed: 12/20/2022]
Abstract
Mesenchymal stem cells (MSC) are adult stem cells with capacity for self-renewal and multi-lineage differentiation. Initially described in the bone marrow, MSC are also present in other organs and tissues. From a therapeutic perspective, because of their easy preparation and immunologic privilege, MSC are emerging as an extremely promising therapeutic agent for tissue regeneration and repair. Studies in animal models of myocardial infarction have demonstrated the ability of transplanted MSC to engraft and differentiate into cardiomyocytes and vascular cells. Most importantly, engrafted MSC secrete a wide array of soluble factors that mediate beneficial paracrine effects and may greatly contribute to cardiac repair. Together, these properties can be harnessed to both prevent and reverse remodeling in the ischemically injured ventricle. In proof-of-concept and phase I clinical trials, MSC therapy improved left ventricular function, induced reverse remodeling, and decreased scar size. In this review we will focus on the current understanding of MSC biology and MSC mechanism of action in cardiac repair.
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Affiliation(s)
- Massimiliano Gnecchi
- Department of Molecular Medicine, University of Pavia, Viale Golgi 19, 27100 Pavia, Italy.
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22
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Kollar K, Seifried E, Henschler R. Therapeutic potential of intravenously administered human mesenchymal stromal cells. Hamostaseologie 2012; 31:269-74. [PMID: 22064918 DOI: 10.5482/ha-1158] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2011] [Accepted: 06/06/2011] [Indexed: 12/17/2022] Open
Abstract
Mesenchymal stem cells (MSC) represent a stem and progenitor cell population that has been shown to promote tissue recovery in pre-clinical and clinical studies. The study of MSC migration following systemic infusion of exogenous MSC is difficult. The challenges facing these efforts are due to a number of factors, including defining culture conditions for MSC, the phenotype of cultured MSC, the differences observed between cultured MSC and freshly isolated MSC. However, even if, MSC populations consist of a mixture of stem and more committed multipotent progenitors, it remains probable that these cell populations are still useful in the clinic as discussed in this review.
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Affiliation(s)
- K Kollar
- Institute for Transfusion Medicine and Immune Hematology, Goethe University, Frankfurt, Germany
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23
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Shah VK, Shalia KK. Stem Cell Therapy in Acute Myocardial Infarction: A Pot of Gold or Pandora's Box. Stem Cells Int 2011; 2011:536758. [PMID: 21804827 PMCID: PMC3142872 DOI: 10.4061/2011/536758] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2010] [Revised: 12/18/2010] [Accepted: 12/29/2010] [Indexed: 01/09/2023] Open
Abstract
Stem cell therapy for conditions characterized by myocyte loss in myocardial infarction and heart failure is intuitively appealing. Stem cells from various sources, including heart itself in preclinical and animal studies, have shown the potential to improve the function of ventricular muscle after ischaemic injury. The clinical experience from worldwide studies have indicated the safety profile but with modest benefits. The predominant mechanisms of transplanted cells for improving cardiac function have pointed towards paracrine effects rather than transdifferentiation into cardiomyocytes. Thus, further investigations should be encouraged towards bench side and bedside to resolve various issues for ensuring the correct type and dosing of cells, time, and method of delivery and identify correct mechanism of functional improvement. An interdisciplinary effort at the scientific, clinical, and the government front will bring successful realization of this therapy for healing the heart and may convert what seems now a Pandora's Box into a Pot of Gold.
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Affiliation(s)
- V K Shah
- Interventional Cardiologist, Sir H.N. Hospital and Research Centre, Raja Rammohan Roy Road, Mumbai 400 004, India
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24
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Duffy GP, D'Arcy S, Ahsan T, Nerem RM, O'Brien T, Barry F. Mesenchymal stem cells overexpressing ephrin-b2 rapidly adopt an early endothelial phenotype with simultaneous reduction of osteogenic potential. Tissue Eng Part A 2010; 16:2755-68. [PMID: 20491587 DOI: 10.1089/ten.tea.2009.0623] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Restoration of the vascular supply to ischemic tissues is of high clinical relevance, and proangiogenic therapies aim to reduce morbidity and mortality rates associated with the onset of cardiovascular disease. Stem cell therapy has been proposed as a potentially useful proangiogenic therapy. Mesenchymal stem cells (MSCs) have been shown to be proangiogenic and produce a number of cytokines involved in vessel development and maturation. Preclinical studies have reported increased angiogenesis after MSC delivery to the heart, and similar outcomes have been reported in recent clinical trials. Stem-cell-mediated neovascularization has been augmented by genetic modification with overexpression of angiogenic cytokines, including vascular endothelial growth factor (VEGF) and platelet-derived growth factor, showing promising results. In this study we aimed to enhance the proangiogenic capability of MSCs. MSCs were genetically modified to overexpress a versatile molecule, Ephrin-B2, involved in tissue morphogenesis and vascular development to enhance inherent neovascularization potential. Using nucleofection, Ephrin-B2 was transiently overexpressed on the cell surface of MSCs to recapitulate embryonic signaling and promote neovascularization. Ephrin-B2-expressing MSCs adopted an early endothelial phenotype under endothelial cell culture conditions increasing expression of von Willebrand factor and VEGF-Receptor 2. The cells had an increased ability to form vessel-like structures, produce VEGF, and incorporate into newly formed endothelial cell structures. These data indicate that MSCs expressing Ephrin-B2 represent a novel proangiogenic cell source to promote neovascularization in ischemic tissues.
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Affiliation(s)
- Garry P Duffy
- Regenerative Medicine Institute (REMEDI), National University of Ireland Galway, Ireland
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25
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Mirotsou M, Jayawardena TM, Schmeckpeper J, Gnecchi M, Dzau VJ. Paracrine mechanisms of stem cell reparative and regenerative actions in the heart. J Mol Cell Cardiol 2010; 50:280-9. [PMID: 20727900 DOI: 10.1016/j.yjmcc.2010.08.005] [Citation(s) in RCA: 343] [Impact Index Per Article: 22.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2010] [Revised: 08/02/2010] [Accepted: 08/03/2010] [Indexed: 12/12/2022]
Abstract
Stem cells play an important role in restoring cardiac function in the damaged heart. In order to mediate repair, stem cells need to replace injured tissue by differentiating into specialized cardiac cell lineages and/or manipulating the cell and molecular mechanisms governing repair. Despite early reports describing engraftment and successful regeneration of cardiac tissue in animal models of heart failure, these events appear to be infrequent and yield too few new cardiomyocytes to account for the degree of improved cardiac function observed. Instead, mounting evidence suggests that stem cell mediated repair takes place via the release of paracrine factors into the surrounding tissue that subsequently direct a number of restorative processes including myocardial protection, neovascularization, cardiac remodeling, and differentiation. The potential for diverse stem cell populations to moderate many of the same processes as well as key paracrine factors and molecular pathways involved in stem cell-mediated cardiac repair will be discussed in this review. This article is part of a special issue entitled, "Cardiovascular Stem Cells Revisited".
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Affiliation(s)
- Maria Mirotsou
- Department of Medicine, Duke University Medical Center & Mandel Center for Hypertension and Atherosclerosis Research, Durham, NC 27710, USA
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26
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Wang W, Li W, Ou L, Flick E, Mark P, Nesselmann C, Lux CA, Gatzen HH, Kaminski A, Liebold A, Lützow K, Lendlein A, Li RK, Steinhoff G, Ma N. Polyethylenimine-mediated gene delivery into human bone marrow mesenchymal stem cells from patients. J Cell Mol Med 2010; 15:1989-98. [PMID: 20629995 PMCID: PMC3918054 DOI: 10.1111/j.1582-4934.2010.01130.x] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Transplantation of mesenchymal stem cells (MSCs) derived from adult bone marrow has been proposed as a potential therapeutic approach for post-infarction left ventricular (LV) dysfunction. However, age-related functional decline of stem cells has restricted their clinical benefits after transplantation into the infarcted myocardium. The limitations imposed on patient cells could be addressed by genetic modification of stem cells. This study was designed to improve our understanding of genetic modification of human bone marrow derived mesenchymal stem cells (hMSCs) by polyethylenimine (PEI, branched with Mw 25 kD), one of non-viral vectors that show promise in stem cell genetic modification, in the context of cardiac regeneration for patients. We optimized the PEI-mediated reporter gene transfection into hMSCs, evaluated whether transfection efficiency is associated with gender or age of the cell donors, analysed the influence of cell cycle on transfection and investigated the transfer of therapeutic vascular endothelial growth factor gene (VEGF). hMSCs were isolated from patients with cardiovascular disease aged from 41 to 85 years. Optimization of gene delivery to hMSCs was carried out based on the particle size of the PEI/DNA complexes, N/P ratio of complexes, DNA dosage and cell viability. The highest efficiency with the cell viability near 60% was achieved at N/P ratio 2 and 6.0 μg DNA/cm2. The average transfection efficiency for all tested samples, middle-age group (<65 years), old-age group (>65 years), female group and male group was 4.32%, 3.85%, 4.52%, 4.14% and 4.38%, respectively. The transfection efficiency did not show any correlation either with the age or the gender of the donors. Statistically, there were two subpopulations in the donors; and transfection efficiency in each subpopulation was linearly related to the cell percentage in S phase. No significant phenotypic differences were observed between these two subpopulations. Furthermore, PEI-mediated therapeutic gene VEGF transfer could significantly enhance the expression level.
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Affiliation(s)
- Weiwei Wang
- Department of Cardiac Surgery, University of Rostock, Rostock, Germany
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27
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D'Agostino B, Sullo N, Siniscalco D, De Angelis A, Rossi F. Mesenchymal stem cell therapy for the treatment of chronic obstructive pulmonary disease. Expert Opin Biol Ther 2010; 10:681-7. [PMID: 20384521 DOI: 10.1517/14712591003610614] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Recent studies have revealed that adult stem cells such as bone marrow-derived cells contribute to lung tissue regeneration and protection, and thus administration of exogenous stem/progenitor cells may be a potent next-generation therapy for COPD. Pathogenesis of COPD is characterized by an upregulation of inflammatory processes leading to irreversible events such as apoptosis of epithelial cells, proteolysis of the terminal air-space and lung extracellular matrix components. The available pharmacological treatments are essentially symptomatic, therefore, there is a need to develop more effective therapeutic strategies. It has been previously demonstrated that transplanted MSC home to the lung in response to lung injury and adopt phenotypes of alveolar epithelial cells, endothelial cells, fibroblasts and bronchial epithelial cells. However, engraftment and differentiation are now felt to be rare occurrences and other mechanisms might be involved and play a more important role. Importantly, MSCs protect lung tissue through suppression of proinflammatory cytokines, and through triggering production of reparative growth factors. Accordingly, it is not clear if and how these cells will be able to repair, to slow or to prevent the disease. This article reviews recent advances in regenerative medicine in COPD and highlights that their potential application although promising and very attractive, are still a far away opinion.
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Affiliation(s)
- Bruno D'Agostino
- Department of Experimental Medicine, Second University of Naples, Section of Pharmacology L Donatelli, via S Maria di Costantinopoli, 16-80138 Napoli, Italy.
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28
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Abstract
Evaluation of: Schachinger V, Erbs S, Elsasser A et al.: Intracoronary bone marrow-derived progenitor cells in acute myocardial infarction. N. Engl. J. Med. 355, 1210-1221 (2006). The Reinfusion of Enriched Progenitor cells And Infarct Remodeling in Acute Myocardial Infarction (REPAIR-AMI) trial, the largest randomized, placebo-controlled trial of stem cell therapy in acute myocardial infarction, studied the efficacy of the intracoronary delivery of bone marrow mononuclear cells (BMCs) versus placebo in patients with acute ST-segment elevation myocardial infarction following successful percutaneous coronary intervention. At 4 month follow-up, patients treated with BMCs had a significant improvement in left ventricular ejection fraction compared with placebo (+5.5 vs +3.0%, absolute difference +2.5%). In addition, treatment with BMCs was associated with a statistically significant reduction in adverse clinical events at 1 year follow-up. Despite these promising findings, other studies have shown mixed results and several unresolved clinical and physiological issues remain. Key findings from ongoing basic and clinical research will define the future role of stem cell therapy for acute myocardial infarction.
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Affiliation(s)
- James S Mills
- Duke Clinical Research Institute, Duke University Medical Center, Box 31286, Durham, NC 27710, USA.
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29
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Haider HK, Ashraf M. Preconditioning and stem cell survival. J Cardiovasc Transl Res 2009; 3:89-102. [PMID: 20560023 DOI: 10.1007/s12265-009-9161-2] [Citation(s) in RCA: 86] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2009] [Accepted: 11/24/2009] [Indexed: 01/01/2023]
Abstract
The harsh ischemic and cytokine-rich microenvironment in the infarcted myocardium, infiltrated by the inflammatory and immune cells, offers a significant challenge to the transplanted donor stem cells. Massive cell death occurs during transplantation as well as following engraftment which significantly lowers the effectiveness of the heart cell therapy. Various approaches have been adopted to overcome this problem nevertheless with multiple limitations with each of these current approaches. Cellular preconditioning and reprogramming by physical, chemical, genetic, and pharmacological manipulation of the cells has shown promise and "prime" the cells to the "state of readiness" to withstand the rigors of lethal ischemia in vitro as well as posttransplantation. This review summarizes the past and present novel approaches of ischemic preconditioning, pharmacological and genetic manipulation using preconditioning mimetics, recombinant growth factor protein treatment, and reprogramming of stem cells to overexpress survival signaling molecules, microRNAs, and trophic factors for intracrine, autocrine, and paracrine effects on cytoprotection.
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Affiliation(s)
- Husnain Kh Haider
- Department of Pathology and Laboratory Medicine, University of Cincinnati, 231-Albert, Sabin Way, OH 45267-0529, USA.
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30
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Abstract
From bone marrow transplants 5 decades ago to the most recent stem cell-derived organ transplants, regenerative medicine is increasingly recognized as an emerging core component of modern practice. In cardiovascular medicine, innovation in stem cell biology has created curative solutions for the treatment of both ischemic and nonischemic cardiomyopathy. Multiple cell-based platforms have been developed, harnessing the regenerative potential of various natural and bioengineered sources. Clinical experience from the first 1000 patients (approximately) who have received stem cell therapy worldwide indicates a favorable safety profile with modest improvement in cardiac function and structural remodeling in the setting of acute myocardial infarction or chronic heart failure. Further investigation is required before early adoption and is ongoing. Broader application in practice will require continuous scientific advances to match each patient with the most effective reparative phenotype, while ensuring optimal cell delivery, dosing, and timing of intervention. An interdisciplinary effort across the scientific and clinical community within academia, biotechnology, and government will drive the successful realization of this next generation of therapeutic agents for the "broken" heart.
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Affiliation(s)
- Bernard J Gersh
- Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN 55905, USA.
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Abstract
From bone marrow transplants 5 decades ago to the most recent stem cell-derived organ transplants, regenerative medicine is increasingly recognized as an emerging core component of modern practice. In cardiovascular medicine, innovation in stem cell biology has created curative solutions for the treatment of both ischemic and nonischemic cardiomyopathy. Multiple cell-based platforms have been developed, harnessing the regenerative potential of various natural and bioengineered sources. Clinical experience from the first 1000 patients (approximately) who have received stem cell therapy worldwide indicates a favorable safety profile with modest improvement in cardiac function and structural remodeling in the setting of acute myocardial infarction or chronic heart failure. Further investigation is required before early adoption and is ongoing. Broader application in practice will require continuous scientific advances to match each patient with the most effective reparative phenotype, while ensuring optimal cell delivery, dosing, and timing of intervention. An interdisciplinary effort across the scientific and clinical community within academia, biotechnology, and government will drive the successful realization of this next generation of therapeutic agents for the "broken" heart.
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Affiliation(s)
- Bernard J Gersh
- Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN 55905, USA.
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IL-18 binding protein-expressing mesenchymal stem cells improve myocardial protection after ischemia or infarction. Proc Natl Acad Sci U S A 2009; 106:17499-504. [PMID: 19805173 DOI: 10.1073/pnas.0908924106] [Citation(s) in RCA: 88] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
IL-18 is a proinflammatory cytokine known to cause tissue injury by inducing inflammation and cell death. Increased levels of IL-18 are associated with myocardial injury after ischemia or infarction. IL-18-binding protein (IL-18BP), the naturally occurring inhibitor of IL-18 activity, decreases the severity of inflammation in response to injury. In the present study, mesenchymal stem cells (MSCs) derived from mice transgenic for over expression of human IL-18BP were tested in rat models of global myocardial ischemia and acute myocardial infarction. Improved myocardial function is associated with production of VEGF, and in vitro, IL-18BP MSCs secreted higher levels of constitutive VEGF compared to wild-type MSCs. Whereas IL-18 increased cell death and reduced VEGF in wild-type MSCs, IL-18BP MSCs were protected. In an isolated heart model, intracoronary infusion of IL-18BP MSCs before ischemia increased postischemic left ventricular (LV) developed pressure to 79.5 + or - 9.47 mmHg compared to 59.3 + or - 7.8 mmHg in wild-type MSCs and 37.8 + or - 5 mmHg in the vehicle group. Similarly, using a coronary artery ligation model, intramyocardial injection of IL-18BP MSCs improved LV ejection fraction to 67.8 + or - 1.76% versus wild-type MSCs (57.4 + or - 1.33%) and vehicle (39.2 + or - 2.07%), increased LV fractional shortening 1.25-fold over wild-type MSCs and 1.95-fold over vehicle, decreased infarct size to 38.8 + or - 2.16% compared to 46.4 + or - 1.92% in wild-type MSCs and 60.7 + or - 2.2% in vehicle, reduced adverse ventricular remodeling, increased myocardial VEGF production, and decreased IL-6 levels. This study provides the concept that IL-18BP genetically modified stem cells improve cardioprotection over that observed with unmodified stem cells.
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Gnecchi M, Melo LG. Bone marrow-derived mesenchymal stem cells: isolation, expansion, characterization, viral transduction, and production of conditioned medium. Methods Mol Biol 2009; 482:281-94. [PMID: 19089363 DOI: 10.1007/978-1-59745-060-7_18] [Citation(s) in RCA: 202] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Mesenchymal stem cells (MSCs) are defined as self-renewing and multipotent cells capable of differentiating into multiple cell types, including osteocytes, chondrocytes, adipocytes, hepatocytes, myocytes, neurons, and cardiomyocytes. MSCs were originally isolated from the bone marrow stroma but they have recently been identified also in other tissues, such as fat, epidermis, and cord blood. Several methods have been used for MSC isolation. The most common method is based on the ability of the MSCs to selectively adhere to plastic surfaces. Phenotypic characterization of MSCs is usually carried out using immunocytochemical detection or fluorescence-activated cell sorting (FACS) analysis of cell surface molecule expression. However, the lack of specific markers renders the characterization of MSCs difficult and sometimes ambiguous. MSCs posses remarkable expansion potential in culture and are highly amenable to genetic modification with various viral vectors rendering them optimal vehicles for cell-based gene therapy. Most importantly, MSC plasticity and the possibility to use them as autologous cells render MSCs suitable for cell therapy and tissue engineering. Furthermore, it is known that MSCs produce and secrete a great variety of cytokines and chemokines that play beneficial paracrine actions when MSCs are used for tissue repair. In this chapter, we describe methods for isolation, ex vivo expansion, phenotypic characterization, and viral infection of MSCs from mouse bone marrow. We also describe a method for preparation of conditioned and concentrated conditioned medium from MSCs. The conditioned medium can be easily tested both in vitro and in vivo when a particular paracrine effect (i.e., cytoprotection) is hypothesized to be an important mechanism of action of the MSCs and/or screened to identify a target paracrine/autocrine mediator.
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Affiliation(s)
- Massimiliano Gnecchi
- Department of Cardiology, Fondazione IRCCS Policlinico San Matteo and University of Pavia, Pavia, Italy
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Abstract
Tissue-resident stem cells or primitive progenitors play an integral role in homeostasis of most organ systems. Recent developments in methodologies to isolate and culture embryonic and somatic stem cells have many new applications poised for clinical and preclinical trials, which will enable the potential of regenerative medicine to be realized. Here, we overview the current progress in therapeutic applications of various stem cells and discuss technical and social hurdles that must be overcome for their potential to be realized.
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Affiliation(s)
- Ali M Riazi
- Department of Chemical Engineering, University of Toronto, Toronto, Ontario, Canada
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Ruvinov E, Dvir T, Leor J, Cohen S. Myocardial repair: from salvage to tissue reconstruction. Expert Rev Cardiovasc Ther 2008; 6:669-86. [PMID: 18510484 DOI: 10.1586/14779072.6.5.669] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Cardiac tissue reconstruction following myocardial infarction represents a major challenge in cardiovascular therapy, as current clinical approaches are limited in their ability to regenerate or replace damaged myocardium. Thus, different novel treatments have been introduced aimed at myocardial salvage and repair. Here, we present a review of recent advancements in cardiac cell, gene-based and tissue engineering therapies. Selected strategies in cell therapy and new tools for myocardial gene transfer are summarized. Finally, we consider novel approaches to myocardial tissue engineering as a platform for the integration of various modalities in an attempt to rejuvenate infarcted tissue in vivo.
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Affiliation(s)
- Emil Ruvinov
- Department of Biotechnology Engineering, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel.
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Haider HK, Ashraf M. Strategies to promote donor cell survival: combining preconditioning approach with stem cell transplantation. J Mol Cell Cardiol 2008; 45:554-66. [PMID: 18561945 DOI: 10.1016/j.yjmcc.2008.05.004] [Citation(s) in RCA: 163] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2008] [Revised: 04/18/2008] [Accepted: 05/02/2008] [Indexed: 12/22/2022]
Abstract
Stem cell transplantation has emerged as a potential modality in cardiovascular therapeutics due to their inherent characteristics of self-renewal, unlimited capacity for proliferation and ability to cross lineage restrictions and adopt different phenotypes. Constrained by extensive death in the unfriendly milieu of ischemic myocardium, the results of heart cell therapy in experimental animal models as well as clinical studies have been less than optimal. Several factors which play a role in early cell death after engraftment in the ischemic myocardium include: absence of survival factors in the transplanted heart, disruption of cell-cell interaction coupled with loss of survival signals from matrix attachments, insufficient vascular supply and elaboration of inflammatory cytokines resulting from ischemia and/or cell death. This article reviews various signaling pathways involved in triggering highly complex forms of cell death and provides critical appreciation of different novel anti-death strategies developed from the knowledge gained from using an ischemic preconditioning approach. The use of pharmacological preconditioning for up-regulation of pro-survival proteins and cardiogenic markers in the transplanted stem cells will be discussed.
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Affiliation(s)
- Husnain Kh Haider
- Department of Pathology and Laboratory Medicine, 231-Albert Sabin Way, University of Cincinnati, OH-45267-0529, USA
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Mias C, Trouche E, Seguelas MH, Calcagno F, Dignat-George F, Sabatier F, Piercecchi-Marti MD, Daniel L, Bianchi P, Calise D, Bourin P, Parini A, Cussac D. Ex vivo pretreatment with melatonin improves survival, proangiogenic/mitogenic activity, and efficiency of mesenchymal stem cells injected into ischemic kidney. Stem Cells 2008; 26:1749-57. [PMID: 18467662 DOI: 10.1634/stemcells.2007-1000] [Citation(s) in RCA: 151] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Bone marrow mesenchymal stem cells (MSCs) have shown great potential in cell therapy of solid organs. Approaches to improving the ability of grafted MSCs to survive and secrete paracrine factors represent one of the challenges for the further development of this novel therapy. In the present study, we designed a strategy of ex vivo pretreatment with the pineal hormone melatonin to improve survival, paracrine activity, and efficiency of MSCs. Using a rat model of acute renal failure, we showed that melatonin pretreatment strongly increased survival of MSCs after intraparenchymal injection. This effect was concomitant with overstimulation of angiogenesis, proliferation of renal cells, and accelerated recovery of renal function. To gain insight into the mechanisms involved in the effects observed in vivo, melatonin was tested in vitro on cultured MSCs. Our results show that through stimulation of specific melatonin receptors, melatonin induced an overexpression of the antioxidant enzyme catalase and superoxide dismutase-1 and increased the resistance of MSCs to hydrogen peroxide-dependent apoptosis. Compared with untreated cells, MSCs incubated with melatonin displayed a higher expression of basic fibroblast growth factor and hepatocyte growth factor. In addition, conditioned culture media from melatonin-treated MSCs stimulated tube formation by endothelial progenitor cells and proliferation of proximal tubule cells in culture. In conclusion, our results show that melatonin behaves as a preconditioning agent increasing survival, paracrine activity, and efficiency of MSCs. The use of this molecule for pretreatment of stem cells may represent a novel and safe approach to improving the beneficial effects of cell therapy of solid organs.
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Affiliation(s)
- Céline Mias
- Institut National de la Santé et de la Recherche Médicale, U858, Institut de Médecine Moléculaire de Rangueil, Toulouse, France
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Cardiomyocyte death and renewal in the normal and diseased heart. Cardiovasc Pathol 2008; 17:349-74. [PMID: 18402842 DOI: 10.1016/j.carpath.2008.02.004] [Citation(s) in RCA: 112] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2007] [Revised: 11/30/2007] [Accepted: 02/04/2008] [Indexed: 02/07/2023] Open
Abstract
During post-natal maturation of the mammalian heart, proliferation of cardiomyocytes essentially ceases as cardiomyocytes withdraw from the cell cycle and develop blocks at the G0/G1 and G2/M transition phases of the cell cycle. As a result, the response of the myocardium to acute stress is limited to various forms of cardiomyocyte injury, which can be modified by preconditioning and reperfusion, whereas the response to chronic stress is dominated by cardiomyocyte hypertrophy and myocardial remodeling. Acute myocardial ischemia leads to injury and death of cardiomyocytes and nonmyocytic stromal cells by oncosis and apoptosis, and possibly by a hybrid form of cell death involving both pathways in the same ischemic cardiomyocytes. There is increasing evidence for a slow, ongoing turnover of cardiomyocytes in the normal heart involving death of cardiomyocytes and generation of new cardiomyocytes. This process appears to be accelerated and quantitatively increased as part of myocardial remodeling. Cardiomyocyte loss involves apoptosis, autophagy, and oncosis, which can occur simultaneously and involve different individual cardiomyocytes in the same heart undergoing remodeling. Mitotic figures in myocytic cells probably represent maturing progeny of stem cells in most cases. Mitosis of mature cardiomyocytes that have reentered the cell cycle appears to be a rare event. Thus, cardiomyocyte renewal likely is mediated primarily by endogenous cardiac stem cells and possibly by blood-born stem cells, but this biological phenomenon is limited in capacity. As a consequence, persistent stress leads to ongoing remodeling in which cardiomyocyte death exceeds cardiomyocyte renewal, resulting in progressive heart failure. Intense investigation currently is focused on cell-based therapies aimed at retarding cardiomyocyte death and promoting myocardial repair and possibly regeneration. Alteration of pathological remodeling holds promise for prevention and treatment of heart failure, which is currently a major cause of morbidity and mortality and a major public health problem. However, a deeper understanding of the fundamental biological processes is needed in order to make lasting advances in clinical therapeutics in the field.
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Chachques JC, Trainini JC, Lago N, Cortes-Morichetti M, Schussler O, Carpentier A. Myocardial Assistance by Grafting a New Bioartificial Upgraded Myocardium (MAGNUM trial): clinical feasibility study. Ann Thorac Surg 2008; 85:901-8. [PMID: 18291168 DOI: 10.1016/j.athoracsur.2007.10.052] [Citation(s) in RCA: 157] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2007] [Revised: 10/12/2007] [Accepted: 10/12/2007] [Indexed: 01/11/2023]
Abstract
BACKGROUND Cell transplantation for the regeneration of ischemic myocardium is limited by poor graft viability and low cell retention. In ischemic cardiomyopathy, the extracellular matrix is deeply altered; therefore, it could be important to associate a procedure aiming at regenerating myocardial cells and restoring the extracellular matrix function. We evaluated the feasibility and safety of intrainfarct cell therapy associated with a cell-seeded collagen scaffold grafted onto infarcted ventricles. METHODS In 20 consecutive patients presenting with left ventricular postischemic myocardial scars and indication for coronary artery bypass graft surgery, bone marrow cells were implanted during surgery. In the last 10 patients, we added a collagen matrix seeded with bone marrow cells, placed onto the scar. RESULTS There was no mortality and any related adverse events (follow-up 10 +/- 3.5 months). New York Heart Association functional class improved in both groups from 2.3 +/- 0.5 to 1.3 +/- 0.5 (matrix, p = 0.0002) versus 2.4 +/- 0.5 to 1.5 +/- 0.5 (no matrix, p = 0.001). Left ventricular end-diastolic volume evolved from 142.4 +/- 24.5 mL to 112.9 +/- 27.3 mL (matrix, p = 0.02) versus 138.9 +/- 36.1 mL to 148.7 +/- 41 mL (no matrix, p = 0.57), left ventricular filling deceleration time improved significantly in the matrix group from 162 +/- 7 ms to 198 +/- 9 ms (p = 0.01) versus the no-matrix group (from 159 +/- 5 ms to 167 +/- 8 ms, p = 0.07). Scar area thickness progressed from 6 +/- 1.4 to 9 mm +/- 1.1 mm (matrix, p = 0.005) versus 5 +/- 1.5 mm to 6 +/- 0.8 mm (no matrix, p = 0.09). Ejection fraction improved in both groups, from 25.3% +/- 7.3% to 32% +/- 5.4% (matrix, p = 0.03) versus 27.2% +/- 6.9% to 34.6% +/- 7.3% (no matrix, p = 0.031). CONCLUSIONS This tissue-engineered approach is feasible and safe and appears to improve the efficiency of cellular cardiomyoplasty. The cell-seeded collagen matrix increases the thickness of the infarct scar with viable tissue and helps to normalize cardiac wall stress in injured regions, thus limiting ventricular remodeling and improving diastolic function.
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Affiliation(s)
- Juan C Chachques
- Department of Cardiovascular Surgery, Pompidou Hospital, Paris, France.
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Nordlie MA, Wold LE, Simkhovich BZ, Sesti C, Kloner RA. Molecular aspects of ischemic heart disease: ischemia/reperfusion-induced genetic changes and potential applications of gene and RNA interference therapy. J Cardiovasc Pharmacol Ther 2006; 11:17-30. [PMID: 16703217 DOI: 10.1177/107424840601100102] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Molecular biologic techniques have a variety of applications in the study of ischemic heart disease, including roles in elucidating cardiac genetic changes resulting from ischemia as well as in developing therapeutic interventions to treat ischemic heart disease. This review describes recent studies documenting genetic changes associated with myocardial ischemia and infarction as well as those investigating the safety and effectiveness of gene therapy for stimulating angiogenesis, protecting the heart against reperfusion injury, and treating heart failure. Also discussed are future research directions, including the potential use of RNA interference and combined stem cell therapy and gene therapy for the treatment of cardiovascular disease.
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Affiliation(s)
- Margaret A Nordlie
- Division of Mathematics and Natural Sciences, University of Mary, Bismarck, ND, USA
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