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Ding JY, Meng TT, Du RL, Song XB, Li YX, Gao J, Ji R, He QY. Bibliometrics of trends in global research on the roles of stem cells in myocardial fibrosis therapy. World J Stem Cells 2024; 16:1086-1105. [PMID: 39734477 PMCID: PMC11669986 DOI: 10.4252/wjsc.v16.i12.1086] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2024] [Revised: 10/05/2024] [Accepted: 11/11/2024] [Indexed: 12/13/2024] Open
Abstract
BACKGROUND Myocardial fibrosis, a condition linked to several cardiovascular diseases, is associated with a poor prognosis. Stem cell therapy has emerged as a potential treatment option and the application of stem cell therapy has been studied extensively. However, a comprehensive bibliometric analysis of these studies has yet to be conducted. AIM To map thematic trends, analyze research hotspots, and project future directions of stem cell-based myocardial fibrosis therapy. METHODS We conducted a bibliometric and visual analysis of studies in the Web of Science Core Collection using VOSviewer and Microsoft Excel. The dataset included 1510 articles published between 2001 and 2024. Countries, organizations, authors, references, keywords, and co-citation networks were examined to identify evolving research trends. RESULTS Our findings revealed a steady increase in the number of publications, with a projected increase to over 200 publications annually by 2030. Initial research focused on stem cell-based therapy, particularly for myocardial infarction and heart failure. More recently, there has been a shift toward cell-free therapy, involving extracellular vesicles, exosomes, and microRNAs. Key research topics include angiogenesis, inflammation, apoptosis, autophagy, and oxidative stress. CONCLUSION This analysis highlights the evolution of stem cell therapies for myocardial fibrosis, with emerging interest in cell-free approaches. These results are expected to guide future scientific exploration and decision-making.
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Affiliation(s)
- Jing-Yi Ding
- Department of Cardiology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Tian-Tian Meng
- Department of Rehabilitation, Dongfang Hospital, Beijing University of Chinese Medicine, Beijing 100071, China
| | - Ruo-Lin Du
- Department of Emergency Medicine, South Branch of Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Xin-Bin Song
- Department of Intensive Care Unit, Zhumadian Hospital of Traditional Chinese Medicine, Zhumadian 463000, Henan Province, China
| | - Yi-Xiang Li
- Department of Chinese Medicine, The Third People's Hospital of Henan Province, Zhengzhou 450000 Henan Province, China
| | - Jing Gao
- Department of Cardiology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Ran Ji
- Department of Intensive Care Unit, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Qing-Yong He
- Department of Cardiology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China.
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Carvalho AB, Kasai-Brunswick TH, Campos de Carvalho AC. Advanced cell and gene therapies in cardiology. EBioMedicine 2024; 103:105125. [PMID: 38640834 PMCID: PMC11052923 DOI: 10.1016/j.ebiom.2024.105125] [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: 10/31/2023] [Revised: 04/01/2024] [Accepted: 04/04/2024] [Indexed: 04/21/2024] Open
Abstract
We review the evidence for the presence of stem/progenitor cells in the heart and the preclinical and clinical data using diverse cell types for the therapy of cardiac diseases. We highlight the failure of adult stem/progenitor cells to ameliorate heart function in most cardiac diseases, with the possible exception of refractory angina. The use of pluripotent stem cell-derived cardiomyocytes is analysed as a viable alternative therapeutic option but still needs further research at preclinical and clinical stages. We also discuss the use of direct reprogramming of cardiac fibroblasts into cardiomyocytes and the use of extracellular vesicles as therapeutic agents in ischemic and non-ischemic cardiac diseases. Finally, gene therapies and genome editing for the treatment of hereditary cardiac diseases, ablation of genes responsible for atherosclerotic disease, or modulation of gene expression in the heart are discussed.
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Affiliation(s)
- Adriana Bastos Carvalho
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil; Instituto Nacional de Ciência e Tecnologia em Medicina Regenerativa, Universidade Federal do RIo de Janeiro, Rio de Janeiro, RJ, Brazil
| | - Tais Hanae Kasai-Brunswick
- Centro Nacional de Biologia Estrutural e Bioimagem (CENABIO), Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil; Instituto Nacional de Ciência e Tecnologia em Medicina Regenerativa, Universidade Federal do RIo de Janeiro, Rio de Janeiro, RJ, Brazil
| | - Antonio Carlos Campos de Carvalho
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil; Centro Nacional de Biologia Estrutural e Bioimagem (CENABIO), Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil; Instituto Nacional de Ciência e Tecnologia em Medicina Regenerativa, Universidade Federal do RIo de Janeiro, Rio de Janeiro, RJ, Brazil.
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3
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Jeong H, Yim HW, Park HJ, Cho Y, Hong H, Kim NJ, Oh IH. Mesenchymal Stem Cell Therapy for Ischemic Heart Disease: Systematic Review and Meta-analysis. Int J Stem Cells 2018; 11:1-12. [PMID: 29482311 PMCID: PMC5984054 DOI: 10.15283/ijsc17061] [Citation(s) in RCA: 61] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2017] [Revised: 01/15/2018] [Accepted: 01/25/2018] [Indexed: 12/23/2022] Open
Abstract
Background and Objectives Mesenchymal stem cells (MSC) have emerged as breakthrough treatments for myocardial infarction. However, the efficacy of MSC remains unclear. The aim of the study was to evaluate treatment effect of MSC in terms of mechanical, regenerative, and clinical outcomes for patients with myocardial infarction (MI) using meta-analysis. Methods A systematic search and critical review of MEDLINE, EMBASE, and Cochrane database literature published from inception through December 2017 was performed. The inclusion criteria were randomized controlled trials, studies on patients with myocardial infarction, and studies compared with placebo as a control group. Results A total of 950 patients from 14 randomized placebo controlled trials were included in the final meta-analysis. MSC treatment showed benefits for mechanical, regenerative, and clinical outcomes. In terms of mechanical outcomes, the LVEF of the MSC treatment group increased by 3.84% (95% CI: 2.32~5.35, I2=43) and the effect was maintained for up to 24 months. Regenerative outcomes were measured by scar mass and WMSI. Scar mass was reduced by −1.13 (95% CI: −1.80 to −0.46, I2=71) and WMSI was reduced by −0.05 (95% CI: −0.07 to −0.03, I2=45) at 6 months after MSC treatment. Mortality rate and incidence of re-hospitalization for HF in MSC group patients trended toward reduced incidence compared to the control group, although this was not statistically significant because of the low event rate. Conclusions The findings of this meta-analysis indicate that MSCs can be beneficial in improving heart function in the treatment of MI. However, the efficacy of MSCs must be further explored through large randomized controlled trials based on rigorous research design.
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Affiliation(s)
- Hyunsuk Jeong
- Department of Preventive Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Hyeon Woo Yim
- Department of Preventive Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Hun-Jun Park
- Division of Cardiology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Youngseung Cho
- Department of Preventive Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Hanter Hong
- Cheong-yang Branch Office of the Community Health Center, Cheongyang, Korea
| | - Na Jin Kim
- Medical Library, The Catholic University of Korea, Seoul, Korea
| | - Il-Hoan Oh
- Catholic High-Performance Cell Therapy Center & Department of Medical Life Science, College of Medicine, The Catholic University of Korea, Seoul, Korea
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Ward MR, Abadeh A, Connelly KA. Concise Review: Rational Use of Mesenchymal Stem Cells in the Treatment of Ischemic Heart Disease. Stem Cells Transl Med 2018; 7:543-550. [PMID: 29665255 PMCID: PMC6052612 DOI: 10.1002/sctm.17-0210] [Citation(s) in RCA: 64] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2017] [Accepted: 03/22/2018] [Indexed: 12/20/2022] Open
Abstract
The capacity of stem and progenitor cells to stimulate cardiac regeneration has been studied for almost 20 years, with very promising preclinical data and mixed clinical results. Several cell types have been studied, identified by their cell surface markers, differentiation capacity and their secreted growth factors. Bone marrow derived mesenchymal stem cells (MSCs) have been found to have potent regenerative capacity, through multiple mechanisms, including mesoderm lineage differentiation, immunomodulation, and paracrine stimulation. MSCs also secrete exosomes and microvesicles, which themselves contain potent angiogenic cytokines or mRNA molecules with effects on their local milieu. This concise review summarizes the mechanisms of MSC-based cardiac regeneration and highlighting results from molecular and preclinical studies. We also discuss clinical trial results to date, and ongoing studies. Furthermore, we discuss novel approaches for the enhancement of MSC based cardiac regeneration, such as genetic modification. Stem Cells Translational Medicine 2018;7:543-550.
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Affiliation(s)
- Michael R Ward
- Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada
| | - Armin Abadeh
- Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada
| | - Kim A Connelly
- Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada.,Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
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Volarevic V, Markovic BS, Gazdic M, Volarevic A, Jovicic N, Arsenijevic N, Armstrong L, Djonov V, Lako M, Stojkovic M. Ethical and Safety Issues of Stem Cell-Based Therapy. Int J Med Sci 2018; 15:36-45. [PMID: 29333086 PMCID: PMC5765738 DOI: 10.7150/ijms.21666] [Citation(s) in RCA: 492] [Impact Index Per Article: 70.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2017] [Accepted: 10/11/2017] [Indexed: 12/13/2022] Open
Abstract
Results obtained from completed and on-going clinical studies indicate huge therapeutic potential of stem cell-based therapy in the treatment of degenerative, autoimmune and genetic disorders. However, clinical application of stem cells raises numerous ethical and safety concerns. In this review, we provide an overview of the most important ethical issues in stem cell therapy, as a contribution to the controversial debate about their clinical usage in regenerative and transplantation medicine. We describe ethical challenges regarding human embryonic stem cell (hESC) research, emphasizing that ethical dilemma involving the destruction of a human embryo is a major factor that may have limited the development of hESC-based clinical therapies. With previous derivation of induced pluripotent stem cells (iPSCs) this problem has been overcome, however current perspectives regarding clinical translation of iPSCs still remain. Unlimited differentiation potential of iPSCs which can be used in human reproductive cloning, as a risk for generation of genetically engineered human embryos and human-animal chimeras, is major ethical issue, while undesired differentiation and malignant transformation are major safety issues. Although clinical application of mesenchymal stem cells (MSCs) has shown beneficial effects in the therapy of autoimmune and chronic inflammatory diseases, the ability to promote tumor growth and metastasis and overestimated therapeutic potential of MSCs still provide concerns for the field of regenerative medicine. This review offers stem cell scientists, clinicians and patient's useful information and could be used as a starting point for more in-depth analysis of ethical and safety issues related to clinical application of stem cells.
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Affiliation(s)
- Vladislav Volarevic
- University of Kragujevac, Serbia, Faculty of Medical Sciences, Department of Microbiology and Immunology, Center for Molecular Medicine and Stem Cell Research
| | - Bojana Simovic Markovic
- University of Kragujevac, Serbia, Faculty of Medical Sciences, Department of Microbiology and Immunology, Center for Molecular Medicine and Stem Cell Research
| | - Marina Gazdic
- University of Kragujevac, Serbia, Faculty of Medical Sciences, Department of Genetics
| | - Ana Volarevic
- University of Kragujevac, Serbia, Faculty of Medical Sciences, Department of Microbiology and Immunology, Center for Molecular Medicine and Stem Cell Research
| | - Nemanja Jovicic
- University of Kragujevac, Serbia, Faculty of Medical Sciences, Department of Histology and Embryology
| | - Nebojsa Arsenijevic
- University of Kragujevac, Serbia, Faculty of Medical Sciences, Department of Microbiology and Immunology, Center for Molecular Medicine and Stem Cell Research
| | | | | | - Majlinda Lako
- Institute of Genetic Medicine, Newcastle University, UK
| | - Miodrag Stojkovic
- University of Kragujevac, Serbia, Faculty of Medical Sciences, Department of Genetics
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Abstract
Cardiovascular disease (CVD) accounts for more deaths globally than any other single disease. There are on average 1.5 million episodes of myocardial infarction (heart attack) each year in the United States alone with roughly one-third resulting in death. There is therefore a major need for developing new and effective strategies to promote cardiac repair. Intramyocardial transplantation of mesenchymal stem cells (MSCs) has emerged as a leading contender in the pursuit of clinical intervention and therapy. MSCs are potent mediators of cardiac repair and are therefore an attractive tool in the development of preclinical and clinical trials. MSCs are capable of secreting a large array of soluble factors, which have had demonstrated effects on pathogenic cardiac remolding, fibrosis, immune activation, and cardiac stem cell proliferation within the damaged heart. MSCs are also capable of differentiation into cardiomyocytes, endothelial cells, and vascular smooth muscle cells, although the relative contribution of trilineage differentiation and paracrine effectors on cardiac repair remains the subject of active investigation.
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Rationale and Design of the First Double-Blind, Placebo-Controlled Trial with Allogeneic Adipose Tissue-Derived Stromal Cell Therapy in Patients with Ischemic Heart Failure: A Phase II Danish Multicentre Study. Stem Cells Int 2017; 2017:8506370. [PMID: 29056973 PMCID: PMC5625749 DOI: 10.1155/2017/8506370] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2017] [Accepted: 08/24/2017] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Ischemic heart failure (IHF) has a poor prognosis in spite of optimal therapy. We have established a new allogeneic Cardiology Stem Cell Centre adipose-derived stromal cell (CSCC_ASC) product from healthy donors. It is produced without animal products, in closed bioreactor systems and cryopreserved as an off-the-shelf product ready to use. STUDY DESIGN A multicentre, double-blind, placebo-controlled phase II study with direct intramyocardial injections of allogeneic CSCC_ASC in patients with chronic IHF. A total of 81 patients will be randomised at 2 : 1 to CSCC_ASC or placebo. There is no HLA tissue type matching needed between the patients and the donors. METHODS The treatment will be delivered by direct injections into the myocardium. The primary endpoint is change in the left ventricle endsystolic volume at 6-month follow-up. Secondary endpoints are safety and changes in left ventricle ejection fraction, myocardial mass, stroke volume, and cardiac output. Other secondary endpoints are change in clinical symptoms, 6-minute walking test, and the quality of life after 6 and 12 months. CONCLUSION The aim of the present study is to demonstrate safety and the regenerative efficacy of the allogeneic CSCC_ASC product from healthy donors in a double-blind, placebo-controlled, multicentre study in patients with IHF.
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A new approach for the pre-clinical optimization of a spatial configuration of bifurcated endovascular prosthesis placed in abdominal aortic aneurysms. PLoS One 2017; 12:e0182717. [PMID: 28793343 PMCID: PMC5549977 DOI: 10.1371/journal.pone.0182717] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2016] [Accepted: 07/24/2017] [Indexed: 11/19/2022] Open
Abstract
Complexity of the spatial configuration of an aortic implant with bifurcation in the distal part is related to changes in blood hemodynamic in the area of bifurcation which may disturb blood flow and lead to thrombus formation. This study was designed to characterize parameters which define spatial configuration of an aortic implant for which the risk of thrombus formation is the smallest. We used AngioCT data from 74 patients, aged 55 ±10 years, after endovascular procedure to prepare 3D geometries of stent-grafts. Computational Fluid Dynamics (CFD) simulations were used to reconstruct blood hemodynamic and simulate thrombus formation. Next, geometric parameters of stent-grafts included the ratio of volume of upper part to the bifurcations, the relation of inlet and outlet diameters of a stent-graft and deformations in the iliac part of the stent-graft were analyzed. We also analyzed tortuosities (spiral twisting of the flow around the flow direction) and bends (the largest angulation in distal part of a stent-graft). The CFD results were confronted with AngioCT data to verify if computer generated thrombus appeared in particular patient. Additionally, geometric parameters of analyzed stent-grafts were used to propose a mathematical tool for prediction of thrombus appearance. The results showed that tortuosities and bends of a stent-graft had the highest impact on thrombus formation. Formation of thrombi was observed in 22% to 31% of cases (at blood hematocrit Hct = 40%) even for small values of tortuosities and bends indicating that these parameters are dominant in determining blood clotting. Our calculated results overlapped with clinical data in 80% to 91%. Therefore, we conclude that tortuosities and bends have high impact on thrombus formation and should be under special attention during stent-graft recommendation and patients’ follow-ups.
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Zhang J, Neoh KG, Kang ET. Electrical stimulation of adipose-derived mesenchymal stem cells and endothelial cells co-cultured in a conductive scaffold for potential orthopaedic applications. J Tissue Eng Regen Med 2017; 12:878-889. [PMID: 28482125 DOI: 10.1002/term.2441] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2016] [Revised: 04/30/2017] [Accepted: 05/03/2017] [Indexed: 12/24/2022]
Abstract
Electrical stimulation (ES) has emerged as a useful tool to regulate cell behaviour, but the effect of ES on mesenchymal stem cell (MSC)/vasculogenic cell co-culture has not been investigated. Herein, human adipose-derived MSCs (AD-MSCs) and umbilical vein endothelial cells (HUVECs) were co-cultured in an electrically conductive polypyrrole/chitosan scaffold. Compared with AD-MSC monoculture, calcium deposition in the co-culture without and with ES (200 μA for 4 h/day) was 139% and 346% higher, respectively, after 7 days. As the application of ES to AD-MSC monoculture only increased calcium deposition by 56% compared with that without ES after 7 days, these results indicate that ES and co-culture with HUVECs have synergistic effects on AD-MSCs' osteogenic differentiation. ES application also significantly enhanced CD31 expression of HUVECs. In HUVEC monoculture, application of ES increased CD31 expression by 224%, whereas the corresponding increase in AD-MSC/HUVEC co-culture with ES application was 62%. The gene expression results indicate that ES enhanced the cellular functions in AD-MSC and HUVEC monoculture via autocrine bone morphogenetic protein-2 (BMP-2) and vascular endothelial growth factor (VEGF), respectively. In co-culture, crosstalk between AD-MSCs and HUVECs due to paracrine BMP-2 and VEGF enhanced the cellular functions compared with the respective monoculture. With application of ES to the AD-MSC/HUVEC co-culture, autocrine signalling was enhanced, resulting in further promotion of cellular functions. These findings illustrate that co-culturing AD-MSC/HUVEC in a conductive scaffold with ES offers potential benefits for bone defect therapy.
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Affiliation(s)
- Jieyu Zhang
- NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Kent Ridge, Singapore
| | - Koon Gee Neoh
- NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Kent Ridge, Singapore.,Department of Chemical and Biomolecular Engineering, National University of Singapore, Kent Ridge, Singapore
| | - En-Tang Kang
- NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Kent Ridge, Singapore.,Department of Chemical and Biomolecular Engineering, National University of Singapore, Kent Ridge, Singapore
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Monteiro LM, Vasques-Nóvoa F, Ferreira L, Pinto-do-Ó P, Nascimento DS. Restoring heart function and electrical integrity: closing the circuit. NPJ Regen Med 2017; 2:9. [PMID: 29302345 PMCID: PMC5665620 DOI: 10.1038/s41536-017-0015-2] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2016] [Revised: 02/19/2017] [Accepted: 03/06/2017] [Indexed: 12/30/2022] Open
Abstract
Cardiovascular diseases are the main cause of death in the world and are often associated with the occurrence of arrhythmias due to disruption of myocardial electrical integrity. Pathologies involving dysfunction of the specialized cardiac excitatory/conductive tissue are also common and constitute an added source of morbidity and mortality since current standard therapies withstand a great number of limitations. As electrical integrity is essential for a well-functioning heart, innovative strategies have been bioengineered to improve heart conduction and/or promote myocardial repair, based on: (1) gene and/or cell delivery; or (2) conductive biomaterials as tools for cardiac tissue engineering. Herein we aim to review the state-of-art in the area, while briefly describing the biological principles underlying the heart electrical/conduction system and how this system can be disrupted in heart disease. Suggestions regarding targets for future studies are also presented.
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Affiliation(s)
- Luís Miguel Monteiro
- i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
- INEB—Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal
- CNC—Center for Neuroscience and Cell Biology, Universidade de Coimbra, Coimbra, Portugal
| | - Francisco Vasques-Nóvoa
- i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
- INEB—Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal
- Departamento de Fisiologia e Cirurgia Cardiotorácica, Faculdade de Medicina da Universidade do Porto, Porto, Portugal
| | - Lino Ferreira
- CNC—Center for Neuroscience and Cell Biology, Universidade de Coimbra, Coimbra, Portugal
| | - Perpétua Pinto-do-Ó
- i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
- INEB—Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal
- ICBAS—Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal
| | - Diana Santos Nascimento
- i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
- INEB—Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal
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Doster DL, Jensen AR, Khaneki S, Markel TA. Mesenchymal stromal cell therapy for the treatment of intestinal ischemia: Defining the optimal cell isolate for maximum therapeutic benefit. Cytotherapy 2016; 18:1457-1470. [PMID: 27745788 DOI: 10.1016/j.jcyt.2016.08.001] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2016] [Revised: 07/16/2016] [Accepted: 08/02/2016] [Indexed: 02/06/2023]
Abstract
Intestinal ischemia is a devastating intraabdominal emergency that often necessitates surgical intervention. Mortality rates can be high, and patients who survive often have significant long-term morbidity. The implementation of traditional medical therapies to prevent or treat intestinal ischemia have been sparse over the last decade, and therefore, the use of novel therapies are becoming more prevalent. Cellular therapy using mesenchymal stromal cells is one such treatment modality that is attracting noteworthy attention in the scientific community. Several groups have seen benefit with cellular therapy, but the optimal cell line has not been identified. The purpose of this review is to: 1) Review the mechanism of intestinal ischemia and reperfusion injury, 2) Identify the mechanisms of how cellular therapy may be therapeutic for this disease, and 3) Compare various MSC tissue sources to maximize potential therapeutic efficacy in the treatment of intestinal I/R diseases.
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Affiliation(s)
- Dominique L Doster
- Department of Surgery, Indiana University Health, Indianapolis, IN, USA; The Indiana University School of Medicine, Indianapolis, IN, USA
| | - Amanda R Jensen
- Department of Surgery, Indiana University Health, Indianapolis, IN, USA; The Indiana University School of Medicine, Indianapolis, IN, USA
| | - Sina Khaneki
- Department of Surgery, Indiana University Health, Indianapolis, IN, USA; The Indiana University School of Medicine, Indianapolis, IN, USA
| | - Troy A Markel
- Department of Surgery, Indiana University Health, Indianapolis, IN, USA; The Indiana University School of Medicine, Indianapolis, IN, USA; Section of Pediatric Surgery, Indiana University Health, Indianapolis, IN, USA; Riley Hospital for Children, Indiana University Health, Indianapolis, IN, USA.
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Kastrup J, Mygind ND, Qayyum AA, Mathiasen AB, Haack-Sørensen M, Ekblond A. Mesenchymal stromal cell therapy in ischemic heart disease. SCAND CARDIOVASC J 2016; 50:293-299. [DOI: 10.1080/14017431.2016.1210213] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Affiliation(s)
- Jens Kastrup
- Department of Cardiology, The Heart Centre, Rigshospitalet, University Hospital of Copenhagen, Copenhagen, Denmark
- Cardiology Stem Cell Centre, The Heart Centre, Rigshospitalet, University Hospital of Copenhagen, Copenhagen, Denmark
| | - Naja Dam Mygind
- Department of Cardiology, The Heart Centre, Rigshospitalet, University Hospital of Copenhagen, Copenhagen, Denmark
| | - Abbas Ali Qayyum
- Department of Cardiology, The Heart Centre, Rigshospitalet, University Hospital of Copenhagen, Copenhagen, Denmark
| | - Anders Bruun Mathiasen
- Department of Cardiology, The Heart Centre, Rigshospitalet, University Hospital of Copenhagen, Copenhagen, Denmark
| | - Mandana Haack-Sørensen
- Cardiology Stem Cell Centre, The Heart Centre, Rigshospitalet, University Hospital of Copenhagen, Copenhagen, Denmark
| | - Annette Ekblond
- Cardiology Stem Cell Centre, The Heart Centre, Rigshospitalet, University Hospital of Copenhagen, Copenhagen, Denmark
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Human Umbilical Cord Mesenchymal Stromal Cell Transplantation in Myocardial Ischemia (HUC-HEART Trial). A Study Protocol of a Phase 1/2, Controlled and Randomized Trial in Combination with Coronary Artery Bypass Grafting. Stem Cell Rev Rep 2016; 11:752-60. [PMID: 26123356 DOI: 10.1007/s12015-015-9601-0] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Mesenchymal stem cells (MSCs), which may be obtained from the bone marrow, have been studied for more than a decade in the setting of coronary artery disease (CAD). Adipose tissue-derived MSCs have recently come into focus and are being tested in a series of clinical trials. MSC-like cells have also been derived from a variety of sources, including umbilical cord stroma, or HUC-MSCs. The HUC-HEART trail (ClinicalTrials.gov Identifier: NCT02323477) is a phase 1/2, controlled, multicenter, randomized clinical study of the intramyocardial delivery of allogeneic HUC-MSCs in patients with chronic ischemic cardiomyopathy. A total of 79 patients (ages 30-80) with left ventricle ejection fractions ranging between 25 and 45% will be randomized in a 2:1:1 pattern in order to receive an intramyocardial injection of either HUC-MSCs or autologous bone marrow-derived mononuclear cells (BM-MNCs) in combination with coronary arterial bypass grafting (CABG) surgery. The control group of patients will receive no cells and undergo CABG alone. Human HUC-MSCs will be isolated, propagated and banked in accordance with a cGMP protocol, whereas the autologous BM-MNCs will be isolated via aspiration from the iliac crest and subsequently process in a closed-circuit cell purification system shortly before cell transplantation. The cell injections will be implemented in 10 peri-infarct areas. Baseline and post-transplantation outcome measures will be primarily utilized to test both the safety and the efficacy of the administered cells for up to 12 months.
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14
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Mesenchymal stem cells suppress cardiac alternans by activation of PI3K mediated nitroso-redox pathway. J Mol Cell Cardiol 2016; 98:138-45. [PMID: 27238412 DOI: 10.1016/j.yjmcc.2016.05.014] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2015] [Revised: 05/03/2016] [Accepted: 05/25/2016] [Indexed: 01/06/2023]
Abstract
BACKGROUND The paracrine action of non-cardiac progenitor cells is robust, but not well understood. Mesenchymal stem cells (MSC) have been shown to enhance calcium (Ca(++)) cycling in myocytes. Therefore, we hypothesized that MSCs can suppress cardiac alternans, an important arrhythmia substrate, by paracrine action on Ca(++) cycling. METHODS AND RESULTS Human cardiac myocyte monolayers derived from iPS cells (hCM) were cultured without or with human MSCs (hMSC) directly or plated on a transwell insert. Ca(++) transient alternans (Ca(++) ALT) and Ca(++) transient duration (CaD) were measured from hCM monolayers following application of 200μM H2O2. Ca(++) ALT in hCM was significantly decreased when cultured with hMSCs directly (97%, p<0.0001) and when cultured with hMSC in the transwell insert (80%, p<0.0001). When hCM with hMSCs were pretreated with PI3K or eNOS inhibitors, Ca(++) ALT was larger than baseline by 20% (p<0.0001) and 36% (p<0.0001), respectively. In contrast, Ca(++) ALT was reduced by 89% compared to baseline (p<0.0001) when hCM monolayers without hMSCs were pretreated with 20μM GSNO. In all experiments, changes in Ca(++) ALT were mirrored by changes in CaD. Finally, real time quantitative PCR revealed no significant differences in mRNA expression of RyR2, SERCA2a, and phospholamban between hCM cultured with or without hMSCs. CONCLUSION Ca(++) ALT is suppressed by hMSCs in a paracrine fashion due to activation of a PI3K-mediated nitroso-redox pathway. These findings demonstrate, for the first time, how stem cell therapy might be antiarrhythmic by suppressing cardiac alternans through paracrine action on Ca(++) cycling.
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Abstract
Stem cell therapy holds the potential to revolutionize the treatment of a number of chronic conditions. Stem cells ability to home in on injured sites of the body, stimulate angiogenesis, tissue regeneration, immunomodulation, anti-inflammatory, and anti-fibrotic factors have attracted their use in the treatment of many conditions. Urology has registered one of the highest experimental successes using stem cell therapy. However, the rate of clinical applications is comparatively lower. This review takes a look at our efforts so far and what needs to be done in order to maximize the clinical benefit we can derive from stem cells.
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Affiliation(s)
- Bridget Wiafe
- 3-007 Li Ka Shing Centre for Health Research Innovation, University of Alberta, Edmonton, AB, Canada, T6G 2E1.
| | | | - Adetola B Adesida
- 3-002E Li Ka Shing Centre for Health Research Innovation, University of Alberta, Edmonton, AB, Canada, T6G 2E1.
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16
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Kim N, Cho SG. New strategies for overcoming limitations of mesenchymal stem cell-based immune modulation. Int J Stem Cells 2015; 8:54-68. [PMID: 26019755 PMCID: PMC4445710 DOI: 10.15283/ijsc.2015.8.1.54] [Citation(s) in RCA: 98] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2015] [Accepted: 05/04/2015] [Indexed: 12/12/2022] Open
Abstract
Mesenchymal stem cells (MSCs) have rapidly been applied in a broad field of immune-mediated disorders since the first successful clinical use of MSCs for treatment of graft-versus-host disease. Despite the lack of supporting data, expectations that MSCs could potentially treat most inflammatory conditions led to rushed application and development of commercialized products. Today, both pre-clinical and clinical studies present mixed results for MSC therapy and the discrepancy between expected and actual efficacy of MSCs in various diseases has evoked a sense of discouragement. Therefore, we believe that MSC therapy may now be at a critical milestone for re-evaluation and re-consideration. In this review, we summarize the current status of MSC-based clinical trials and focus on the discrepancy between expected and actual outcome of MSC therapy from bench to bedside. Importantly, we discuss the underlying limitations of MSCs and suggest a new guideline for MSC therapy in hopes of improving their therapeutic efficacy.
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Affiliation(s)
- Nayoun Kim
- Institute for Translational Research and Molecular Imaging, The Catholic University of Korea College of Medicine, Seoul, Korea ; Laboratory of Immune Regulation, Convergent Research Consortium for Immunologic Disease, Seoul, Korea
| | - Seok-Goo Cho
- Institute for Translational Research and Molecular Imaging, The Catholic University of Korea College of Medicine, Seoul, Korea ; Laboratory of Immune Regulation, Convergent Research Consortium for Immunologic Disease, Seoul, Korea ; Catholic Blood and Marrow Transplantation Center, Seoul St. Mary's Hospital, The Catholic University of Korea College of Medicine, Seoul, Korea
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17
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Adipose-Derived Stem Cells for Therapeutic Applications. Regen Med 2015. [DOI: 10.1007/978-1-4471-6542-2_9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
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18
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Mayfield AE, Tilokee EL, Davis DR. Resident cardiac stem cells and their role in stem cell therapies for myocardial repair. Can J Cardiol 2014; 30:1288-98. [PMID: 25092406 DOI: 10.1016/j.cjca.2014.03.018] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2014] [Revised: 03/14/2014] [Accepted: 03/17/2014] [Indexed: 02/06/2023] Open
Abstract
Despite advances in treatment, heart failure remains one of the top killers in Canada. This recognition motivated a new research focus to harness the fundamental repair properties of the human heart. Since then, cardiac stem cells (CSCs) have emerged as a promising cell candidate to regenerate damaged hearts. The rationale of this approach is simple with ex vivo amplification of CSCs from clinical-grade biopsies, followed by delivery to areas of injury, where they engraft and regenerate the heart. In this review we will summarize recent advances and discuss future developments in CSC-mediated cardiac repair to treat the growing number of Canadians living with and dying from heart failure.
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Affiliation(s)
| | | | - Darryl R Davis
- University of Ottawa Heart Institute, Ottawa, Ontario, Canada.
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Richardson JD, Nelson AJ, Zannettino ACW, Gronthos S, Worthley SG, Psaltis PJ. Optimization of the cardiovascular therapeutic properties of mesenchymal stromal/stem cells-taking the next step. Stem Cell Rev Rep 2014; 9:281-302. [PMID: 22529015 DOI: 10.1007/s12015-012-9366-7] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Despite current treatment options, cardiac failure is associated with significant morbidity and mortality highlighting a compelling clinical need for novel therapeutic approaches. Based on promising pre-clinical data, stem cell therapy has been suggested as a possible therapeutic strategy. Of the candidate cell types evaluated, mesenchymal stromal/stem cells (MSCs) have been widely evaluated due to their ease of isolation and ex vivo expansion, potential allogeneic utility and capacity to promote neo-angiogenesis and endogenous cardiac repair. However, the clinical application of MSCs for mainstream cardiovascular use is currently hindered by several important limitations, including suboptimal retention and engraftment and restricted capacity for bona fide cardiomyocyte regeneration. Consequently, this has prompted intense efforts to advance the therapeutic properties of MSCs for cardiovascular disease. In this review, we consider the scope of benefit from traditional plastic adherence-isolated MSCs and the lessons learned from their conventional use in preclinical and clinical studies. Focus is then given to the evolving strategies aimed at optimizing MSC therapy, including discussion of cell-targeted techniques that encompass the preparation, pre-conditioning and manipulation of these cells ex vivo, methods to improve their delivery to the heart and innovative substrate-directed strategies to support their interaction with the host myocardium.
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Affiliation(s)
- James D Richardson
- Cardiovascular Research Centre, Royal Adelaide Hospital and Department of Medicine, University of Adelaide, Adelaide, South Australia, Australia
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20
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Silvestre JS, Smadja DM, Lévy BI. Postischemic revascularization: from cellular and molecular mechanisms to clinical applications. Physiol Rev 2013; 93:1743-802. [PMID: 24137021 DOI: 10.1152/physrev.00006.2013] [Citation(s) in RCA: 171] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
After the onset of ischemia, cardiac or skeletal muscle undergoes a continuum of molecular, cellular, and extracellular responses that determine the function and the remodeling of the ischemic tissue. Hypoxia-related pathways, immunoinflammatory balance, circulating or local vascular progenitor cells, as well as changes in hemodynamical forces within vascular wall trigger all the processes regulating vascular homeostasis, including vasculogenesis, angiogenesis, arteriogenesis, and collateral growth, which act in concert to establish a functional vascular network in ischemic zones. In patients with ischemic diseases, most of the cellular (mainly those involving bone marrow-derived cells and local stem/progenitor cells) and molecular mechanisms involved in the activation of vessel growth and vascular remodeling are markedly impaired by the deleterious microenvironment characterized by fibrosis, inflammation, hypoperfusion, and inhibition of endogenous angiogenic and regenerative programs. Furthermore, cardiovascular risk factors, including diabetes, hypercholesterolemia, hypertension, diabetes, and aging, constitute a deleterious macroenvironment that participates to the abrogation of postischemic revascularization and tissue regeneration observed in these patient populations. Thus stimulation of vessel growth and/or remodeling has emerged as a new therapeutic option in patients with ischemic diseases. Many strategies of therapeutic revascularization, based on the administration of growth factors or stem/progenitor cells from diverse sources, have been proposed and are currently tested in patients with peripheral arterial disease or cardiac diseases. This review provides an overview from our current knowledge regarding molecular and cellular mechanisms involved in postischemic revascularization, as well as advances in the clinical application of such strategies of therapeutic revascularization.
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Mathiasen AB, Haack-Sørensen M, Jørgensen E, Kastrup J. Autotransplantation of mesenchymal stromal cells from bone-marrow to heart in patients with severe stable coronary artery disease and refractory angina--final 3-year follow-up. Int J Cardiol 2013; 170:246-51. [PMID: 24211066 DOI: 10.1016/j.ijcard.2013.10.079] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2013] [Accepted: 10/21/2013] [Indexed: 01/16/2023]
Abstract
BACKGROUND The study assessed long-term safety and efficacy of intramyocardial injection of autologous bone-marrow derived mesenchymal stromal cells (BMMSCs) in patients with severe stable coronary artery disease (CAD) and refractory angina. METHODS Thirty-one patients with severe stable CAD and refractory angina were included. Patients had reversible myocardial ischemia and no further revascularization options. Autologous BMMSCs were isolated, culture expanded and stimulated with vascular endothelial growth-factor to facilitate endothelial differentiation. BMMSCs were injected into an ischemic, viable region of the myocardium. Patients were followed for 3 years. RESULTS We found significant clinical improvements in exercise time (p=0.0016), angina class (CCS) (p<0.0001), weekly number of angina attacks (p<0.0001) and use of nitroglycerine from (p=0.0017). In the Seattle Angina Questionnaire there were significant improvements in physical limitation score, angina stability score, angina frequency score and quality of life score (all p<0.0001). When comparing all hospital admissions from 3 years before to 3 years after treatment, we observed highly reduced admission rates for stable angina (p<0.0001), revascularization (p=0.003) and overall cardiovascular disease (p<0.0001). No early or late side-effects of the treatment were observed. CONCLUSIONS The final 3-year follow-up data after intramyocardial injection of autologous BMMSCs, in patients with severe CAD and refractory angina, demonstrated sustained clinical effects, reduced hospital admissions for cardiovascular disease and excellent long-term safety. The results indicate that autotransplantation of BMMSCs to the heart does not only improve symptoms but also slows down disease progression.
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Affiliation(s)
- Anders Bruun Mathiasen
- Cardiac Stem Cell Laboratory, The Heart Centre, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; Cardiac Catheterization Laboratory 2014, The Heart Centre, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
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22
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Abstract
Cell therapy with Multipotent Mesenchymal Stromal Cells (MSC) holds enormous promise for the treatment of a large number of degenerative and immune/inflammatory diseases. Their multilineage differentiation potential, immunoprivilege and capacity of promoting recovery of damaged tissues coupled with anti-inflammatory and immunosuppressive properties are the focus of a multitude of clinical studies currently underway. The recognized clinical potential of MSC repairing/immunomodulatory effects now encompasses graft-versus-host disease, hematologic malignancies, cardiovascular diseases, neurologic and inherited diseases, autoimmune diseases, organ transplantation, refractory wounds, and bone/cartilage defects among others. However, it has been suggested that both the need of extensive ex vivo culture for MSC clinical use, and their proangiogenic, anti-apoptotic and immunomodulatory properties may act together as tumor promoters, raising significant safety concerns. This paper will review the available data on in vitro MSC maldifferentiation and the ability of MSC to sustain tumor growth in vivo, with the aim to clarify whether MSC-based therapeutic approaches may carry actual risk of malignancies.
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23
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Abstract
Mesenchymal stem cells (MSCs) are self-renewing, multipotent progenitor cells with multilineage potential to differentiate into cell types of mesodermal origin, such as adipocytes, osteocytes, and chondrocytes. In addition, MSCs can migrate to sites of inflammation and exert potent immunosuppressive and anti-inflammatory effects through interactions between lymphocytes associated with both the innate and adaptive immune system. Along with these unique therapeutic properties, their ease of accessibility and expansion suggest that use of MSCs may be a useful therapeutic approach for various disorders. In the clinical setting, MSCs are being explored in trials of various conditions, including orthopedic injuries, graft versus host disease following bone marrow transplantation, cardiovascular diseases, autoimmune diseases, and liver diseases. Furthermore, genetic modification of MSCs to overexpress antitumor genes has provided prospects for clinical use as anticancer therapy. Here, we highlight the currently reported uses of MSCs in clinical trials and discuss their efficacy as well as their limitations.
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Affiliation(s)
- Nayoun Kim
- Laboratory of Immune Regulation, Convergent Research Consortium for Immunologic Disease, Seoul, Korea
| | - Seok-Goo Cho
- Laboratory of Immune Regulation, Convergent Research Consortium for Immunologic Disease, Seoul, Korea
- Department of Hematology, Catholic Blood and Marrow Transplantation Center, Seoul St. Mary's Hospital, The Catholic University of Korea College of Medicine, Seoul, Korea
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Ichim TE, Warbington T, Cristea O, Chin JL, Patel AN. Intracavernous administration of bone marrow mononuclear cells: a new method of treating erectile dysfunction? J Transl Med 2013; 11:139. [PMID: 23758954 PMCID: PMC3718667 DOI: 10.1186/1479-5876-11-139] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2013] [Accepted: 04/23/2013] [Indexed: 02/06/2023] Open
Abstract
While PDE5 inhibitors have revolutionized treatment of ED, approximately 30% of patients are non-responsive. A significant cause of this is vascular and smooth muscle dysfunction, as well as nerve atrophy. Autologous administration of bone marrow mononuclear cells (BMMC) has been performed in over 2000 cardiac patients without adverse effects, for stimulation of angiogenesis/regeneration. Despite its ease of access, and dependence on effective vasculature for function, comparatively little has been perform in terms of BMMC therapy for ED. Here we outline the rationale for use of autologous BMMC in patients with ED, as well as provide early safety data on the first use of this procedure clinically.
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Affiliation(s)
- Thomas E Ichim
- Institute for Molecular Medicine, Huntington Beach, CA, USA.
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25
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Critical path in cardiac stem cell therapy: an update on cell delivery. Cytotherapy 2013; 15:399-415. [DOI: 10.1016/j.jcyt.2012.11.003] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2012] [Revised: 09/25/2012] [Accepted: 11/02/2012] [Indexed: 01/14/2023]
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Ravichandran R, Venugopal JR, Sundarrajan S, Mukherjee S, Ramakrishna S. Minimally invasive cell-seeded biomaterial systems for injectable/epicardial implantation in ischemic heart disease. Int J Nanomedicine 2012; 7:5969-94. [PMID: 23271906 PMCID: PMC3526148 DOI: 10.2147/ijn.s37575] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
Myocardial infarction (MI) is characterized by heart-wall thinning, myocyte slippage, and ventricular dilation. The injury to the heart-wall muscle after MI is permanent, as after an abundant cell loss the myocardial tissue lacks the intrinsic capability to regenerate. New therapeutics are required for functional improvement and regeneration of the infarcted myocardium, to overcome harmful diagnosis of patients with heart failure, and to overcome the shortage of heart donors. In the past few years, myocardial tissue engineering has emerged as a new and ambitious approach for treating MI. Several left ventricular assist devices and epicardial patches have been developed for MI. These devices and acellular/cellular cardiac patches are employed surgically and sutured to the epicardial surface of the heart, limiting the region of therapeutic benefit. An injectable system offers the potential benefit of minimally invasive release into the myocardium either to restore the injured extracellular matrix or to act as a scaffold for cell delivery. Furthermore, intramyocardial injection of biomaterials and cells has opened new opportunities to explore and also to augment the potentials of this technique to ease morbidity and mortality rates owing to heart failure. This review summarizes the growing body of literature in the field of myocardial tissue engineering, where biomaterial injection, with or without simultaneous cellular delivery, has been pursued to enhance functional and structural outcomes following MI. Additionally, this review also provides a complete outlook on the tissue-engineering therapies presently being used for myocardial regeneration, as well as some perceptivity into the possible issues that may hinder its progress in the future.
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Affiliation(s)
- Rajeswari Ravichandran
- Healthcare and Energy Materials Laboratory, National University of Singapore, Singapore
- Department of Mechanical Engineering, National University of Singapore, Singapore
| | | | - Subramanian Sundarrajan
- Healthcare and Energy Materials Laboratory, National University of Singapore, Singapore
- Department of Mechanical Engineering, National University of Singapore, Singapore
| | - Shayanti Mukherjee
- Healthcare and Energy Materials Laboratory, National University of Singapore, Singapore
| | - Seeram Ramakrishna
- Healthcare and Energy Materials Laboratory, National University of Singapore, Singapore
- Department of Mechanical Engineering, National University of Singapore, Singapore
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Veronesi F, Giavaresi G, Tschon M, Borsari V, Nicoli Aldini N, Fini M. Clinical use of bone marrow, bone marrow concentrate, and expanded bone marrow mesenchymal stem cells in cartilage disease. Stem Cells Dev 2012; 22:181-92. [PMID: 23030230 DOI: 10.1089/scd.2012.0373] [Citation(s) in RCA: 110] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Mesenchymal stem cells (MSCs) from bone marrow (BM) are widely used for bone and less for cartilage tissue regeneration due to their self-renewal and differentiating properties into osteogenic or chondrogenic lineages. This review considers the last decade of clinical trials involving a two-step procedure, by expanding in vitro MSCs from BM, or the so called "one-step" procedure, using BM in toto or BM concentrate, for the regeneration of cartilage and osteochondral tissue defects. The following conclusions were drawn: (1) Cartilage defects that can be repaired by the two-step technique are about twice the size as those where the one-step method is used; (2) the two-step procedure is especially used for the treatment of osteoarthritic lesions, whereas the one-step procedure is used for osteochondral defects; (3) the number of transplanted cells ranges between 3.8×10(6) and 11.2×10(6) cells/mL, and the period of cell culture expansion of implanted MSCs varies widely with regard to the two-step procedure; (4) hyaluronic or collagenic scaffolds are used in all the clinical studies analyzed for both techniques; (5) the follow-up of the two-step procedure is longer than that of the one-step method, despite having a lower number of patients; and, finally, (6) the mean age of the patients (about 39 years old) is similar in both procedures. Clinical results underline the safety and good and encouraging outcomes for the use of MSCs in clinics. Although more standardized procedures are required, the length of follow-up and the number of patients observed should be augmented, and the design of trials should be implemented to achieve evidence-based results.
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Affiliation(s)
- Francesca Veronesi
- Laboratory of Preclinical and Surgical Studies, Rizzoli Orthopedic Institute, Via Di Barbiano 1/10, Bologna, Italy
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Robbers LFHJ, Nijveldt R, Beek AM, Kemme MJB, Delewi R, Hirsch A, van der Laan AM, van der Vleuten PA, Piek JJ, Zijlstra F, van Rossum AC. Intracoronary infusion of mononuclear cells after PCI-treated myocardial infarction and arrhythmogenesis: is it safe? Neth Heart J 2012; 20:133-7. [PMID: 22351557 PMCID: PMC3286504 DOI: 10.1007/s12471-012-0251-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
Abstract
To reduce long-term morbidity after revascularised acute myocardial infarction, different therapeutic strategies have been investigated. Cell therapy with mononuclear cells from bone marrow (BMMC) or peripheral blood (PBMC) has been proposed to attenuate the adverse processes of remodelling and subsequent heart failure. Previous trials have suggested that cell therapy may facilitate arrhythmogenesis. In the present substudy of the HEBE cell therapy trial, we investigated whether intracoronary cell therapy alters the prevalence of ventricular arrhythmias after 1 month or the rate of severe arrhythmogenic events (SAE) in the first year. In 164 patients of the trial we measured function and infarct size with cardiovascular magnetic resonance (CMR) imaging. Holter registration was performed after 1 month from which the number of triplets (3 successive PVCs) and ventricular tachycardias (VT, ≥4 successive PVCs) was assessed. Thirty-three patients (20%) showed triplets and/or VTs, with similar distribution amongst the groups (triplets: control n = 8 vs. BMMC n = 9, p = 1.00; vs. PBMC n = 10, p = 0.67. VT: control n = 9 vs. BMMC n = 9, p = 0.80; vs. PBMC n = 11, p = 0.69). SAE occurred in 2 patients in the PBMC group and 1 patient in the control group. In conclusion, intracoronary cell therapy is not associated with an increase in ventricular arrhythmias or SAE.
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Affiliation(s)
- L F H J Robbers
- Department of Cardiology, VU University Medical Center, ZH 5 F003, PO Box 7057, 1007 MB, Amsterdam, the Netherlands
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Rationale and design of the first randomized, double-blind, placebo-controlled trial of intramyocardial injection of autologous bone-marrow derived Mesenchymal Stromal Cells in chronic ischemic Heart Failure (MSC-HF Trial). Am Heart J 2012; 164:285-91. [PMID: 22980293 DOI: 10.1016/j.ahj.2012.05.026] [Citation(s) in RCA: 68] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2011] [Accepted: 05/25/2012] [Indexed: 01/16/2023]
Abstract
BACKGROUND Stem cell therapy is an emerging treatment modality in cardiovascular disease. The best cell type and delivery method in different cardiovascular diseases remain to be determined. STUDY DESIGN The MSC-HF trial is a phase 2, single-center, double-blind, randomized, placebo-controlled trial of intramyocardial delivery of autologous bone-marrow derived mesenchymal stromal cells (MSCs) in patients with chronic ischemic heart failure. A total of 60 patients will be randomized in a 2:1 pattern to receive intramyocardial injections of either MSCs or placebo. Patients will be followed up for 12 months. METHODS Bone marrow will be obtained by aspiration from the iliac crest. Mesenchymal stromal cells will be isolated, and culture will be expanded for 6 to 8 weeks. A total of 12 to 15 MSC or placebo injections will be placed in an ischemic viable region of the myocardium using the electromechanical NOGA-XP system (Biologics Delivery Systems Group, Johnson & Johnson, Irwindale, CA). ENDPOINTS The primary endpoint is change in left ventricle end-systolic volume, measured by magnetic resonance imaging (MRI) or computed tomography (CT) at 6-month follow-up. Secondary endpoints are left ventricle ejection fraction, ventricular volumes, wall thickness, and systolic wall thickening measured by MRI or CT in addition to measurement of myocardial scar tissue by MRI. Other secondary endpoints are safety of treatment, clinical symptoms and functional capacity, weekly angina attacks, use of short-term nitroglycerine, and quality of life. CONCLUSION A randomized, double-blind, placebo-controlled, clinical trial of intramyocardial delivery of MSCs in patients with ischemic heart failure has been set up to confirm the positive findings in open-labeled clinical trials.
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Cell and gene therapy for arrhythmias: Repair of cardiac conduction damage. J Geriatr Cardiol 2012; 8:147-58. [PMID: 22783301 PMCID: PMC3390069 DOI: 10.3724/sp.j.1263.2011.00147] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2011] [Revised: 08/10/2011] [Accepted: 08/17/2011] [Indexed: 11/25/2022] Open
Abstract
Action potentials generated in the sinoatrial node (SAN) dominate the rhythm and rate of a healthy human heart. Subsequently, these action potentials propagate to the whole heart via its conduction system. Abnormalities of impulse generation and/or propagation in a heart can cause arrhythmias. For example, SAN dysfunction or conduction block of the atrioventricular node can lead to serious bradycardia which is currently treated with an implanted electronic pacemaker. On the other hand, conduction damage may cause reentrant tachyarrhythmias which are primarily treated pharmacologically or by medical device-based therapies, including defibrillation and tissue ablation. However, drug therapies sometimes may not be effective or are associated with serious side effects. Device-based therapies for cardiac arrhythmias, even with well developed technology, still face inadequacies, limitations, hardware complications, and other challenges. Therefore, scientists are actively seeking other alternatives for antiarrhythmic therapy. In particular, cells and genes used for repairing cardiac conduction damage/defect have been investigated in various studies both in vitro and in vivo. Despite the complexities of the excitation and conduction systems of the heart, cell and gene-based strategies provide novel alternatives for treatment or cure of cardiac arrhythmias. This review summarizes some highlights of recent research progress in this field.
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Liu Y, Tse HF. The proarrhythmic risk of cell therapy for cardiovascular diseases. Expert Rev Cardiovasc Ther 2012; 9:1593-601. [PMID: 22103878 DOI: 10.1586/erc.11.171] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Stem cell therapy is an emerging therapeutic approach for the treatment of cardiovascular diseases. Experimental studies have demonstrated that different types of stem cells, including bone marrow-derived cells, mesenchymal stem cells, skeletal myoblasts, and cardiac progenitor cells and embryonic stem cells, can improve cardiac function after myocardial injuries. Nevertheless, the potential proarrhythmic risk after stem cell transplantation remains a major concern. Several mechanisms, including the immaturity of electrical phenotypes of the transplanted cardiomyocytes, poor cell-cell coupling and cardiac nerve sprouting, may contribute to arrhythmogenic risk after stem cell transplantation. This review summarizes the potential theoretical arrhythmogenic mechanisms associated with different types of stem cells for the treatment of cardiovascular diseases. Nevertheless, current experimental and clinical data on the proarrhythmic risk for different types of stem cell transplantation are limited, and await further experimental and clinical investigation.
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Affiliation(s)
- Yuan Liu
- Cardiology Division, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, HKSAR, China
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Wei F, Wang TZ, Zhang J, Yuan ZY, Tian HY, Ni YJ, Zhuo XZ, Han K, Liu Y, Lu Q, Bai HY, Ma AQ. Mesenchymal stem cells neither fully acquire the electrophysiological properties of mature cardiomyocytes nor promote ventricular arrhythmias in infarcted rats. Basic Res Cardiol 2012; 107:274. [PMID: 22744762 DOI: 10.1007/s00395-012-0274-4] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2012] [Revised: 04/30/2012] [Accepted: 05/25/2012] [Indexed: 12/28/2022]
Abstract
Electrophysiological properties of implanted mesenchymal stem cells (MSCs) in infarcted hearts remain unclear, and their proarrhythmic effect is still controversial. The intent of this study was to investigate electrophysiological properties and proarrhythmic effects of MSCs in infarcted hearts. Rats were randomly divided into a myocardial infarction (MI) group, a MI-DMEM group (received DMEM medium injection) and MI-MSCs group (received MSCs injection). Survival analysis showed that the majority of engrafted MSCs died at day 9 after transplantation. Engrafted MSCs expressed cardiac markers (MYH, cTnI, Cx43), cardiac ion channel genes (Kv1.4, Kv4.2 and Kir2.1) and potassium currents (I (to), I (K1) and I (KDR)), but did not express Nav1.5, Cav1.2, Na(+) current and Ca(2+) current during their survival. When induced by Ca(2+), implanted MSCs exhibited no contraction ability after being isolated from the heart. Following 8-week electrocardiography monitoring, the cumulative occurrence of ventricular arrhythmias (VAs) was not different among the three groups. However, the prolonged QRS duration in infarcted rats without VAs was significantly decreased in the MI-MSCs group compared with the other two groups. The inducibility of VAs in the MI-MSCs group was much lower than that in the MI and MI-DMEM groups (41.20 vs. 86.67 % and 92.86 %; P < 0.0125). The ventricular effective refractory period in MI-MSCs group was prolonged in comparison with that in the MI and MI-DMEM groups (56.0 ± 8.8 vs. 47.7 ± 8.8 ms and 45.7 ± 6.2 ms; P < 0.01). These results demonstrate that MSCs do not acquire the electrophysiological properties of mature cardiomyocytes during the survival period in the infarcted hearts. However, they can alleviate the electrical vulnerability and do not promote ventricular arrhythmias.
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Affiliation(s)
- Feng Wei
- Department of Cardiovascular Medicine, First Affiliated Hospital of the Xi'an Jiaotong University School of Medicine, Shaanxi, 710061, People's Republic of China
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Mesenchymal stem cells for cardiac regeneration: translation to bedside reality. Stem Cells Int 2012; 2012:646038. [PMID: 22754578 PMCID: PMC3382381 DOI: 10.1155/2012/646038] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2012] [Accepted: 04/03/2012] [Indexed: 12/11/2022] Open
Abstract
Cardiovascular disease (CVD) is the leading cause of death worldwide. According to the World Health Organization (WHO), an estimate of 17.3 million people died from CVDs in 2008 and by 2030, the number of deaths is estimated to reach almost 23.6 million. Despite the development of a variety of treatment options, heart failure management has failed to inhibit myocardial scar formation and replace the lost cardiomyocyte mass with new functional contractile cells. This shortage is complicated by the limited ability of the heart for self-regeneration. Accordingly, novel management approaches have been introduced into the field of cardiovascular research, leading to the evolution of gene- and cell-based therapies. Stem cell-based therapy (aka, cardiomyoplasty) is a rapidly growing alternative for regenerating the damaged myocardium and attenuating ischemic heart disease. However, the optimal cell type to achieve this goal has not been established yet, even after a decade of cardiovascular stem cell research. Mesenchymal stem cells (MSCs) in particular have been extensively investigated as a potential therapeutic approach for cardiac regeneration, due to their distinctive characteristics. In this paper, we focus on the therapeutic applications of MSCs and their transition from the experimental benchside to the clinical bedside.
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Xu X, Xia J, Yang X, Huang X, Gao D, Zhou J, Lian J, Zhou J. Intermediate-conductance Ca(2+) -activated potassium and volume-sensitive chloride channels in endothelial progenitor cells from rat bone marrow mononuclear cells. Acta Physiol (Oxf) 2012; 205:302-13. [PMID: 22168445 DOI: 10.1111/j.1748-1716.2011.02398.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2011] [Revised: 02/17/2011] [Accepted: 12/08/2011] [Indexed: 12/24/2022]
Abstract
AIM Bone marrow endothelial progenitor cells (BMEPCs) are believed to be a promising cell source for regenerative medicine; however, their electrophysiology properties have not been fully clarified, which is important to the clinical application of BMEPCs. The current study was designed to determine the transmembrane ion currents and mRNA expression levels of related ion channel subunits in rat BMEPCs. METHODS Bone marrow mononuclear cells were isolated by density gradient separation and cultured in EPC medium. The transmembrane ion currents were determined using whole-cell patch-voltage clamp technique, and the levels of mRNA and protein expressions of functional ionic channels were measured using RT-PCR and western immunoblot analysis. RESULTS We observed two types of ionic currents in undifferentiated rat BMEPCs. One was Ca(2+) -activated potassium current (I(kca) ), which was seen in approx. 90% of cells when 1 μm Ca(2+) was employed in pipette solution, and it was predominantly inhibited by intermediate-conductance I(kca) inhibitor clotrimazole. The other one was volume-sensitive chloride current (I(cl) ), which was detected in 85.7% of cells when BMEPCs were subjected to K(+) -free hypotonic extracellular solution, whose currents could be inhibited by 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB). The corresponding ion channel genes and proteins, KCNN4 for I(kca) and Clcn3 for I(cl) , were confirmed by RT-PCR and western immunoblot analysis of BMEPCs. CONCLUSION Our results demonstrated for the first time that rat BMEPCs expressed intermediate-conductance Ca(2+) -activated potassium currents and volume-sensitive chloride currents, and corresponding genes and proteins of these two channels are KCNN4 and Clcn3 respectively.
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Affiliation(s)
- X. Xu
- Lihuili Hospital; Ningbo University School of Medicine; Ningbo; China
| | - J. Xia
- Lihuili Hospital; Ningbo University School of Medicine; Ningbo; China
| | - X. Yang
- Lihuili Hospital; Ningbo University School of Medicine; Ningbo; China
| | - X. Huang
- Lihuili Hospital; Ningbo University School of Medicine; Ningbo; China
| | - D. Gao
- Lihuili Hospital; Ningbo University School of Medicine; Ningbo; China
| | - J. Zhou
- Lihuili Hospital; Ningbo University School of Medicine; Ningbo; China
| | - J. Lian
- Lihuili Hospital; Ningbo University School of Medicine; Ningbo; China
| | - J. Zhou
- Lihuili Hospital; Ningbo University School of Medicine; Ningbo; China
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Mesenchymal Stromal Cell Phenotype is not Influenced by Confluence during Culture Expansion. Stem Cell Rev Rep 2012; 9:44-58. [DOI: 10.1007/s12015-012-9386-3] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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Haack-Sørensen M, Friis T, Mathiasen AB, Jørgensen E, Hansen L, Dickmeiss E, Ekblond A, Kastrup J. Direct intramyocardial mesenchymal stromal cell injections in patients with severe refractory angina: one-year follow-up. Cell Transplant 2012; 22:521-8. [PMID: 22472086 DOI: 10.3727/096368912x636830] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
In patients with stable coronary artery disease (CAD) and refractory angina, we performed direct intramyocardial injections of autologous mesenchymal stromal cells (MSC) and followed the safety and efficacy of the treatment for 12 months. A total of 31 patients with stable CAD, moderate to severe angina, normal left ventricular ejection fraction, and no further revascularization options were included. Bone marrow MSCs were isolated and culture expanded for 6-8 weeks and then stimulated with vascular endothelial growth factor (VEGF) for 1 week. The 12-month follow-up demonstrated that it was safe to culture expand MSCs and use the cells for clinical treatment. The patients' maximal metabolic equivalent (MET) during exercise increased from 4.23 MET at baseline to 4.72 MET at 12-month follow-up (p < 0.001), Canadian Cardiovascular Society Class (CCS) was reduced from 3.0 to 0.8 (p < 0.001), angina attacks per week from 13.8 to 3.2 (p < 0.001), and nitroglycerin consumption from 10.7 to 3.4 per week (p < 0.001). In addition, Seattle Angina Questionnaire (SAQ) evaluations demonstrated highly significant improvements in physical limitation, angina stability, angina frequency, and quality of life (p < 0.001 for all). It is safe in the intermediate/long term to treat patients with stable CAD using autologous culture expanded MSCs. Previously reported, early and highly significant improvements in exercise capacity and clinical symptoms persist after 12 months. The results are encouraging, and a larger controlled study is warranted.
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Affiliation(s)
- Mandana Haack-Sørensen
- Cardiac Stem Cell Laboratory and Catheterization Laboratory, The Hearth Centre, Rigshospitalet Copenhagen University Hospital, Copenhagen, Denmark
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Rodriguez JP, Murphy MP, Hong S, Madrigal M, March KL, Minev B, Harman RJ, Chen CS, Timmons RB, Marleau AM, Riordan NH. Autologous stromal vascular fraction therapy for rheumatoid arthritis: rationale and clinical safety. Int Arch Med 2012; 5:5. [PMID: 22313603 PMCID: PMC3296619 DOI: 10.1186/1755-7682-5-5] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2011] [Accepted: 02/08/2012] [Indexed: 02/08/2023] Open
Abstract
Advancements in rheumatoid arthritis (RA) treatment protocols and introduction of targeted biological therapies have markedly improved patient outcomes, despite this, up to 50% of patients still fail to achieve a significant clinical response. In veterinary medicine, stem cell therapy in the form of autologous stromal vascular fraction (SVF) is an accepted therapeutic modality for degenerative conditions with 80% improvement and no serious treatment associated adverse events reported. Clinical translation of SVF therapy relies on confirmation of veterinary findings in targeted patient populations. Here we describe the rationale and preclinical data supporting the use of autologous SVF in treatment of RA, as well as provide 1, 3, 6, and 13 month safety outcomes in 13 RA patients treated with this approach.
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Zhang ZY, Teoh SH, Hui JHP, Fisk NM, Choolani M, Chan JKY. The potential of human fetal mesenchymal stem cells for off-the-shelf bone tissue engineering application. Biomaterials 2012; 33:2656-72. [PMID: 22217806 DOI: 10.1016/j.biomaterials.2011.12.025] [Citation(s) in RCA: 108] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2011] [Accepted: 12/13/2011] [Indexed: 12/13/2022]
Abstract
Mesenchymal stem cells (MSCs) have become one of the most promising cell sources for bone tissue engineering (BTE) applications. In this review, we first highlight recent progress in the understanding of MSC biology, their in vivo niche, multi-faceted contribution to fracture healing and bone re-modelling, and their role in BTE. A literature review from clinicaltrials.gov and Pubmed on clinical usage of MSC for both orthopedic and non-orthopedic indications suggests that translational use of MSC for BTE indications is likely to bear fruit in the ensuing decade. Last, we disscuss the profound influence of ontological and antomical origins of MSC on their proliferation and osteogenesis and demonstrated human fetal MSC (hfMSC) as a superior cellular candidate for off-the-shelf BTE applications. This relates to their superior proliferation capacity, more robust osteogenic potential and lower immunogenecity, as compared to MSC from perinatal and postnatal sources. Furthermore, we discuss our experience in developing a hfMSC based BTE strategy with the integrated use of bioreactor-based dynamic priming within macroporous scaffolds, now ready for evaluation in clinical trials. In conclusion, hfMSC is likely the most promising cell source for allogeneic based BTE application, with proven advantages compared to other MSC based ones.
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Affiliation(s)
- Zhi-Yong Zhang
- Mechanical Engineering, Faculty of Engineering, National University of Singapore, Singapore
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Choi YH, Kurtz A, Stamm C. Mesenchymal stem cells for cardiac cell therapy. Hum Gene Ther 2011; 22:3-17. [PMID: 21062128 DOI: 10.1089/hum.2010.211] [Citation(s) in RCA: 99] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Despite refinements of medical and surgical therapies, heart failure remains a fatal disease. Myocardial infarction is the most common cause of heart failure, and only palliative measures are available to relieve symptoms and prolong the patient's life span. Because mammalian cardiomyocytes irreversibly exit the cell cycle at about the time of birth, the heart has traditionally been considered to lack any regenerative capacity. This paradigm, however, is currently shifting, and the cellular composition of the myocardium is being targeted by various regeneration strategies. Adult progenitor and stem cell treatment of diseased human myocardium has been carried out for more than 10 years (Menasche et al., 2001; Stamm et al., 2003), and it has become clear that, in humans, the regenerative capacity of hematopoietic stem cells and endothelial progenitor cells, despite potent proangiogenic effects, is limited (Stamm et al., 2009). More recently, mesenchymal stem cells (MSCs) and related cell types are being evaluated in preclinical models of heart disease as well as in clinical trials (see Published Clinical Trials, below). MSCs have the capacity to self-renew and to differentiate into lineages that normally originate from the embryonic mesenchyme (connective tissues, blood vessels, blood-related organs) (Caplan, 1991; Prockop, 1997; Pittenger et al., 1999). The current definition of MSCs includes plastic adherence in cell culture, specific surface antigen expression (CD105(+)/CD90(+)/CD73(+), CD34(-)/CD45(-)/CD11b(-) or CD14(-)/CD19(-) or CD79α(-)/HLA-DR1(-)), and multilineage in vitro differentiation potential (osteogenic, chondrogenic, and adipogenic) (Dominici et al., 2006 ). If those criteria are not met completely, the term "mesenchymal stromal cells" should be used for marrow-derived adherent cells, or other terms for MSC-like cells of different origin. For the purpose of this review, MSCs and related cells are discussed in general, and cell type-specific properties are indicated when appropriate. We first summarize the preclinical data on MSCs in models of heart disease, and then appraise the clinical experience with MSCs for cardiac cell therapy.
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Friis T, Haack-Sørensen M, Mathiasen AB, Ripa RS, Kristoffersen US, Jørgensen E, Hansen L, Bindslev L, Kjær A, Hesse B, Dickmeiss E, Kastrup J. Mesenchymal stromal cell derived endothelial progenitor treatment in patients with refractory angina. SCAND CARDIOVASC J 2011; 45:161-8. [PMID: 21486102 DOI: 10.3109/14017431.2011.569571] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
AIMS We evaluated the feasibility, safety and efficacy of intra-myocardial injection of autologous mesenchymal stromal cells derived endothelial progenitor cell (MSC) in patients with stable coronary artery disease (CAD) and refractory angina in this first in man trial. METHODS AND RESULTS A total of 31 patients with stable CAD, moderate to severe angina and no further revascularization options, were included. Bone marrow MSC were isolated and culture expanded for 6-8 weeks. It was feasible and safe to establish in-hospital culture expansion of autologous MSC and perform intra-myocardial injection of MSC. After six months follow-up myocardial perfusion was unaltered, but the patients increased exercise capacity (p < 0.001), reduction in CCS Class (p < 0.001), angina attacks (p < 0.001) and nitroglycerin consumption (p < 0.001), and improved Seattle Angina Questionnaire (SAQ) evaluations (p < 0.001). For all parameters there was a tendency towards improved outcome with increasing numbers of cells injected. In the MRI substudy: ejection fraction (p < 0.001), systolic wall thickness (p = 0.03) and wall thickening (p = 0.03) all improved. CONCLUSIONS The study demonstrated that it was safe to treat patients with stable CAD with autologous culture expanded MSC. Moreover, MSC treated patients had significant improvement in left ventricular function and exercise capacity, in addition to an improvement in clinical symptoms and SAQ evaluations.
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Affiliation(s)
- Tina Friis
- Cardiac Stem Cell Laboratory and Catheterization Laboratory 2014, The Hearth Centre, Rigshospitalet Copenhagen University Hospital, Copenhagen, Denmark
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Wang J, Liao L, Tan J. Mesenchymal-stem-cell-based experimental and clinical trials: current status and open questions. Expert Opin Biol Ther 2011; 11:893-909. [PMID: 21449634 DOI: 10.1517/14712598.2011.574119] [Citation(s) in RCA: 87] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Mesenchymal stem cells (MSCs) possess remarkable self-renewal ability and are able to differentiate into various cell lineages. MSCs can also enhance tissue repair and angiogenesis through a paracrine mechanism. It has been recognized that these cells hold great promise for tissue regeneration and treatment of immune-related diseases. AREAS COVERED This review aims at discussing the mechanisms of MSC-mediated immunomodulation and tissue repair and the related clinical trials, with special emphasis on factors that influence the efficiency of MSC-based therapy, including the source of MSCs, cell passage, cell dose, timing and route of administration. EXPERT OPINION MSCs may facilitate tissue repair through cell replacement and/or improving the microenvironment by releasing growth factors. Some of these factors also mediate the immunomodulatory effects of MSCs. It is important to establish global guidelines, protocols and standards for production and clinical trials of MSCs, so that MSCs can become a therapeutic agent with a reliable efficacy and good safety.
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Affiliation(s)
- Jin Wang
- Organ Transplant Institute, Fuzhou General Hospital, Xiamen University, Fuzhou, China.
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Endothelial progenitor cells: novel biomarker and promising cell therapy for cardiovascular disease. Clin Sci (Lond) 2011; 120:263-83. [PMID: 21143202 DOI: 10.1042/cs20100429] [Citation(s) in RCA: 156] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Bone-marrow-derived EPCs (endothelial progenitor cells) play an integral role in the regulation and protection of the endothelium, as well as new vessel formation. Peripheral circulating EPC number and function are robust biomarkers of vascular risk for a multitude of diseases, particularly CVD (cardiovascular disease). Importantly, using EPCs as a biomarker is independent of both traditional and non-traditional risk factors (e.g. hypertension, hypercholesterolaemia and C-reactive protein), with infused ex vivo-expanded EPCs showing potential for improved endothelial function and either reducing the risk of events or enhancing recovery from ischaemia. However, as the number of existing cardiovascular risk factors is variable between patients, simple EPC counts do not adequately describe vascular disease risk in all clinical conditions and, as such, the risk of CVD remains. It is likely that this limitation is attributable to variation in the definition of EPCs, as well as a difference in the interaction between EPCs and other cells involved in vascular control such as pericytes, smooth muscle cells and macrophages. For EPCs to be used regularly in clinical practice, agreement on definitions of EPC subtypes is needed, and recognition that function of EPCs (rather than number) may be a better marker of vascular risk in certain CVD risk states. The present review focuses on the identification of measures to improve individual risk stratification and, further, to potentially individualize patient care to address specific EPC functional abnormalities. Herein, we describe that future therapeutic use of EPCs will probably rely on a combination of strategies, including optimization of the function of adjunct cell types to prime tissues for the effect of EPCs.
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Abstract
Chronic ischemic heart disease patients are already being treated worldwide with bone marrow stem cells both in the context of clinical studies and in therapy trials. By combining this therapy with established revascularization procedures such as bypass surgery, a high level of patient safety can be achieved. To date, no stem cell-related cardiac complications following intramyocardial injection of bone marrow-derived stem cells during CABG (coronary artery bypass graft) surgery have been reported. The functional advantage conferred by surgical bone marrow stem cell therapy is a 7.2% increase in LVEF (left ventricular ejection fraction) compared to controls. Randomized placebo-controlled trials, like the German trial PERFECT, are needed to obtain a more evidence-based assessment of this therapy.
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Kastrup J. Stem cells therapy for cardiovascular repair in ischemic heart disease: How to predict and secure optimal outcome? EPMA J 2011. [PMID: 23199132 PMCID: PMC3405371 DOI: 10.1007/s13167-011-0062-5] [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] [Indexed: 01/14/2023]
Abstract
Coronary artery disease is a growing problem worldwide. Early treatment with stabilizing drugs and revascularization by percutaneous coronary intervention or by-pass surgery has reduced the mortality significantly, but it is still the most common cause of death and a major cause of hospital admissions in industrialized countries. Treatment with stem cells with the potential to regenerate the damaged myocardium is a relatively new approach. However, the results from clinical studies on stem cell therapy for cardiac regeneration in patients with acute or chronic ischemic heart disease have been inconsistent. Some of the discrepancy could be due differences in study designs or patient selection. The review will based on conducted clinical stem cell trials try to elucidate how to predict and personalize this new treatment approach.
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Affiliation(s)
- Jens Kastrup
- Cardiac Stem Cell laboratory and Cardiac Catheterization Laboratory 2014, The Hearth Centre, Rigshospitalet, Copenhagen University Hospital and Faculty of Health Sciences, Blegdamsvej 9, DK-2100 Copenhagen, Denmark
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Adult stem cells for cardiac tissue engineering. J Mol Cell Cardiol 2011; 50:312-9. [DOI: 10.1016/j.yjmcc.2010.08.009] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2010] [Revised: 07/15/2010] [Accepted: 08/06/2010] [Indexed: 12/17/2022]
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Intracoronary delivery of mesenchymal stem cells reduces proarrhythmogenic risks in swine with myocardial infarction. Ir J Med Sci 2011; 180:379-85. [PMID: 21286844 DOI: 10.1007/s11845-011-0687-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2010] [Accepted: 01/17/2011] [Indexed: 01/07/2023]
Abstract
INTRODUCTION The electrophysiological consequences of mesenchymal stem cell (MSC) therapy in ischemic heart disease have not been fully understood. METHODS Swine myocardial infarction (MI) model by intracoronary balloon occlusion received MSC solution or 0.9% NaCl. Six weeks later, heart rate turbulence (HRT), dispersion of action potential durations (APD) and repolarization time (RT) (APDd and RTd), slope of APD reconstitution curve and programmed electrical stimulation were used to evaluate the ventricular arrhythmic risks. RESULTS MSC treatment could significantly ameliorate the abnormal HRT, APD(90), APDd, RT and RTd. The slope of APD reconstitution curve in MSC group was higher than control group but lower than MI group. MSC therapy markedly reduced inducible malignant ventricular arrhythmias (VAs), and improved impaired cardiac performances and cardiac fibrosis. CONCLUSIONS This study provides strong evidence that MSC infusion via intracoronary route does not cause VAs but tends to reduce the risk of malignant VAs.
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Friis T, Haack-Sørensen M, Hansen SK, Hansen L, Bindslev L, Kastrup J. Comparison of mesenchymal stromal cells from young healthy donors and patients with severe chronic coronary artery disease. Scandinavian Journal of Clinical and Laboratory Investigation 2011; 71:193-202. [DOI: 10.3109/00365513.2010.550310] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
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Porada CD, Almeida-Porada G. Mesenchymal stem cells as therapeutics and vehicles for gene and drug delivery. Adv Drug Deliv Rev 2010; 62:1156-66. [PMID: 20828588 DOI: 10.1016/j.addr.2010.08.010] [Citation(s) in RCA: 150] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2010] [Revised: 08/26/2010] [Accepted: 08/27/2010] [Indexed: 12/17/2022]
Abstract
Mesenchymal stem cells (MSCs) possess a set of several fairly unique properties which make them ideally suited both for cellular therapies/regenerative medicine, and as vehicles for gene and drug delivery. These include: 1) relative ease of isolation; 2) the ability to differentiate into a wide variety of seemingly functional cell types of both mesenchymal and non-mesenchymal origin; 3) the ability to be extensively expanded in culture without a loss of differentiative capacity; 4) they are not only hypoimmunogenic, but they produce immunosuppression upon transplantation; 5) their pronounced anti-inflammatory properties; and 6) their ability to home to damaged tissues, tumors, and metastases following in vivo administration. In this review, we summarize the latest research in the use of mesenchymal stem cells in regenerative medicine, as immunomodulatory/anti-inflammatory agents, and as vehicles for transferring both therapeutic genes in genetic disease and genes designed to destroy malignant cells.
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Wang D, Zhang F, Shen W, Chen M, Yang B, Zhang Y, Cao K. Mesenchymal stem cell injection ameliorates the inducibility of ventricular arrhythmias after myocardial infarction in rats. Int J Cardiol 2010; 152:314-20. [PMID: 20674997 DOI: 10.1016/j.ijcard.2010.07.025] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2010] [Accepted: 07/04/2010] [Indexed: 11/24/2022]
Abstract
BACKGROUND Mesenchymal stem cell transplantation is a promising new therapy to improve cardiac function after myocardial infarction (MI). The electrophysiological consequences of MSC implantation has not been systematically studied. METHODS We investigated the electrophysiological and arrhythmogenic effects of mesenchymal stem cells (MSCs) therapy in experimental infarction model. Rats were subjected to MI operation by LAD ligation and randomly allocated to receive intramyocardially injection PBS (MI-PBS) or 5 × 10(5) EGFP labeled MSCs (MI-MSCs). Electrophysiological study, histological examination, and western blotting were performed 2 weeks after cell transplantation. RESULTS Programmed electrical stimulation (PES) showed a significant reduced inducible ventricular tachycardias (VTs), raised ventricular fibrillation threshold (VFT) and prolonged ventricular effective refractory period (VERP) in MSC-treated rats compared to PBS-treated animals. MSC implantation led to markedly longer action potential duration (APD) and shorter activation time (AT) in infarcted border zone (IBZ) of left ventricular epicardium compared with PBS-treated hearts. Histological study revealed that fibrotic area and collagen deposition in infarcted region were significantly lower in MI-MSC group than in MI-PBS group. Abnormal alterations of Connexin 43 including reduction and lateralization were significantly attenuated by MSC treatment. CONCLUSIONS This study provide strong evidence that MSC implantation ameliorates interstitial fibrosis and the remodeling of gap junction, attenuates focal heterogeneity of reporlarization and conduction and reduces vulnerability to VTs. The results suggest that MSC transplantation might emerge as a new preventive strategy against VAs besides improving cardiac performance in ischemic heart disease.
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Affiliation(s)
- Deguo Wang
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, PR China
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