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Lee H, Cho HJ, Han Y, Lee SH. Mid- to long-term efficacy and safety of stem cell therapy for acute myocardial infarction: a systematic review and meta-analysis. Stem Cell Res Ther 2024; 15:290. [PMID: 39256845 PMCID: PMC11389242 DOI: 10.1186/s13287-024-03891-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Accepted: 08/21/2024] [Indexed: 09/12/2024] Open
Abstract
BACKGROUND This comprehensive systematic review and meta-analysis investigated the mid- to long-term efficacy and safety of stem cell therapy in patients with acute myocardial infarction (AMI). METHODS The study encompassed 79 randomized controlled trials with 7103 patients, rendering it the most up-to-date and extensive analysis in this field. This study specifically focused on the impact of stem cell therapy on left ventricular ejection fraction (LVEF), major adverse cardiac events (MACE), and infarct size. RESULTS Stem cell therapy significantly improved LVEF at 6, 12, 24, and 36 months post-transplantation compared to control values, indicating its potential for long-term cardiac function enhancement. A trend toward reduced MACE occurrence was observed in the intervention groups, suggesting the potential of stem cell therapy to lower the risk of cardiovascular death, reinfarction, and stroke. Significant LVEF improvements were associated with long cell culture durations exceeding 1 week, particularly when combined with high injected cell quantities (at least 108 cells). No significant reduction in infarct size was observed. CONCLUSIONS This review highlights the potential of stem cell therapy as a promising therapeutic approach for patients with AMI, offering sustained LVEF improvement and a potential reduction in MACE risk. However, further research is required to optimize cell culture techniques, determine the optimal timing and dosage, and investigate procedural variations to maximize the efficacy and safety of stem cell therapy in this context.
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Affiliation(s)
- Hyeongsuk Lee
- College of Nursing, Research Institute of AI and Nursing Science, Gachon University, 191 Hambakmoero, Yeonsu-gu, Incheon, 21936, South Korea
| | - Hyun-Jai Cho
- Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea
| | - Yeonjung Han
- College of Nursing, Research Institute of AI and Nursing Science, Gachon University, 191 Hambakmoero, Yeonsu-gu, Incheon, 21936, South Korea
| | - Seon Heui Lee
- College of Nursing, Research Institute of AI and Nursing Science, Gachon University, 191 Hambakmoero, Yeonsu-gu, Incheon, 21936, South Korea.
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2
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Cho S, Xia I, Lee S, Park C, Yoon YS. Generation of Directly Reprogrammed Human Endothelial Cells. Methods Mol Biol 2024; 2835:155-164. [PMID: 39105914 DOI: 10.1007/978-1-0716-3995-5_14] [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] [Indexed: 08/07/2024]
Abstract
Direct reprogramming provides a novel breakthrough for generating functional endothelial cells (ECs) without the need for intermediate stem or progenitor states, offering a promising resource for cardiovascular research and treatment. ETV2 is a key transcription factor that has been identified as a pioneering factor for specifying endothelial lineage. Achieving precise ETV2 induction is essential for effective endothelial reprogramming, and maintaining the reprogrammed cellular phenotype relies on a specific combination of growth factors and small molecules. Thus, we hereby provide a straightforward and comprehensive protocol for generating two distinct types of reprogrammed ECs (rECs) from human dermal fibroblasts (HDFs). Early rECs demonstrate a robust neovascularization property but lack the mature EC phenotype, while late rECs exhibit phenotypical similarity to human postnatal ECs and have a neovascularization capacity similar to early rECs. Both cell types can be derived from human somatic source cells, making them suitable for personalized disease investigations, drug discovery, and disease therapy.
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Affiliation(s)
- Seonggeon Cho
- Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA
| | - Iris Xia
- Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA
| | - Sangho Lee
- Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA
| | - Changwon Park
- Louisiana State University Health Sciences Center, Department of Molecular & Cellular Physiology, Shreveport, LA, USA
- Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, South Korea
| | - Young-Sup Yoon
- Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA.
- Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, South Korea.
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3
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Hosseinpour A, Hosseinpour H, Attar A. Preventive Effect of Bone Marrow Mononuclear Cell Transplantation on Acute Myocardial Infarction-Induced Heart Failure: A Meta-analysis of Randomized Controlled Trials. Cardiovasc Drugs Ther 2023; 37:1143-1153. [PMID: 35876933 DOI: 10.1007/s10557-022-07359-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/11/2022] [Indexed: 11/03/2022]
Abstract
PURPOSE Heart failure (HF) is a major complication of acute myocardial infarction (AMI). Transplantation of bone marrow mononuclear cells (BM-MNC) in the setting of AMI has been proposed as a means for myocardial tissue regeneration. Several trials have explored the outcomes of these cells on surrogate end points such as left ventricular ejection fraction (LVEF) in patients with AMI. However, the data regarding the clinical efficacy are infrequent. Here, we performed a meta-analysis investigating the effect of BM-MNCs injection on the rate of hospitalization for HF in the long-term follow-up period. METHODS PubMed, Scopus, and Cochrane databases were queried with various combinations of keywords through May 2, 2022. A random-effects meta-analysis was performed to calculate risk ratio (RR) and 95% confidence interval (CI) of hospitalization for HF, all-cause mortality, and stroke rate. Subgroup analyses for hospitalization based on time and cell dose were performed. RESULTS A total of 2150 patients with AMI across 22 trials were included for quantitative synthesis. At long-term follow-up, AMI patients treated with an intracoronary injection of BM-MNCs were less likely to be hospitalized for heart failure compared to the control group receiving standard treatment (RR = 0.54, 95% CI = [0.37; 0.78], p = 0.002). There was no association between BM-MNC therapy and all-cause mortality (RR = 0.69, 95% CI = [0.47; 1.01], p = 0.05) and stroke (RR = 1.12, 95% CI= [0.24; 5.21], p = 0.85). CONCLUSION Autologous injection of BM-MNC in the setting of AMI may be associated with decreased risk of hospitalization of heart failure in the long term. However, its effect on all-cause mortality and stroke rate is questionable.
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Affiliation(s)
- Alireza Hosseinpour
- Department of Cardiovascular Medicine, School of Medicine, Shiraz University of Medical Sciences, Zand Street, Shiraz, Iran
| | | | - Armin Attar
- Department of Cardiovascular Medicine, School of Medicine, Shiraz University of Medical Sciences, Zand Street, Shiraz, Iran.
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Cho S, Aakash P, Lee S, Yoon YS. Endothelial cell direct reprogramming: Past, present, and future. J Mol Cell Cardiol 2023; 180:22-32. [PMID: 37080451 PMCID: PMC10330356 DOI: 10.1016/j.yjmcc.2023.04.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Revised: 04/04/2023] [Accepted: 04/17/2023] [Indexed: 04/22/2023]
Abstract
Ischemic cardiovascular disease still remains as a leading cause of morbidity and mortality despite various medical, surgical, and interventional therapy. As such, cell therapy has emerged as an attractive option because it tackles underlying problem of the diseases by inducing neovascularization in ischemic tissue. After overall failure of adult stem or progenitor cells, studies attempted to generate endothelial cells (ECs) from pluripotent stem cells (PSCs). While endothelial cells (ECs) differentiated from PSCs successfully induced vascular regeneration, differentiating volatility and tumorigenic potential is a concern for their clinical applications. Alternatively, direct reprogramming strategies employ lineage-specific factors to change cell fate without achieving pluripotency. ECs have been successfully reprogrammed via ectopic expression of transcription factors (TFs) from endothelial lineage. The reprogrammed ECs induced neovascularization in vitro and in vivo and thus demonstrated their therapeutic value in animal models of vascular insufficiency. Methods of delivering reprogramming factors include lentiviral or retroviral vectors and more clinically relevant, non-integrative adenoviral and episomal vectors. Most studies made use of fibroblast as a source cell for reprogramming, but reprogrammability of other clinically relevant source cell types has to be evaluated. Specific mechanisms and small molecules that are involved in the aforementioned processes tackles challenges associated with direct reprogramming efficiency and maintenance of reprogrammed EC characteristics. After all, this review provides summary of past and contemporary methods of direct endothelial reprogramming and discusses the future direction to overcome these challenges to acquire clinically applicable reprogrammed ECs.
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Affiliation(s)
- Seonggeon Cho
- Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA
| | - Parthasarathy Aakash
- Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA
| | - Sangho Lee
- Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA.
| | - Young-Sup Yoon
- Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA; Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Republic of Korea.
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5
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Xie J, Jiang L, Wang J, Yin Y, Wang R, Du L, Chen T, Ni Z, Qiao S, Gong H, Xu B, Xu Q. Multilineage contribution of CD34 + cells in cardiac remodeling after ischemia/reperfusion injury. Basic Res Cardiol 2023; 118:17. [PMID: 37147443 PMCID: PMC10163140 DOI: 10.1007/s00395-023-00981-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Revised: 02/25/2023] [Accepted: 02/26/2023] [Indexed: 05/07/2023]
Abstract
The ambiguous results of multiple CD34+ cell-based therapeutic trials for patients with heart disease have halted the large-scale application of stem/progenitor cell treatment. This study aimed to delineate the biological functions of heterogenous CD34+ cell populations and investigate the net effect of CD34+ cell intervention on cardiac remodeling. We confirmed, by combining single-cell RNA sequencing on human and mouse ischemic hearts and an inducible Cd34 lineage-tracing mouse model, that Cd34+ cells mainly contributed to the commitment of mesenchymal cells, endothelial cells (ECs), and monocytes/macrophages during heart remodeling with distinct pathological functions. The Cd34+-lineage-activated mesenchymal cells were responsible for cardiac fibrosis, while CD34+Sca-1high was an active precursor and intercellular player that facilitated Cd34+-lineage angiogenic EC-induced postinjury vessel development. We found through bone marrow transplantation that bone marrow-derived CD34+ cells only accounted for inflammatory response. We confirmed using a Cd34-CreERT2; R26-DTA mouse model that the depletion of Cd34+ cells could alleviate the severity of ventricular fibrosis after ischemia/reperfusion (I/R) injury with improved cardiac function. This study provided a transcriptional and cellular landscape of CD34+ cells in normal and ischemic hearts and illustrated that the heterogeneous population of Cd34+ cell-derived cells served as crucial contributors to cardiac remodeling and function after the I/R injury, with their capacity to generate diverse cellular lineages.
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Affiliation(s)
- Jun Xie
- Department of Cardiology, Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing Universityrsity, State Key Laboratory of Pharmaceutical Biotechnology, No. 321 Zhongshan Road, Nanjing, 210008, Jiangsu, People's Republic of China
| | - Liujun Jiang
- Department of Cardiology, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, Zhejiang Province, People's Republic of China
| | - Junzhuo Wang
- Department of Cardiology, Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing Universityrsity, State Key Laboratory of Pharmaceutical Biotechnology, No. 321 Zhongshan Road, Nanjing, 210008, Jiangsu, People's Republic of China
| | - Yong Yin
- Department of Cardiology, Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing Universityrsity, State Key Laboratory of Pharmaceutical Biotechnology, No. 321 Zhongshan Road, Nanjing, 210008, Jiangsu, People's Republic of China
| | - Ruilin Wang
- Department of Cardiology, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, Zhejiang Province, People's Republic of China
| | - Luping Du
- Department of Cardiology, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, Zhejiang Province, People's Republic of China
| | - Ting Chen
- Department of Cardiology, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, Zhejiang Province, People's Republic of China
- Alibaba-Zhejiang University Joint Research Center of Future Digital Healthcare, Hangzhou, People's Republic of China
| | - Zhichao Ni
- Department of Cardiology, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, Zhejiang Province, People's Republic of China
| | - Shuaihua Qiao
- Department of Cardiology, Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing Universityrsity, State Key Laboratory of Pharmaceutical Biotechnology, No. 321 Zhongshan Road, Nanjing, 210008, Jiangsu, People's Republic of China
| | - Hui Gong
- Department of Cardiology, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, Zhejiang Province, People's Republic of China
| | - Biao Xu
- Department of Cardiology, Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing Universityrsity, State Key Laboratory of Pharmaceutical Biotechnology, No. 321 Zhongshan Road, Nanjing, 210008, Jiangsu, People's Republic of China.
| | - Qingbo Xu
- Department of Cardiology, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, Zhejiang Province, People's Republic of China.
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6
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Kanda M, Nagai T, Kondo N, Matsuura K, Akazawa H, Komuro I, Kobayashi Y. Pericardial Grafting of Cardiac Progenitor Cells in Self-Assembling Peptide Scaffold Improves Cardiac Function After Myocardial Infarction. Cell Transplant 2023; 32:9636897231174078. [PMID: 37191272 PMCID: PMC10192947 DOI: 10.1177/09636897231174078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Revised: 04/03/2023] [Accepted: 04/19/2023] [Indexed: 05/17/2023] Open
Abstract
Many studies have explored cardiac progenitor cell (CPC) therapy for heart disease. However, optimal scaffolds are needed to ensure the engraftment of transplanted cells. We produced a three-dimensional hydrogel scaffold (CPC-PRGmx) in which high-viability CPCs were cultured for up to 8 weeks. CPC-PRGmx contained an RGD peptide-conjugated self-assembling peptide with insulin-like growth factor-1 (IGF-1). Immediately after creating myocardial infarction (MI), we transplanted CPC-PRGmx into the pericardial space on to the surface of the MI area. Four weeks after transplantation, red fluorescent protein-expressing CPCs and in situ hybridization analysis in sex-mismatched transplantations revealed the engraftment of CPCs in the transplanted scaffold (which was cellularized with host cells). The average scar area of the CPC-PRGmx-treated group was significantly smaller than that of the non-treated group (CPC-PRGmx-treated group = 46 ± 5.1%, non-treated MI group = 59 ± 4.5%; p < 0.05). Echocardiography showed that the transplantation of CPC-PRGmx improved cardiac function and attenuated cardiac remodeling after MI. The transplantation of CPCs-PRGmx promoted angiogenesis and inhibited apoptosis, compared to the untreated MI group. CPCs-PRGmx secreted more vascular endothelial growth factor than CPCs cultured on two-dimensional dishes. Genetic fate mapping revealed that CPC-PRGmx-treated mice had more regenerated cardiomyocytes than non-treated mice in the MI area (CPC-PRGmx-treated group = 0.98 ± 0.25%, non-treated MI group = 0.25 ± 0.04%; p < 0.05). Our findings reveal the therapeutic potential of epicardial-transplanted CPC-PRGmx. Its beneficial effects may be mediated by sustainable cell viability, paracrine function, and the enhancement of de novo cardiomyogenesis.
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Affiliation(s)
- Masato Kanda
- Department of Cardiovascular Medicine,
Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Toshio Nagai
- Department of Cardiology, Chemotherapy
Research Institute, KAKEN Hospital, International University of Health and Welfare,
Ichikawa-shi, Japan
| | - Naomichi Kondo
- Department of Cardiovascular Medicine,
Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Katsuhisa Matsuura
- Institute of Advanced Biomedical
Engineering and Science, Tokyo Women’s Medical University, Tokyo, Japan
- Department of Cardiology, Tokyo Women’s
Medical University, Tokyo, Japan
| | - Hiroshi Akazawa
- Department of Cardiovascular Medicine,
Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Issei Komuro
- Department of Cardiovascular Medicine,
Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Yoshio Kobayashi
- Department of Cardiovascular Medicine,
Graduate School of Medicine, Chiba University, Chiba, Japan
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Abdel-Latif A, Ahmed T, Leung SW, Alnabelsi T, Tarhuni W, Sekela ME. Autologous CD133 + Cells and Laser Revascularization in patients with severe Ischemic Cardiomyopathy. Stem Cell Rev Rep 2022; 19:817-822. [PMID: 36376770 DOI: 10.1007/s12015-022-10479-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/07/2022] [Indexed: 11/16/2022]
Abstract
OBJECTIVE We tested the hypothesis that targeted TMLR combined with intramyocardial injection of autologous CD 133+ progenitor cells is safe and feasible in patients with chronic ischemic cardiomyopathy (ICM) and no revascularization options. METHODS Eight male patients (age 62 ± 2.4 years) with multivessel severe ischemic heart disease and no revascularization options were enrolled. Autologous CD 133 + endothelial progenitor cells were derived and purified from the bone marrow on the day of surgery using the clinical-grade closed CliniMACS system. Using a lateral thoracotomy approach, TMLR was performed, followed by transmyocardial transplantation of purified CD133 + cells (mean number of transplanted cells: 12.5 × 106) in the region surrounding the TMLR sites. These sites were selected based on ischemia on pre-procedure perfusion imaging. We performed clinical and myocardial perfusion imaging pre-procedure and then at 6- and 12-month follow-up. RESULTS No major complications or death occurred during the procedure or during the peri-operative hospital stay. One patient died of cardiac cause 6 months post-procedure. There was a reported short-term improvement in anginal and heart failure symptoms and a modest reduction in the ischemic score as assessed by perfusion imaging. CONCLUSIONS Our phase 1 clinical study examining the combination therapy of targeted transmyocardial laser revascularization therapy and autologous CD133 + endothelial progenitor cells in patients with chronic ICM and no revascularization options demonstrates the feasibility and short-term safety of this combined approach and warrants future larger phase 2 randomized clinical studies.
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Affiliation(s)
- Ahmed Abdel-Latif
- Department of Cardiovascular Medicine, Division of Cardiology, University of Kentucky, Lexington, KY, USA
- Department of Cardiovascular Medicine, Division of Cardiology, University of Michigan, Ann Arbor, MI, USA
| | - Taha Ahmed
- Department of Cardiovascular Medicine, Division of Cardiology, University of Kentucky, Lexington, KY, USA
| | - Steve W Leung
- Department of Cardiovascular Medicine, Division of Cardiology, University of Kentucky, Lexington, KY, USA
| | - Talal Alnabelsi
- Department of Cardiovascular Medicine, Division of Cardiology, University of Kentucky, Lexington, KY, USA
| | - Wadea Tarhuni
- Department of Internal Medicine, Division of Cardiology, Canadian Cardiac Research Center, University of Saskatchewan, SK, Saskatoon, Canada
| | - Michael E Sekela
- Department of Cardiothoracic Surgery, University of Kentucky, Lexington, KY, USA.
- Heart Transplant, Division of Cardiothoracic Surgery, University of Kentucky, Lexington, KY, USA.
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8
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Pu X, Zhu P, Zhou X, He Y, Wu H, Du L, Gong H, Sun X, Chen T, Zhu J, Xu Q, Zhang H. CD34 + cell atlas of main organs implicates its impact on fibrosis. Cell Mol Life Sci 2022; 79:576. [PMID: 36315271 PMCID: PMC11803001 DOI: 10.1007/s00018-022-04606-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 09/22/2022] [Accepted: 10/11/2022] [Indexed: 11/03/2022]
Abstract
RATIONALE CD34+ cells are believed being progenitors that may be used to treat cardiovascular disease. However, the exact identity and the role of CD34+ cells in physiological and pathological conditions remain unclear. METHODS We performed single-cell RNA sequencing analysis to provide a cell atlas of normal tissue/organ and pathological conditions. Furthermore, a genetic lineage tracing mouse model was used to investigate the role of CD34+ cells in angiogenesis and organ fibrosis. RESULTS Single-cell RNA sequencing analysis revealed a heterogeneous population of CD34+ cells in both physiological and pathological conditions. Using a genetic lineage tracing mouse model, we showed that CD34+ cells not only acquired endothelial cell fate involved in angiogenesis, but also, CD34+ cells expressing Pi16 may transform into myofibroblast and thus participate in organ fibrosis. CONCLUSION A heterogeneous CD34+ cells serve as a contributor not only to endothelial regeneration but also a wound healing response that may provide therapeutic insights into fibrosis.
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Affiliation(s)
- Xiangyuan Pu
- Department of Cardiology, the First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, Hangzhou, China
| | - Pengwei Zhu
- Department of Cardiology, the First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, Hangzhou, China
| | - Xuhao Zhou
- Department of Cardiology, the First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, Hangzhou, China
| | - Yangyan He
- Department of Vascular Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Hong Wu
- Department of Cardiology, the First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, Hangzhou, China
| | - Luping Du
- Department of Cardiology, the First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, Hangzhou, China
| | - Hui Gong
- Department of Cardiology, the First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, Hangzhou, China
| | - Xiaotong Sun
- Department of Cardiology, the First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, Hangzhou, China
| | - Ting Chen
- Department of Cardiology, the First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, Hangzhou, China
- Alibaba-Zhejiang University Joint Research Center of Future Digital Healthcare, Hangzhou, China
| | - Jianhua Zhu
- Department of Cardiology, the First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, Hangzhou, China.
| | - Qingbo Xu
- Department of Cardiology, the First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, Hangzhou, China.
| | - Hongkun Zhang
- Department of Vascular Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
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9
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Mahmud S, Alam S, Emon NU, Boby UH, Kamruzzaman, Ahmed F, Monjur-Al-Hossain ASM, Tahamina A, Rudra S, Ajrin M. Opportunities and challenges in stem cell therapy in cardiovascular diseases: Position standing in 2022. Saudi Pharm J 2022; 30:1360-1371. [PMID: 36249945 PMCID: PMC9563042 DOI: 10.1016/j.jsps.2022.06.017] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2022] [Accepted: 06/17/2022] [Indexed: 10/29/2022] Open
Abstract
This study intends to evaluate the development, importance, pre-clinical and clinical study evaluation of stem cell therapy for the treatment of cardiovascular disease. Cardiovascular disease is one of the main causes of fatality in the whole world. Though there are great progressions in the pharmacological and other interventional treatment options, heart diseases remain a common disorder that causes long-term warnings. Recent accession promotes the symptoms and slows down the adverse effects regarding cardiac remodelling. But they cannot locate the problems of immutable loss of cardiac tissues. In this case, stem cell treatment holds a promising challenge. Stem cells are the cells that are capable of differentiating into many cells according to their needs. So, it is assumed that these cells can distinguish into many cells and if these cells can be individualized into cardiac cells then they can be used to replace the damaged tissues of the heart. There is some abridgment in this therapy, none the less stem cell therapy remains a hopeful destination in the treatment of heart disease.
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Affiliation(s)
- Shabnur Mahmud
- School of Health and Life Sciences, Department of Pharmaceutical Sciences, North South University, Dhaka 1229, Bangladesh
| | - Safaet Alam
- Pharmaceutical Sciences Research Division, BCSIR Laboratories, Dhaka, Bangladesh Council of Scientific and Industrial Research (BCSIR), Dr. Qudrat-I-Khuda Road, Dhanmondi, Dhaka 1205, Bangladesh
| | - Nazim Uddin Emon
- Department of Pharmacy, Faculty of Science and Engineering, International Islamic University Chittagong, Chittagong 4318, Bangladesh
| | - Umme Habiba Boby
- Department of Pharmacy, Faculty of Science and Engineering, International Islamic University Chittagong, Chittagong 4318, Bangladesh
| | - Kamruzzaman
- Department of Pharmacy, Faculty of Science and Engineering, International Islamic University Chittagong, Chittagong 4318, Bangladesh
| | - Firoj Ahmed
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Dhaka, Dhaka 1205, Bangladesh
| | - A S M Monjur-Al-Hossain
- Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Dhaka, Dhaka 1205, Bangladesh
| | - Afroza Tahamina
- Department of Botany, Faculty of Biological Sciences, University of Chittagong, Chattogram 4331, Bangladesh
| | - Sajib Rudra
- Department of Botany, Faculty of Biological Sciences, University of Chittagong, Chattogram 4331, Bangladesh
| | - Marzina Ajrin
- Department of Pharmacy, University of Science and Technology Chittagong, Chittagong 4202, Bangladesh
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10
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Studying Epigenetics of Cardiovascular Diseases on Chip Guide. CARDIOGENETICS 2022. [DOI: 10.3390/cardiogenetics12030021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Epigenetics is defined as the study of inheritable changes in the gene expressions and phenotypes that occurs without altering the normal DNA sequence. These changes are mainly due to an alteration in chromatin or its packaging, which changes the DNA accessibility. DNA methylation, histone modification, and noncoding or microRNAs can best explain the mechanism of epigenetics. There are various DNA methylated enzymes, histone-modifying enzymes, and microRNAs involved in the cause of various CVDs (cardiovascular diseases) such as cardiac hypertrophy, heart failure, and hypertension. Moreover, various CVD risk factors such as diabetes mellitus, hypoxia, aging, dyslipidemia, and their epigenetics are also discussed together with CVDs such as CHD (coronary heart disease) and PAH (pulmonary arterial hypertension). Furthermore, different techniques involved in epigenetic chromatin mapping are explained. Among these techniques, the ChIP-on-chip guide is explained with regard to its role in cardiac hypertrophy, a final form of heart failure. This review focuses on different epigenetic factors that are involved in causing cardiovascular diseases.
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11
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Attar A, Hosseinpour A, Hosseinpour H, Kazemi A. Major cardiovascular events after bone marrow mononuclear cell transplantation following acute myocardial infarction: an updated post-BAMI meta-analysis of randomized controlled trials. BMC Cardiovasc Disord 2022; 22:259. [PMID: 35681123 PMCID: PMC9185901 DOI: 10.1186/s12872-022-02701-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 06/03/2022] [Indexed: 11/23/2022] Open
Abstract
Background The effect of bone marrow-derived mononuclear cells (BM-MNCs) after acute myocardial infarction (AMI) on myocardial function indices such as left ventricular ejection fraction has been widely studied. However, the effect of this intervention on major adverse cardiovascular events (MACE) was not the principal purpose of most investigations and its role is unclear. The aim of this study was to investigate the possible long-term clinical efficacy of BM-MNCs on MACE after AMI. Methods A comprehensive search was conducted through electronic databases for potentially eligible randomized trials investigating the impact of BM-MNC therapy following acute MI on clinical outcomes. Risk of bias of the eligible studies was assessed using the Cochrane Collaboration’s tool. The effect of treatment was displayed by risk ratio (RR) and its 95% confidence interval (CI) using random-effects model. Results Initial database searching found 1540 records and 23 clinical trials with a total of 2286 participants eligible for meta-analysis. Injection of BM-MNCs was associated with lower risk of composite end points of hospitalization for congestive heart failure (CHF), re-infarction, and cardiac-related mortality (91/1191 vs. 111/812, RR = 0.643, 95% CI = 0.489 to 0.845, p = 0.002). This effect was derived from both reduction of CHF (47/1220 vs. 62/841, RR = 0.568, 95% CI = 0.382 to 0.844, p = 0.005) and re-infarction rate (23/1159 vs. 30/775, RR = 0.583, 95% CI = 0.343 to 0.991, p = 0.046), but not cardiac-related mortality (28/1290 vs. 31/871, RR = 0.722, 95% CI = 0.436 to 1.197, p = 0.207). Conclusion This is the first meta-analysis focused on the cardiovascular outcomes of stem cell therapy after AMI and it revealed that transplantation of BM-MNCs may reduce composite endpoint of hospitalization for CHF, re-infarction, and cardiac related mortality driven mainly by reducing reinfarction and hospitalization for heart failure rates but not cardiovascular mortality. Supplementary Information The online version contains supplementary material available at 10.1186/s12872-022-02701-x.
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Affiliation(s)
- Armin Attar
- Department of Cardiovascular Medicine, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
| | - Alireza Hosseinpour
- Department of Cardiovascular Medicine, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | | | - Asma Kazemi
- Nutrition Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
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12
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Hosseinpour A, Kheshti F, Kazemi A, Attar A. Comparing the effect of bone marrow mono-nuclear cells with mesenchymal stem cells after acute myocardial infarction on improvement of left ventricular function: a meta-analysis of clinical trials. Stem Cell Res Ther 2022; 13:203. [PMID: 35578329 PMCID: PMC9109324 DOI: 10.1186/s13287-022-02883-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Accepted: 05/03/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND The effect of transplantation of bone-marrow mononuclear cells (BM-MNCs) and mesenchymal stem cells (MSCs) on ejection fraction (LVEF) has been studied in patients with acute myocardial infarction (AMI) in clinical trials. This raises the question that which type of cell may help improve LVEF better in AMI patients. No meta-analysis of clinical trials has yet addressed this question. METHODS Electronic databases were searched thoroughly to find eligible trials on the effects of transplantation of BM-MNCs and MSCs in patients with AMI. The primary outcome was improvement in LVEF. Data were synthesized using random-effects meta-analysis. For maximizing the credibility of subgroup analysis, we used the instrument for assessing the Credibility of Effect Modification of Analyses (ICEMAN) for meta-analyses. RESULTS A total of 36 trials (26 on BM-MNCs and 10 on MSCs) with 2489 patients (1466 were transplanted [1241 with BM-MNCs and 225 with MSCs] and 1023 as controls) were included. Both types of cells showed significant improvements in ejection fraction in short-term follow-up (BM-MNCs: WMD = 2.13%, 95% CI = 1.23 to 3.04, p < 0.001; MSCs: WMD = 3.71%, 95% CI = 2.32 to 5.09, p < 0.001), and according to ICEMAN criteria, MSCs are more effective. For selected population of patients who received stem cell transplantation in early course after AMI (less than 11 days), this effect was even more pronounced (BM-MNC: WMD = 3.07%, 95% CI = 1.97 to 4.17, p < 0.001, I2 = 40.7%; MSCs: WMD = 5.65%, 95% CI = 3.47 to 7.84, p < 0.001, I2 = 84.6%). CONCLUSION Our results showed that transplantation of MSCs after AMI might increase LVEF more than BM-MNCs; also, based on ICEMAN, there was likely effect modification between subgroups although uncertainty still remained.
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Affiliation(s)
- Alireza Hosseinpour
- Department of Cardiovascular Medicine, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Fatemeh Kheshti
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Asma Kazemi
- Nutrition Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Armin Attar
- Department of Cardiovascular Medicine, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
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13
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Transplantation of MITO cells, mitochondria activated cardiac progenitor cells, to the ischemic myocardium of mouse enhances the therapeutic effect. Sci Rep 2022; 12:4344. [PMID: 35318358 PMCID: PMC8941106 DOI: 10.1038/s41598-022-08583-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Accepted: 03/10/2022] [Indexed: 12/14/2022] Open
Abstract
Given the potential for myocardial stem cell transplantation as a promising treatment for heart failure, numerous clinical trials have been conducted and its usefulness has been clearly confirmed. However, the low rate of engraftment of transplanted cells has become a clinical problem, and this needs to be improved in the case of transplanting cells to the heart. To address this issue, we report on attempts to prepare mitochondria-activated stem cells (MITO cells) for use in transplantation. MITO cells, which is cardiac progenitor cells (CPCs) activated by the mitochondrial delivery of resveratrol with an anti-oxidant and mitochondrial activation effects were successfully prepared using a mitochondrial targeting nanocarrier (MITO-Porter). The purpose of this study was to validate the therapeutic effect of cell transplantation by the MITO cells using a mouse model of myocardial ischemia–reperfusion. Mouse CPCs were used as transplanted cells. The transplantation of CPCs and MITO cells were conducted after myocardial ischemia–reperfusion, and the therapeutic effect was determined. The MITO cells transplanted group showed increase in postoperative weight gain, improve cardiac function and inhibition of fibrosis compared to the non-transplanted group and the CPC group. The transplantation of MITO cells to the ischemic myocardium showed a stronger transplantation effect compared to conventional CPC transplantation.
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14
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Murata K, Masumoto H. Systems for the functional evaluation of human heart tissues derived from pluripotent stem cells. Stem Cells 2022; 40:537-545. [PMID: 35303744 PMCID: PMC9216506 DOI: 10.1093/stmcls/sxac022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Accepted: 03/06/2022] [Indexed: 11/13/2022]
Abstract
Human pluripotent stem cells (hPSCs) are expected to be a promising cell source in regenerative medicine and drug discovery for the treatment of various intractable diseases. An approach for creating a three-dimensional (3D) structure from hPSCs that mimics human cardiac tissue functions has made it theoretically possible to conduct drug discovery and cardiotoxicity tests by assessing pharmacological responses in human cardiac tissues by a screening system using a compound library. The myocardium functions as a tissue composed of organized vascular networks, supporting stromal cells and cardiac muscle cells. Considering this, the reconstruction of tissue structure by various cells of cardiovascular lineages, such as vascular cells and cardiac muscle cells, is desirable for the ideal conformation of hPSC-derived cardiac tissues. Heart-on-a-chip, an organ-on-a-chip system to evaluate the physiological pump function of 3D cardiac tissues might hold promise in medical researches such as drug discovery and regenerative medicine. Here, we review various modalities to evaluate the function of human stem cell-derived cardiac tissues and introduce heart-on-a-chip systems that can recapitulate physiological parameters of hPSC-derived cardiac tissues.
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Affiliation(s)
- Kozue Murata
- Clinical Translational Research Program, RIKEN Center for Biosystems Dynamics Research, Kobe, Japan.,Department of Cardiovascular Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.,Institute for Advancement of Clinical and Translational Science, Kyoto University Hospital, Kyoto, Japan
| | - Hidetoshi Masumoto
- Clinical Translational Research Program, RIKEN Center for Biosystems Dynamics Research, Kobe, Japan.,Department of Cardiovascular Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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15
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Xu S, Qiu Y, Tao J. The challenges and optimization of cell-based therapy for cardiovascular disease. J Transl Int Med 2021; 9:234-238. [PMID: 35136722 PMCID: PMC8802397 DOI: 10.2478/jtim-2021-0017] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
With the hope of achieving real cardiovascular repair, cell-based therapy raised as a promising strategy for the treatment of cardiovascular disease (CVD) in the past two decades. Various types of cells have been studied for their reparative potential for CVD in the ensuing years. Despite the exciting results from animal experiments, the outcome of clinical trials is unsatisfactory and the development of cell-based therapy for CVD has hit a plateau nowadays. Thus, it is important to summarize the obstacles we are facing in this field in order to explore possible solutions for optimizing cell-based therapy and achieving real clinical application.
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Affiliation(s)
- Shiyue Xu
- Department of Hypertension and Vascular Disease, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou510080, Guangdong Province, China
- Department of Biomedical Engineering, Molecular Cardiology Program, School of Medicine and School of Engineering, University of Alabama at BirminghamBirminghamUnited States
| | - Yumin Qiu
- Department of Hypertension and Vascular Disease, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou510080, Guangdong Province, China
| | - Jun Tao
- Department of Hypertension and Vascular Disease, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou510080, Guangdong Province, China
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16
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Human Induced Pluripotent Stem Cell-Derived Vascular Cells: Recent Progress and Future Directions. J Cardiovasc Dev Dis 2021; 8:jcdd8110148. [PMID: 34821701 PMCID: PMC8622843 DOI: 10.3390/jcdd8110148] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Revised: 11/01/2021] [Accepted: 11/02/2021] [Indexed: 12/12/2022] Open
Abstract
Human induced pluripotent stem cells (hiPSCs) hold great promise for cardiovascular regeneration following ischemic injury. Considerable effort has been made toward the development and optimization of methods to differentiate hiPSCs into vascular cells, such as endothelial and smooth muscle cells (ECs and SMCs). In particular, hiPSC-derived ECs have shown robust potential for promoting neovascularization in animal models of cardiovascular diseases, potentially achieving significant and sustained therapeutic benefits. However, the use of hiPSC-derived SMCs that possess high therapeutic relevance is a relatively new area of investigation, still in the earlier investigational stages. In this review, we first discuss different methodologies to derive vascular cells from hiPSCs with a particular emphasis on the role of key developmental signals. Furthermore, we propose a standardized framework for assessing and defining the EC and SMC identity that might be suitable for inducing tissue repair and regeneration. We then highlight the regenerative effects of hiPSC-derived vascular cells on animal models of myocardial infarction and hindlimb ischemia. Finally, we address several obstacles that need to be overcome to fully implement the use of hiPSC-derived vascular cells for clinical application.
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17
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Evolution of Stem Cells in Cardio-Regenerative Therapy. Stem Cells 2021. [DOI: 10.1007/978-3-030-77052-5_7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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18
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Hess A, Thackeray JT, Wollert KC, Bengel FM. Radionuclide Image-Guided Repair of the Heart. JACC Cardiovasc Imaging 2020; 13:2415-2429. [DOI: 10.1016/j.jcmg.2019.11.007] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Revised: 10/23/2019] [Accepted: 11/05/2019] [Indexed: 01/12/2023]
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19
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Murata K, Ikegawa M, Minatoya K, Masumoto H. Strategies for immune regulation in iPS cell-based cardiac regenerative medicine. Inflamm Regen 2020; 40:36. [PMID: 33005258 PMCID: PMC7523082 DOI: 10.1186/s41232-020-00145-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Accepted: 09/09/2020] [Indexed: 01/14/2023] Open
Abstract
Cardiac regenerative therapy is expected to be a promising therapeutic option for the treatment of severe cardiovascular diseases. Artificial tissues or organoids made from cardiovascular cell lineages differentiated from human induced pluripotent stem cells (iPSCs) are expected to regenerate the damaged heart. Even though immune rejection rarely occurs when iPSC-derived graft and the recipient have the same HLA type, in some cases, such as tissue transplantation onto hearts, the HLA matching would not be sufficient to fully control immune rejection. The present review introduces recent immunomodulatory strategies in iPSC-based transplantation therapies other than MHC matching including the induction of immune tolerance through iPSC-derived antigen-presenting cells, simultaneous transplantation of syngeneic mesenchymal stem cells, and using the universal donor cells such as gene editing-based HLA modulation in iPSCs to regulate T cell compatibility. In addition, we present future perspectives for proper adjustment of immunosuppression therapy after iPSC-derived tissue/organoid-based cardiac regenerative therapies by identifying biomarkers monitoring immune rejection.
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Affiliation(s)
- Kozue Murata
- Clinical Translational Research Program, RIKEN Center for Biosystems Dynamics Research, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047 Japan.,Institute for Advancement of Clinical and Translational Science, Kyoto University Hospital, Kyoto, Japan
| | - Masaya Ikegawa
- Department of Life and Medical Systems, Faculty of Life and Medical Sciences, Doshisha University, Kyoto, Japan
| | - Kenji Minatoya
- Institute for Advancement of Clinical and Translational Science, Kyoto University Hospital, Kyoto, Japan.,Department of Cardiovascular Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Hidetoshi Masumoto
- Clinical Translational Research Program, RIKEN Center for Biosystems Dynamics Research, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047 Japan.,Department of Cardiovascular Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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20
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Poglajen G, Frljak S, Zemljič G, Cerar A, Okrajšek R, Šebeštjen M, Vrtovec B. Stem Cell Therapy for Chronic and Advanced Heart Failure. Curr Heart Fail Rep 2020; 17:261-270. [PMID: 32783146 DOI: 10.1007/s11897-020-00477-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
PURPOSE OF REVIEW The purpose of this review is to discuss recent advances in the field of cell therapy in patients with heart failure with reduced ejection fraction (HFrEF) of ischemic (iCMP) and nonischemic (dCMP) etiology, heart failure with preserved ejection fraction (HFpEF), and in advanced heart failure patients undergoing mechanical circulatory support (LVAD). RECENT FINDINGS In HFrEF patients (iCMP and dCMP cohorts), autologous and/or allogeneic cell therapy was shown to improve myocardial performance, patients' functional capacity, and neurohumoral activation. In HFpEF patient population, the concept of cell therapy in novel and remains largely unexplored. However, initial data are very encouraging and suggest at least a similar benefit in improvements of myocardial performance (also diastolic function of the left ventricle), exercise capacity, and neurohumoral activation. Recently, cell therapy was explored in the sickest population of advanced heart failure patients undergoing LVAD support also showing a potential benefit in promoting myocardial reverse remodeling and recovery. In the past decade, several cell therapy-based clinical trials showed promising results in various chronic and advanced heart failure patient cohorts. Future cell treatment strategies should aim for more personalized therapeutic approaches by defining optimal stem cell type or their combination, dose, and delivery method for an individual patient adjusted for patient's age and stage/duration of heart failure.
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Affiliation(s)
- Gregor Poglajen
- Department of Cardiology, Advanced Heart Failure and Transplantation Center, University Medical Center Ljubljana, Zaloška cesta 7, 1000, Ljubljana, Slovenia. .,Medical Faculty, University of Ljubljana, Ljubljana, Slovenia.
| | - Sabina Frljak
- Department of Cardiology, Advanced Heart Failure and Transplantation Center, University Medical Center Ljubljana, Zaloška cesta 7, 1000, Ljubljana, Slovenia
| | - Gregor Zemljič
- Department of Cardiology, Advanced Heart Failure and Transplantation Center, University Medical Center Ljubljana, Zaloška cesta 7, 1000, Ljubljana, Slovenia
| | - Andraž Cerar
- Department of Cardiology, Advanced Heart Failure and Transplantation Center, University Medical Center Ljubljana, Zaloška cesta 7, 1000, Ljubljana, Slovenia
| | - Renata Okrajšek
- Department of Cardiology, Advanced Heart Failure and Transplantation Center, University Medical Center Ljubljana, Zaloška cesta 7, 1000, Ljubljana, Slovenia
| | - Miran Šebeštjen
- Department of Cardiology, Advanced Heart Failure and Transplantation Center, University Medical Center Ljubljana, Zaloška cesta 7, 1000, Ljubljana, Slovenia
| | - Bojan Vrtovec
- Department of Cardiology, Advanced Heart Failure and Transplantation Center, University Medical Center Ljubljana, Zaloška cesta 7, 1000, Ljubljana, Slovenia.,Medical Faculty, University of Ljubljana, Ljubljana, Slovenia
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21
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Turner D, Rieger AC, Balkan W, Hare JM. Clinical-based Cell Therapies for Heart Disease-Current and Future State. Rambam Maimonides Med J 2020; 11:RMMJ.10401. [PMID: 32374254 PMCID: PMC7202446 DOI: 10.5041/rmmj.10401] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Patients have an ongoing unmet need for effective therapies that reverse the cellular and functional damage associated with heart damage and disease. The discovery that ~1%-2% of adult cardiomyocytes turn over per year provided the impetus for treatments that stimulate endogenous repair mechanisms that augment this rate. Preclinical and clinical studies provide evidence that cell-based therapy meets these therapeutic criteria. Recent and ongoing studies are focused on determining which cell type(s) works best for specific patient population(s) and the mechanism(s) by which these cells promote repair. Here we review clinical and preclinical stem cell studies and anticipate future directions of regenerative medicine for heart disease.
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Affiliation(s)
- Darren Turner
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Angela C. Rieger
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Wayne Balkan
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida, USA
- Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Joshua M. Hare
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida, USA
- Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA
- To whom correspondence should be addressed. E-mail:
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22
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Li J, Hu S, Cheng K. Engineering better stem cell therapies for treating heart diseases. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:569. [PMID: 32775370 PMCID: PMC7347786 DOI: 10.21037/atm.2020.03.44] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
For decades, stem cells and their byproducts have shown efficacy in repairing tissues and organs in numerous pre-clinical studies and some clinical trials, providing hope for possible cures for many important diseases. However, the translation of stem cell therapy for heart diseases from bench to bed is still hampered by several limitations. The therapeutic benefits of stem cells are mediated by a combo of mechanisms. In this review, we will provide a brief summary of stem cell therapies for ischemic heart disease. Basically, we will talk about these barriers for the clinical application of stem cell-based therapies, the investigation of mechanisms behind stem-cell based cardiac regeneration and also, what bioengineers can do and have been doing on the translational stage of stem cell therapies for heart repair.
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Affiliation(s)
- Junlang Li
- Department of Molecular Biomedical Sciences, North Carolina State University, Raleigh, NC, USA.,Joint Department of Biomedical Engineering, North Carolina State University & University of North Carolina at Chapel Hill, Raleigh, NC, USA
| | - Shiqi Hu
- Department of Molecular Biomedical Sciences, North Carolina State University, Raleigh, NC, USA.,Joint Department of Biomedical Engineering, North Carolina State University & University of North Carolina at Chapel Hill, Raleigh, NC, USA
| | - Ke Cheng
- Department of Molecular Biomedical Sciences, North Carolina State University, Raleigh, NC, USA.,Joint Department of Biomedical Engineering, North Carolina State University & University of North Carolina at Chapel Hill, Raleigh, NC, USA
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23
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Chan JL, Miller JG, Zhou Y, Robey PG, Stroncek DF, Arai AE, Sachdev V, Horvath KA. Intramyocardial Bone Marrow Stem Cells in Patients Undergoing Cardiac Surgical Revascularization. Ann Thorac Surg 2020; 109:1142-1149. [PMID: 31526779 PMCID: PMC8045460 DOI: 10.1016/j.athoracsur.2019.07.093] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2019] [Revised: 07/04/2019] [Accepted: 07/29/2019] [Indexed: 01/14/2023]
Abstract
BACKGROUND Bone marrow stromal or stem cells (BMSCs) remain a promising potential therapy for ischemic cardiomyopathy. The primary objective of this study was to evaluate the safety and feasibility of direct intramyocardial injection of autologous BMSCs in patients undergoing transmyocardial revascularization (TMR) or coronary artery bypass graft surgery (CABG). METHODS A phase I trial was conducted on adult patients who had ischemic heart disease with depressed left ventricular ejection fraction and who were scheduled to undergo TMR or CABG. Autologous BMSCs were expanded for 3 weeks before the scheduled surgery. After completion of surgical revascularization, BMSCs were directly injected into ischemic myocardium. Safety and feasibility of therapy were assessed. Cardiac functional status and changes in quality of life were evaluated at 1 year. RESULTS A total of 14 patients underwent simultaneous BMSC and surgical revascularization therapy (TMR+BMSCs = 10; CABG+BMSCs = 4). BMSCs were successfully expanded, and no significant complications occurred as a result of the procedure. Regional contractility in the cell-treated areas demonstrated improvement at 12 months compared with baseline (TMR+BMSCs Δ strain: -4.6% ± 2.1%; P = .02; CABG+MSCs Δ strain: -4.2% ± 6.0%; P = .30). Quality of life was enhanced, with substantial reduction in angina scores at 1 year after treatment (TMR+BMSCs: 1.3 ± 1.2; CABG+MSCs: 1.0 ± 1.4). CONCLUSIONS In this phase I trial, direct intramyocardial injection of autologous BMSCs in conjunction with TMR or CABG was technically feasible and could be performed safely. Preliminary results demonstrate improved cardiac function and quality of life in patients at 1 year after treatment.
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Affiliation(s)
- Joshua L Chan
- Cardiothoracic Surgery Research Program, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland
| | - Justin G Miller
- Cardiothoracic Surgery Research Program, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland
| | - Yifu Zhou
- Cardiothoracic Surgery Research Program, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland
| | - Pamela G Robey
- NIH Bone Marrow Stromal Cell Transplantation Center, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland
| | - David F Stroncek
- Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland
| | - Andrew E Arai
- Advanced Cardiovascular Imaging Group, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland
| | - Vandana Sachdev
- Echocardiography Laboratory, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland
| | - Keith A Horvath
- Cardiothoracic Surgery Research Program, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland.
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24
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Yang D, O’Brien CG, Ikeda G, Traverse JH, Taylor DA, Henry TD, Bolli R, Yang PC. Meta-analysis of short- and long-term efficacy of mononuclear cell transplantation in patients with myocardial infarction. Am Heart J 2020; 220:155-175. [PMID: 31821904 PMCID: PMC7173405 DOI: 10.1016/j.ahj.2019.09.005] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Accepted: 09/04/2019] [Indexed: 01/18/2023]
Abstract
BACKGROUND Mononuclear cells (MNCs) have been tested in clinical trials across multiple cardiovascular pathologies with mixed results. Major adverse cardiac events (MACE) and markers of cardiovascular capacity have been particularly challenging to interpret because of small size. This meta-analysis is aimed to assess the efficacy of MNC therapy in randomized clinical trials to identify the markers of efficiency that could influence future trial design. METHODS PubMed, Embase, Cochrane library, and ClinicalTrials.gov were searched from inception through November 8, 2018. Changes in left ventricular ejection fraction (LVEF) and infarct size from baseline to follow-up were selected as primary outcomes. Changes in the left ventricular end-systolic volume, left ventricular end-diastolic volume, brain natriuretic peptide/N-terminal pro-B-type natriuretic peptide, 6-minute walk test, New York Heart Association class, and MACE incidences were considered secondary outcomes. RESULTS In short-term follow-up, patients treated with MNCs demonstrated a significant increase in absolute LVEF of 2.21% (95% CI 1.59-2.83; P < .001; I2 = 32%) and 6.01% (95% CI 4.45-7.57; P < .001; I2 = 0%) in acute myocardial infarction (AMI) and ischemic cardiomyopathy studies, respectively. This effect was sustained in long-term follow-up. MNC therapy significantly reduced left ventricular end-systolic volume; however, infarct size, 6-minute walk test, New York Heart Association class, and MACE rates were comparable. CONCLUSIONS MNC therapy may convey a modest but sustained increase in LVEF in ischemic cardiomyopathy patients, supporting further investigation. AMI trials, however, demonstrated minimal improvement in LVEF of unclear clinical significance, suggesting a limited role for MNC therapy in AMI.
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Affiliation(s)
- Dan Yang
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, China,Division of Cardiovascular Medicine, Department of Medicine, and Cardiovascular Institute, Stanford University School of Medicine, CA94305, USA
| | - Connor Galen O’Brien
- Division of Cardiovascular Medicine, Department of Medicine, and Cardiovascular Institute, Stanford University School of Medicine, CA94305, USA
| | - Gentaro Ikeda
- Division of Cardiovascular Medicine, Department of Medicine, and Cardiovascular Institute, Stanford University School of Medicine, CA94305, USA
| | - Jay H. Traverse
- Minneapolis Heart Institute Foundation, Abbott Northwestern Hospital, Minneapolis, MN55407, USA
| | - Doris A. Taylor
- Regenerative Medicine Research, Texas Heart Institute, PO Box 20345, Houston, TX 77225-0345 USA
| | - Timothy D. Henry
- The Carl and Edyth Lindner Center for Research and Education, The Christ Hospital Health Network, Cincinnati, OH45219, USA
| | - Roberto Bolli
- Institute of Molecular Cardiology, University of Louisville, KY40202, USA
| | - Phillip C. Yang
- Division of Cardiovascular Medicine, Department of Medicine, and Cardiovascular Institute, Stanford University School of Medicine, CA94305, USA
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Anti-CD3 Antibody Treatment Reduces Scar Formation in a Rat Model of Myocardial Infarction. Cells 2020; 9:cells9020295. [PMID: 31991811 PMCID: PMC7072364 DOI: 10.3390/cells9020295] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Revised: 01/18/2020] [Accepted: 01/21/2020] [Indexed: 02/07/2023] Open
Abstract
Introduction: Antibody treatment with anti-thymocyte globulin (ATG) has been shown to be cardioprotective. We aimed to evaluate which single anti-T-cell epitope antibody alters chemokine expression at a level similar to ATG and identified CD3, which is a T-cell co-receptor mediating T-cell activation. Based on these results, the effects of anti-CD3 antibody treatment on angiogenesis and cardioprotection were tested in vitro and in vivo. Methods: Concentrations of IL-8 and MCP-1 in supernatants of human peripheral blood mononuclear cell (PBMC) cultures following distinct antibody treatments were evaluated by Enzyme-linked Immunosorbent Assay (ELISA). In vivo, anti-CD3 antibodies or vehicle were injected intravenously in rats subjected to acute myocardial infarction (AMI). Chemotaxis and angiogenesis were evaluated using tube and migration assays. Intracellular pathways were assessed using Western blot. Extracellular vesicles (EVs) were quantitatively evaluated using fluorescence-activated cell scanning, exoELISA, and nanoparticle tracking analysis. Also, microRNA profiles were determined by next-generation sequencing. Results: Only PBMC stimulation with anti-CD3 antibody led to IL-8 and MCP-1 changes in secretion, similar to ATG. In a rat model of AMI, systemic treatment with an anti-CD3 antibody markedly reduced infarct scar size (27.8% (Inter-quartile range; IQR 16.2–34.9) vs. 12.6% (IQR 8.3–27.2); p < 0.01). The secretomes of anti-CD3 treated PBMC neither induced cardioprotective pathways in cardiomyocytes nor pro-angiogenic mechanisms in human umbilical vein endothelial cell (HUVECs) in vitro. While EVs quantities remained unchanged, PBMC incubation with an anti-CD3 antibody led to alterations in EVs miRNA expression. Conclusion: Treatment with an anti-CD3 antibody led to decreased scar size in a rat model of AMI. Whereas cardioprotective and pro-angiogenetic pathways were unaltered by anti-CD3 treatment, qualitative changes in the EVs miRNA expression could be observed, which might be causal for the observed cardioprotective phenotype. We provide evidence that EVs are a potential cardioprotective treatment target. Our findings will also provide the basis for a more detailed analysis of putatively relevant miRNA candidates.
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Żak MM, Gkontra P, Clemente C, Squadrito ML, Ferrarini A, Mota RA, Oliver E, Rocha S, Agüero J, Vázquez J, De Palma M, Ibáñez B, Arroyo AG. Sequential Bone-Marrow Cell Delivery of VEGFA/S1P Improves Vascularization and Limits Adverse Cardiac Remodeling After Myocardial Infarction in Mice. Hum Gene Ther 2019; 30:893-905. [DOI: 10.1089/hum.2018.194] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Affiliation(s)
- Magdalena M. Żak
- Vascular Pathophysiology Area, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
| | - Polyxeni Gkontra
- Vascular Pathophysiology Area, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
| | - Cristina Clemente
- Vascular Pathophysiology Area, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
| | - Mario Leonardo Squadrito
- École Polytechnique Federale de Lausanne (EPFL), ISREC-Swiss Institute for Experimental Cancer Research, Lausanne, Switzerland
| | - Alessia Ferrarini
- Proteomics Unit, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
| | - Rubén A. Mota
- Animal Facility, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
| | - Eduardo Oliver
- Myocardial Pathology Area, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
| | - Susana Rocha
- Vascular Pathophysiology Area, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
| | - Jaume Agüero
- Myocardial Pathology Area, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
- CIBER-CV, Madrid, Spain
| | - Jesús Vázquez
- Proteomics Unit, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
- CIBER-CV, Madrid, Spain
| | - Michele De Palma
- École Polytechnique Federale de Lausanne (EPFL), ISREC-Swiss Institute for Experimental Cancer Research, Lausanne, Switzerland
| | - Borja Ibáñez
- Myocardial Pathology Area, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
- CIBER-CV, Madrid, Spain
| | - Alicia G. Arroyo
- Vascular Pathophysiology Area, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
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Di Stefano AB, Massihnia D, Grisafi F, Castiglia M, Toia F, Montesano L, Russo A, Moschella F, Cordova A. Adipose tissue, angiogenesis and angio-MIR under physiological and pathological conditions. Eur J Cell Biol 2019; 98:53-64. [DOI: 10.1016/j.ejcb.2018.11.005] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2018] [Revised: 11/28/2018] [Accepted: 11/29/2018] [Indexed: 01/06/2023] Open
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Huang B, Huang LF, Zhao L, Zeng Z, Wang X, Cao D, Yang L, Ye Z, Chen X, Liu B, He TC, Wang X. Microvesicles (MIVs) secreted from adipose-derived stem cells (ADSCs) contain multiple microRNAs and promote the migration and invasion of endothelial cells. Genes Dis 2019; 7:225-234. [PMID: 32215292 PMCID: PMC7083715 DOI: 10.1016/j.gendis.2019.04.005] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2019] [Accepted: 04/11/2019] [Indexed: 12/14/2022] Open
Abstract
Extracellular vesicles (EVs) such as microvesicles (MIVs) play an important role in intercellular communications. MIVs are small membrane vesicles sized 100–1000 nm in diameter that are released by many types of cells, such as mesenchymal stem cells (MSCs), tumor cells and adipose-derived stem cells (ADSC). As EVs can carry out autocrine and paracrine functions by controlling multiple cell processes, it is conceivable that EVs can be used as delivery vehicles for treating several clinical conditions, such as to improve cardiac angiogenesis after myocardial infarction (MI). Here, we seek to investigate whether ADSC-derived MIVs contain microRNAs that regulate angiogenesis and affect cell migration of endothelial cells. We first characterized the ADSC-derived MIVs and found that the MIVs had a size range of 100–300 nm, and expressed the MIV marker protein Alix. We then analyzed the microRNAs in ADSCs and ADSC-derived MIVs and demonstrated that ADSC-derived MIVs selectively released a panel of microRNAs, several of which were related to angiogenesis, including two members of the let-7 family. Furthermore, we demonstrated that ADSC-derived MIVs promoted the cell migration and invasion of the HUVEC endothelial cells. The PKH26-labeled ADSC-derived MIVs were effectively uptaken into the cytoplasm of HUVEC cells. Collectively, our results demonstrate that the ADSC-derived MIVs can promote migration and invasion abilities of endothelial cells, suggesting pro-angiogenetic potential. Future studies should focus on investigating the roles and mechanisms through which ADSC-derived MIVs regulate angiogenesis.
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Affiliation(s)
- Bo Huang
- Ministry of Education Key Laboratory of Diagnostic Medicine and School of Laboratory Medicine, and The Affiliated Hospitals of Chongqing Medical University, Chongqing Medical University, Chongqing, 400016, China.,Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL, 60637, USA.,Department of Clinical Laboratory Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, China
| | - Lin-Feng Huang
- Department of Clinical Laboratory Medicine, Jiangxi Maternal and Child Health Hospital, Nanchang, 330006, China
| | - Ling Zhao
- Ministry of Education Key Laboratory of Diagnostic Medicine and School of Laboratory Medicine, and The Affiliated Hospitals of Chongqing Medical University, Chongqing Medical University, Chongqing, 400016, China.,Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL, 60637, USA
| | - Zongyue Zeng
- Ministry of Education Key Laboratory of Diagnostic Medicine and School of Laboratory Medicine, and The Affiliated Hospitals of Chongqing Medical University, Chongqing Medical University, Chongqing, 400016, China.,Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL, 60637, USA
| | - Xi Wang
- Ministry of Education Key Laboratory of Diagnostic Medicine and School of Laboratory Medicine, and The Affiliated Hospitals of Chongqing Medical University, Chongqing Medical University, Chongqing, 400016, China.,Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL, 60637, USA
| | - Daigui Cao
- Ministry of Education Key Laboratory of Diagnostic Medicine and School of Laboratory Medicine, and The Affiliated Hospitals of Chongqing Medical University, Chongqing Medical University, Chongqing, 400016, China.,Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL, 60637, USA.,Department of Orthopaedic Surgery, Chongqing General Hospital Affiliated with the University of Chinese Academy of Sciences, Chongqing, 400013, China
| | - Lijuan Yang
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL, 60637, USA.,Department of Obstetrics and Gynecology, The First Hospital of Lanzhou University, Lanzhou, 730030, China
| | - Zhenyu Ye
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL, 60637, USA.,Department of General Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, China
| | - Xian Chen
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL, 60637, USA.,Department of Clinical Laboratory Medicine, The Affiliated Hospital of Qingdao University, Qingdao, 266061, China
| | - Bin Liu
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL, 60637, USA.,Department of Biology, School of Life Sciences, Southwest University, Chongqing, 400715, China
| | - Tong-Chuan He
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL, 60637, USA
| | - Xiaozhong Wang
- Department of Clinical Laboratory Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, China
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Li X, Xie X, Yu Z, Chen Y, Qu G, Yu H, Luo B, Lei Y, Li Y. Bone marrow mesenchymal stem cells-derived conditioned medium protects cardiomyocytes from hypoxia/reoxygenation-induced injury through Notch2/mTOR/autophagy signaling. J Cell Physiol 2019; 234:18906-18916. [PMID: 30953350 DOI: 10.1002/jcp.28530] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2018] [Revised: 02/15/2019] [Accepted: 02/19/2019] [Indexed: 12/20/2022]
Abstract
Bone marrow mesenchymal stem cells (BMSC) can ameliorate ischemic injury of various tissues. However, the molecular mechanisms involved remain to be clarified. In this study, we intend to investigate the effects of BMSC-derived conditioned medium (BMSC-CM) on hypoxia/reoxygenation (H/R)-induced injury of H9c2 myocardial cells, and the potential mechanisms. Cell injury was determined through level of cell viability, lactate dehydrogenase (LDH) release, total intracellular reactive oxygen species (ROS), mitochondrial membrane potential (Δψm), and cell apoptosis. Autophagic activity of cells was detected through levels of the autophagy-associated proteins and autophagic flux. Results showed that BMSC-CM alleviated H/R-induced injury in H9c2 cells, as demonstrated by increased cell viability and Δψm, decreased ROS production, LDH release, and cell apoptosis. Furthermore, the H/R treatment induced a decrease in autophagic activity and an increase in Notch2 signaling activation in H9c2 cells. In the presence of BMSC-CM, the autophagic activity impaired by the H/R treatment was upregulated with decreased phosphorylation of mTOR, and the activation of Notch2 signaling was downregulated. These effects of BMSC-CM could be replicated by Notch signaling inhibitor. In contrast, inhibitors of cell autophagy including chloroquine (CQ) and 3-methyladenine, diminished the protective effects of BMSC-CM. Taken together results, our study showed that BMSC-CM could protect H9c2 cells from H/R-induced injury potentially through regulating Notch2/mTOR/autophagy signaling. These findings may provide a novel insight into the mechanisms of BMSC-CM in therapy of myocardial ischemia/reperfusion injury as well as other ischemic diseases.
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Affiliation(s)
- Xianyu Li
- Department of Pathophysiology & Hubei Province Key Laboratory of Allergy and Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, China.,Department of Pathophysiology, School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, China
| | - Xiaolin Xie
- Department of Pathophysiology & Hubei Province Key Laboratory of Allergy and Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Zhui Yu
- Department of Critical Care Medicine, Renmin Hospital, Wuhan University, Wuhan, China
| | - Yun Chen
- Department of Pathophysiology & Hubei Province Key Laboratory of Allergy and Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Gaojing Qu
- Department of Pathophysiology & Hubei Province Key Laboratory of Allergy and Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Han Yu
- Department of Pathophysiology & Hubei Province Key Laboratory of Allergy and Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Bin Luo
- Department of Pathophysiology & Hubei Province Key Laboratory of Allergy and Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Yifeng Lei
- The Institute of Technological Sciences & School of Power and Mechanical Engineering, Wuhan University, Wuhan, China
| | - Yinping Li
- Department of Pathophysiology & Hubei Province Key Laboratory of Allergy and Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, China
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Cardioprotective microRNAs: Lessons from stem cell-derived exosomal microRNAs to treat cardiovascular disease. Atherosclerosis 2019; 285:1-9. [PMID: 30939341 DOI: 10.1016/j.atherosclerosis.2019.03.016] [Citation(s) in RCA: 157] [Impact Index Per Article: 26.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2019] [Revised: 02/28/2019] [Accepted: 03/21/2019] [Indexed: 12/20/2022]
Abstract
The stem cell-based therapy has emerged as a promising therapeutic strategy for treating cardiovascular ischemic diseases (CVIDs), such as myocardial infarction (MI). However, some important functional shortcomings of stem cell transplantation, such as immune rejection, tumorigenicity and infusional toxicity, have overshadowed stem cell therapy in the setting of cardiovascular diseases (CVDs). Accumulating evidence suggests that the therapeutic effects of transplanted stem cells are predominately mediated by secreting paracrine factors, importantly, microRNAs (miRs) present in the secreted exosomes. Therefore, novel cell-free therapy based on the stem cell-secreted exosomal miRs can be considered as a safe and effective alternative tool to stem cell therapy for the treatment of CVDs. Stem cell-derived miRs have recently been found to transfer, via exosomes, from a transplanted stem cell into a recipient cardiac cell, where they regulate various cellular process, such as proliferation, apoptosis, stress responses, as well as differentiation and angiogenesis. The present review aimed to summarize cardioprotective exosomal miRs secreted by transplanted stem cells from various sources, including embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), mesenchymal stem cells (MSCs), and cardiac stem/progenitor cells, which showed beneficial modulatory effects on the myocardial infracted heart. In summary, stem cell-exosomal miRs, including miR-19a, mirR-21, miR-21-5p, miR-21-a5p, miR-22 miR-24, miR-26a, miR-29, miR-125b-5p, miR-126, miR-201, miR-210, and miR-294, have been shown to have cardioprotective effects by enhancing cardiomyocyte survival and function and attenuating cardiac fibrosis. Additionally, MCS-exosomal miRs, including miR-126, miR-210, miR-21, miR-23a-3p and miR-130a-3p, are found to exert cardioprotective effects through induction of angiogenesis in ischemic heart after MI.
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Mahara A, Kobayashi N, Hirano Y, Yamaoka T. Sonoporation-based labeling of mesenchymal stem cells with polymeric MRI contrast agents for live-cell tracking. Polym J 2019. [DOI: 10.1038/s41428-019-0177-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
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Liu YW, Fang YH, Su CT, Hwang SM, Liu PY, Wu SN. The biochemical and electrophysiological profiles of amniotic fluid-derived stem cells following Wnt signaling modulation cardiac differentiation. Cell Death Discov 2019; 5:59. [PMID: 30701091 PMCID: PMC6349909 DOI: 10.1038/s41420-019-0143-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2018] [Revised: 12/31/2018] [Accepted: 01/08/2019] [Indexed: 12/12/2022] Open
Abstract
Owing to the beneficial properties of amniotic fluid-derived stem cells (AFSCs), including pluripotency and the lack of ethical issues associated with embryonic stem cells (ESCs), they should be a promising cell source for regenerative medicine. However, how to differentiate AFSCs into contracting cardiomyocytes has not been established. In this study, a well-established, direct cardiac differentiation protocol involving the modulation of Wnt signaling was used to differentiate Oct 3/4+ AFSCs into cardiomyocytes. By day 14 of cardiomyocyte differentiation, these AFSCs expressed cardiac-specific genes (i.e., cardiac troponin T and myosin light chain 2v) and proteins but could not spontaneously contract. Using the patch-clamp technique, we further characterized the electrophysiological properties of human ESC-derived cardiomyocytes (hESC-CMs) and differentiated AFSCs. We used different configurations to investigate membrane potentials and ion currents in differentiated AFSCs and hESC-CMs. Under cell-attached voltage- or whole-cell current-clamp modes, we recorded spontaneous action currents (ACs) or action potentials (APs) in hESC-CMs but not in differentiated AFSCs. Compared to hESC-CMs, differentiated AFSCs showed significantly diminished activity of both BKCa and IKCa channels, which might lead to a lack of spontaneous ACs and APs in differentiated AFSCs. These results indicated that this well-established Wnt signaling modulating cardiac differentiation protocol was insufficient to induce the differentiation of functional cardiomyocytes from Oct 3/4+ AFSCs. Therefore, AFSC may not be an ideal candidate for cardiomyocyte differentiation.
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Affiliation(s)
- Yen-Wen Liu
- Division of Cardiology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, 138 Sheng-Li Rd. North District, Tainan, 70403 Taiwan
- Institute of Clinical Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Yi-Hsein Fang
- Institute of Clinical Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chi-Ting Su
- Division of Nephrology, Department of Internal Medicine, National Taiwan University Hospital, Yun-Lin Branch, Yun-Lin, Taiwan
| | - Shiaw-Min Hwang
- Bioresource Collection and Research Center, Food Industry Research and Development Institute, Hsinchu, Taiwan
| | - Ping-Yen Liu
- Division of Cardiology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, 138 Sheng-Li Rd. North District, Tainan, 70403 Taiwan
- Institute of Clinical Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Sheng-Nan Wu
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, 1 University Rd, East District, Tainan, Taiwan
- Department of Physiology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
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Qi Z, Liu S, Duan F. Effects of bone marrow mononuclear cells delivered through a graft vessel in patients with previous myocardial infarction and chronic heart failure: An echocardiographic study of left ventricular dyssynchrony. JOURNAL OF CLINICAL ULTRASOUND : JCU 2018; 46:512-518. [PMID: 30160313 DOI: 10.1002/jcu.22609] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/02/2018] [Revised: 04/28/2018] [Accepted: 05/13/2018] [Indexed: 06/08/2023]
Abstract
OBJECTIVES Several trials are investigating the delivery of stem cells to treat ischemic cardiomyopathy. The aim of this study was the echocardiographic evaluation of the effectiveness of isolated coronary artery bypass graft (CABG) combined with bone marrow mononuclear cells (BMMNC) delivered through the graft vessels to improve left ventricular dyssynchrony in patients with previous myocardial infarction and chronic heart failure. METHODS 42 patients with previous myocardial infarction and chronic heart failure were randomly allocated to either the CABG only group (n = 18) or the CABG with BMMNC graft group (n = 24group). We used 2D strain imaging to measure the absolute difference in time-to-peak radial strain between the earliest and the latest activated segments on LV short-axis images at the apical (RSTa), at the mitral annulus (RSTb), and at the papillary muscle (RSTm) level. RESULTS The effective rate of LV dyssynchrony improvement was significantly higher in the CABG + BMMNC than in the CABG only group (RSTb: 91.7% vs 50%, P < .05; RSTm: 78.6% vs 35.7%, P < .05; RSTa: 92.3% vs 50%, P < .05). The deterioration rate of LV synchrony was significantly lower in the CABG + BMMNC than in the CABG only group for RSTb (8.3% vs 70%, P < .05;) and RSTm (0 vs 50%, P < .05), but not for RSTa (18.2% vs 37.5%, P > .05). CONCLUSIONS Combining CABG with BMMNC delivering provided a better improvement of left ventricular dyssynchrony than CABG only.
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Affiliation(s)
- Zhi Qi
- The Department of Ultrasound, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Sheng Liu
- The Department of Cardiovascular Surgery, Fuwai Hospital & Cardiovascular Institute, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences & Tsinghua University, Peking Union Medical College, Beijing, China
| | - Fujian Duan
- Department of Echocardiography, Fuwai Hospital & Cardiovascular Institute, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences & Tsinghua University, Peking Union Medical College, Beijing
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Jara Avaca M, Gruh I. Bioengineered Cardiac Tissue Based on Human Stem Cells for Clinical Application. ADVANCES IN BIOCHEMICAL ENGINEERING/BIOTECHNOLOGY 2018; 163:117-146. [PMID: 29218360 DOI: 10.1007/10_2017_24] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Engineered cardiac tissue might enable novel therapeutic strategies for the human heart in a number of acquired and congenital diseases. With recent advances in stem cell technologies, namely the availability of pluripotent stem cells, the generation of potentially autologous tissue grafts has become a realistic option. Nevertheless, a number of limitations still have to be addressed before clinical application of engineered cardiac tissue based on human stem cells can be realized. We summarize current progress and pending challenges regarding the optimal cell source, cardiomyogenic lineage specification, purification, safety of genetic cell engineering, and genomic stability. Cardiac cells should be combined with clinical grade scaffold materials for generation of functional myocardial tissue in vitro. Scale-up to clinically relevant dimensions is mandatory, and tissue vascularization is most probably required both for preclinical in vivo testing in suitable large animal models and for clinical application. Graphical Abstract.
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Affiliation(s)
- Monica Jara Avaca
- Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Department for Cardiothoracic, Vascular and Transplantation Surgery (HTTG), Hannover Medical School (MHH) & Cluster of Excellence REBIRTH, Hannover, Germany
| | - Ina Gruh
- Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Department for Cardiothoracic, Vascular and Transplantation Surgery (HTTG), Hannover Medical School (MHH) & Cluster of Excellence REBIRTH, Hannover, Germany.
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Dolati S, Yousefi M, Mahdipour M, Afrasiabi Rad A, Pishgahi A, Nouri M, Jodati AR. Mesenchymal stem cell and bone marrow mononuclear cell therapy for cardiomyopathy: From bench to bedside. J Cell Biochem 2018; 120:45-55. [DOI: 10.1002/jcb.27531] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Accepted: 08/01/2018] [Indexed: 12/19/2022]
Affiliation(s)
- Sanam Dolati
- Aging Research Institute, Tabriz University of Medical Sciences Tabriz Iran
- Drug Applied Research Center, Tabriz University of Medical Sciences Tabriz Iran
- Student’s Research Committee, Tabriz University of Medical Sciences Tabriz Iran
| | - Mehdi Yousefi
- Drug Applied Research Center, Tabriz University of Medical Sciences Tabriz Iran
- Stem Cell Research Center, Tabriz University of Medical Sciences Tabriz Iran
- Department of Immunology Tabriz University of Medical Sciences Tabriz Iran
| | - Mahdi Mahdipour
- Stem Cell Research Center, Tabriz University of Medical Sciences Tabriz Iran
- Department of Reproductive Biology Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences Tabriz Iran
| | - Abbas Afrasiabi Rad
- Cardiovascular Research Center, Tabriz University of Medical Sciences Tabriz Iran
- Department of Cardiac Surgery Tabriz University of Medical Tabriz Iran
| | - Alireza Pishgahi
- Department of Physical Medicine and Rehabilitation Physical Medicine and Rehabilitation Research Center, Tabriz University of Medical Science Tabriz Iran
| | - Mohammad Nouri
- Stem Cell Research Center, Tabriz University of Medical Sciences Tabriz Iran
- Department of Reproductive Biology Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences Tabriz Iran
| | - Ahmad Reza Jodati
- Cardiovascular Research Center, Tabriz University of Medical Sciences Tabriz Iran
- Department of Cardiac Surgery Tabriz University of Medical Tabriz Iran
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Mak WC, Magne B, Cheung KY, Atanasova D, Griffith M. Thermo-rheological responsive microcapsules for time-dependent controlled release of human mesenchymal stromal cells. Biomater Sci 2018; 5:2241-2250. [PMID: 28972602 DOI: 10.1039/c7bm00663b] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Human mesenchymal stromal cells (hMSCs) are adult-source cells that have been extensively evaluated for cell-based therapies. hMSCs delivered by intravascular injection have been reported to accumulate at the sites of injury to promote tissue repair and can also be employed as vectors for the delivery of therapeutic genes. However, the full potential of hMSCs remains limited as the cells are lost after injection due to anoikis and the adverse pathologic environment. Encapsulation of cells has been proposed as a means of increasing cell viability. However, controlling the release of therapeutic cells over time to target tissue still remains a challenge today. Here, we report the design and development of thermo-rheological responsive hydrogels that allow for precise, time dependent controlled-release of hMSCs. The encapsulated hMSCs retained good viability from 76% to 87% dependent upon the hydrogel compositions. We demonstrated the design of different blended hydrogel composites with modulated strength (S parameter) and looseness of hydrogel networks (N parameter) to control the release of hMSCs from thermo-responsive hydrogel capsules. We further showed the feasibility for controlled-release of encapsulated hMSCs within 3D matrix scaffolds. We reported for the first time by a systematic analysis that there is a direct correlation between the thermo-rheological properties associated with the degradation of the hydrogel composite and the cell release kinetics. This work therefore provides new insights into the further development of smart carrier systems for stem cell therapy.
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Affiliation(s)
- W C Mak
- Department of Clinical and Experimental Medicine, Linköping University, SE58185, Linköping, Sweden.
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Baeza Garzón F, Pan Álvarez-Ossorio M, Romero Moreno MÁ, Martín Palanco V, Herrera Arroyo C, Suárez de Lezo Cruz Conde J. Reserva coronaria y función ventricular izquierda tras la terapia regenerativa en pacientes con infarto anterior agudo revascularizado. Rev Esp Cardiol (Engl Ed) 2018. [DOI: 10.1016/j.recesp.2017.07.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
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Abstract
Despite considerable advances in medicine, cardiovascular disease is still rising, with ischemic heart disease being the leading cause of death and disability worldwide. Thus extensive efforts are continuing to establish effective therapeutic modalities that would improve both quality of life and survival in this patient population. Novel therapies are being investigated not only to protect the myocardium against ischemia-reperfusion injury but also to regenerate the heart. Stem cell therapy, such as potential use of human mesenchymal stem cells and induced pluripotent stem cells and their exosomes, will make it possible not only to address molecular mechanisms of cardiac conditioning, but also to develop new therapies for ischemic heart disease. Despite the studies and progress made over the last 15 years on the use of stem cell therapy for cardiovascular disease, the efforts are still in their infancy. Even though the expectations have been high, the findings indicate that most of the clinical trials generally have been small and the results inconclusive. Because of many negative findings, there is certain pessimism that cardiac cell therapy is likely to yield any meaningful results over the next decade or so. Similar to other new technologies, early failures are not unusual and they may be followed by impressive success. Nevertheless, there has been considerable attention to safety by the clinical investigators because the adverse events of stem cell therapy have been impressively rare. In summary, although regenerative biology might not help the cardiovascular patient in the near term, it is destined to do so over the next several decades.
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Affiliation(s)
- Maia Terashvili
- Department of Physiology, Medical College of Wisconsin, Milwaukee, WI
| | - Zeljko J Bosnjak
- Department of Physiology, Medical College of Wisconsin, Milwaukee, WI.
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Wang C, Han X, Li Y, Zhang B. Impact of bone marrow mononuclear cells therapy on left ventricular function in patients with ST-elevated myocardial infarction: A meta-analysis. Medicine (Baltimore) 2018; 97:e0359. [PMID: 29668587 PMCID: PMC5916710 DOI: 10.1097/md.0000000000010359] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
BACKGROUND Bone marrow mononuclear cell (BMMNC) therapy has been used as an adjunctive treatment in patients with ST-elevated myocardial infarction (STEMI). However, the therapeutic efficacy of this approach remains controversial. The present meta-analysis is aimed to evaluate the impact of cell therapy on left ventricular function after STEMI. METHODS We searched through PubMed and EMBASE databases till 2017 for all relevant publications using certain search terms. Randomized controlled trials investigating the effect of BMMNC therapy in patients with STEMI who underwent percutaneous coronary intervention were selected. Wall motion score index (WMSI), infarct size, wall thickening, and myocardial perfusion were our endpoints. RESULTS A total of 24 trials with 1536 patients were included in our study. Overall, as observed in our data, cell therapy reduced infarct size by -2.32 (95% confidence interval [CI] -4.03, -0.62; P = .007; I = 24%) and improved myocardial perfusion by -3.04 (95% CI -3.94, -2.15; P < .001; I = 0%). However, there was no significant difference between treatment group and control group in WMSI or wall thickening. CONCLUSION Intracoronary BMMNC infusion is safe for patients with STEMI. It is also associated with improvement of infarct size and myocardial perfusion. Further multicenter randomized trials should be conducted to validate the therapeutic efficacy of this treatment.
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Shafei AES, Ali MA, Ghanem HG, Shehata AI, Abdelgawad AA, Handal HR, ElSayed AS, Ashaal AE, Ali MM, El-Shal AS. Mechanistic effects of mesenchymal and hematopoietic stem cells: New therapeutic targets in myocardial infarction. J Cell Biochem 2018; 119:5274-5286. [PMID: 29266431 DOI: 10.1002/jcb.26637] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2017] [Accepted: 12/19/2017] [Indexed: 12/16/2022]
Abstract
Myocardial infarction (MI) results in dysfunction and irreversible loss of cardiomyocytes and is of the most serious health threats today. Mesenchymal stem cells (MSCs) and hematopoietic stem cells (HSCs) have been explored as promising cell therapy in MI and regenerative therapy. Recently, reports investigated the potential therapeutic effects of MSCs or HSCs transplantation after MI in numerous experimental and clinical studies; however, their results are controversy and needs more explorations. The current review is an attempt to clarify the therapeutic potentials of MSCs and HSCs in MI therapy, as well as their possible effects; especially the paracrine one and the exosome-derived stem cell among animal models as well as clinical trials conducted within the last 10 years. In this context, various sources of MSCs and HSCs have been addressed in helping cardiac regeneration by either revitalizing the cardiac stem cells niche or revascularizing the arteries and veins of the heart. In addition, both MSCs and HSCs could produce paracrine mediators and growth factors which led to cardiomyocytes protection, angiogenesis, immunemodulation, antioxidants, anti-apoptotic, anti-inflammatory, antifibrotic, as well as increasing cardiac contractility. Recently, microRNAs (miRNAs), post-transcriptional regulators of gene expression, and long non-coding RNA (lncRNA), a miRNA sponge, are recent stem cell-derived mediators can be promising targets of MSCs and HSCs through their paracrine effects. Although MSCs and HSCs have achieved considerable achievements, however, some challenges still remain that need to be overcome in order to establish it as a successful technique. The present review clarified the mechanistic potentials of MSCs and HSCs especially paracrine effects involved in MI including human and animal studies and the challenges challenges regarding type, differentiation, route, and number of injections.
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Affiliation(s)
- Ayman El-Sayed Shafei
- Biomedical Research Department, Military Armed Forces College of Medicine (AFCM), Cairo, Egypt
| | - Mahmoud A Ali
- Biomedical Research Department, Military Armed Forces College of Medicine (AFCM), Cairo, Egypt
| | - Hazem G Ghanem
- Undergraduate Student, Armed Forces College of Medicine, Cairo, Egypt
| | - Ahmed I Shehata
- Undergraduate Student, Armed Forces College of Medicine, Cairo, Egypt
| | | | - Hossam R Handal
- Undergraduate Student, Armed Forces College of Medicine, Cairo, Egypt
| | | | - Ahmed E Ashaal
- Undergraduate Student, Armed Forces College of Medicine, Cairo, Egypt
| | - Mazen M Ali
- Undergraduate Student, Armed Forces College of Medicine, Cairo, Egypt
| | - Amal S El-Shal
- Department of Medical Biochemistry and Molecular biology, Faculty of Medicine, Zagazig University, Zagazig, Egypt
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Han J, Kim YS, Lim MY, Kim HY, Kong S, Kang M, Choo YW, Jun JH, Ryu S, Jeong HY, Park J, Jeong GJ, Lee JC, Eom GH, Ahn Y, Kim BS. Dual Roles of Graphene Oxide To Attenuate Inflammation and Elicit Timely Polarization of Macrophage Phenotypes for Cardiac Repair. ACS NANO 2018; 12:1959-1977. [PMID: 29397689 DOI: 10.1021/acsnano.7b09107] [Citation(s) in RCA: 173] [Impact Index Per Article: 24.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/24/2023]
Abstract
Development of localized inflammatory environments by M1 macrophages in the cardiac infarction region exacerbates heart failure after myocardial infarction (MI). Therefore, the regulation of inflammation by M1 macrophages and their timely polarization toward regenerative M2 macrophages suggest an immunotherapy. Particularly, controlling cellular generation of reactive oxygen species (ROS), which cause M1 differentiation, and developing M2 macrophage phenotypes in macrophages propose a therapeutic approach. Previously, stem or dendritic cells were used in MI for their anti-inflammatory and cardioprotective potentials and showed inflammation modulation and M2 macrophage progression for cardiac repair. However, cell-based therapeutics are limited due to invasive cell isolation, time-consuming cell expansion, labor-intensive and costly ex vivo cell manipulation, and low grafting efficiency. Here, we report that graphene oxide (GO) can serve as an antioxidant and attenuate inflammation and inflammatory polarization of macrophages via reduction in intracellular ROS. In addition, GO functions as a carrier for interleukin-4 plasmid DNA (IL-4 pDNA) that propagates M2 macrophages. We synthesized a macrophage-targeting/polarizing GO complex (MGC) and demonstrated that MGC decreased ROS in immune-stimulated macrophages. Furthermore, DNA-functionalized MGC (MGC/IL-4 pDNA) polarized M1 to M2 macrophages and enhanced the secretion of cardiac repair-favorable cytokines. Accordingly, injection of MGC/IL-4 pDNA into mouse MI models attenuated inflammation, elicited early polarization toward M2 macrophages, mitigated fibrosis, and improved heart function. Taken together, the present study highlights a biological application of GO in timely modulation of the immune environment in MI for cardiac repair. Current therapy using off-the-shelf material GO may overcome the shortcomings of cell therapies for MI.
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Affiliation(s)
- Jin Han
- School of Chemical and Biological Engineering, Seoul National University , Seoul, 08826, Republic of Korea
| | - Yong Sook Kim
- Biomedical Research Institute, Chonnam National University Hospital , Gwangju, 61469, Republic of Korea
| | - Min-Young Lim
- School of Chemical and Biological Engineering, Seoul National University , Seoul, 08826, Republic of Korea
| | - Han Young Kim
- School of Chemical and Biological Engineering, Seoul National University , Seoul, 08826, Republic of Korea
| | - Saerom Kong
- School of Chemical and Biological Engineering, Seoul National University , Seoul, 08826, Republic of Korea
| | - Mikyung Kang
- Interdisciplinary Program of Bioengineering, Seoul National University , Seoul, 08826, Republic of Korea
| | - Yeon Woong Choo
- School of Chemical and Biological Engineering, Seoul National University , Seoul, 08826, Republic of Korea
| | - Ju Hee Jun
- Cell Regeneration Research Center, Chonnam National University Hospital , Gwangju, 61469, Republic of Korea
| | - Seungmi Ryu
- Interdisciplinary Program of Bioengineering, Seoul National University , Seoul, 08826, Republic of Korea
| | - Hye-Yun Jeong
- Cell Regeneration Research Center, Chonnam National University Hospital , Gwangju, 61469, Republic of Korea
| | - Jooyeon Park
- School of Chemical and Biological Engineering, Seoul National University , Seoul, 08826, Republic of Korea
| | - Gun-Jae Jeong
- School of Chemical and Biological Engineering, Seoul National University , Seoul, 08826, Republic of Korea
| | - Jong-Chan Lee
- School of Chemical and Biological Engineering, Seoul National University , Seoul, 08826, Republic of Korea
| | - Gwang Hyeon Eom
- Department of Pharmacology, Chonnam National University Medical School , Gwangju, 61469, Republic of Korea
| | - Youngkeun Ahn
- Cell Regeneration Research Center, Chonnam National University Hospital , Gwangju, 61469, Republic of Korea
- Department of Cardiology, Chonnam National University Hospital , Gwangju, 61649, Republic of Korea
- BK21 PLUS Centre for Creative Biomedical Scientists, Chonnam National University Medical School , 160 Baekseo-ro, Gwangju, 61469, Republic of Korea
| | - Byung-Soo Kim
- School of Chemical and Biological Engineering, Seoul National University , Seoul, 08826, Republic of Korea
- Interdisciplinary Program of Bioengineering, Seoul National University , Seoul, 08826, Republic of Korea
- Institute of Chemical Processes, Seoul National University , Seoul, 08826, Republic of Korea
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Mayourian J, Ceholski DK, Gorski PA, Mathiyalagan P, Murphy JF, Salazar SI, Stillitano F, Hare JM, Sahoo S, Hajjar RJ, Costa KD. Exosomal microRNA-21-5p Mediates Mesenchymal Stem Cell Paracrine Effects on Human Cardiac Tissue Contractility. Circ Res 2018; 122:933-944. [PMID: 29449318 DOI: 10.1161/circresaha.118.312420] [Citation(s) in RCA: 133] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2018] [Revised: 02/09/2018] [Accepted: 02/13/2018] [Indexed: 01/08/2023]
Abstract
RATIONALE The promising clinical benefits of delivering human mesenchymal stem cells (hMSCs) for treating heart disease warrant a better understanding of underlying mechanisms of action. hMSC exosomes increase myocardial contractility; however, the exosomal cargo responsible for these effects remains unresolved. OBJECTIVE This study aims to identify lead cardioactive hMSC exosomal microRNAs to provide a mechanistic basis for optimizing future stem cell-based cardiotherapies. METHODS AND RESULTS Integrating systems biology and human engineered cardiac tissue (hECT) technologies, partial least squares regression analysis of exosomal microRNA profiling data predicted microRNA-21-5p (miR-21-5p) levels positively correlate with contractile force and calcium handling gene expression responses in hECTs treated with conditioned media from multiple cell types. Furthermore, miR-21-5p levels were significantly elevated in hECTs treated with the exosome-enriched fraction of the hMSC secretome (hMSC-exo) versus untreated controls. This motivated experimentally testing the human-specific role of miR-21-5p in hMSC-exo-mediated increases of cardiac tissue contractility. Treating hECTs with miR-21-5p alone was sufficient to recapitulate effects observed with hMSC-exo on hECT developed force and expression of associated calcium handling genes (eg, SERCA2a and L-type calcium channel). Conversely, knockdown of miR-21-5p in hMSCs significantly diminished exosomal procontractile and associated calcium handling gene expression effects on hECTs. Western blots supported miR-21-5p effects on calcium handling gene expression at the protein level, corresponding to significantly increased calcium transient amplitude and decreased decay time constant in comparison to miR-scramble control. Mechanistically, cotreating with miR-21-5p and LY294002, a PI3K inhibitor, suppressed these effects. Finally, mathematical simulations predicted the translational capacity for miR-21-5p treatment to restore calcium handling in mature ischemic adult human cardiomyocytes. CONCLUSIONS miR-21-5p plays a key role in hMSC-exo-mediated effects on cardiac contractility and calcium handling, likely via PI3K signaling. These findings may open new avenues of research to harness the role of miR-21-5p in optimizing future stem cell-based cardiotherapies.
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Affiliation(s)
- Joshua Mayourian
- From the Cardiovascular Research Center, Department of Cardiology, Icahn School of Medicine at Mount Sinai, New York, NY (J.M., D.K.C., P.A.G., P.M., J.F.M., S.I.S., F.S., S.S., R.J.H., K.D.C.); and Interdisciplinary Stem Cell Institute, Department of Cardiology, University of Miami Miller School of Medicine, Miami, FL (J.M.H.)
| | - Delaine K Ceholski
- From the Cardiovascular Research Center, Department of Cardiology, Icahn School of Medicine at Mount Sinai, New York, NY (J.M., D.K.C., P.A.G., P.M., J.F.M., S.I.S., F.S., S.S., R.J.H., K.D.C.); and Interdisciplinary Stem Cell Institute, Department of Cardiology, University of Miami Miller School of Medicine, Miami, FL (J.M.H.)
| | - Przemek A Gorski
- From the Cardiovascular Research Center, Department of Cardiology, Icahn School of Medicine at Mount Sinai, New York, NY (J.M., D.K.C., P.A.G., P.M., J.F.M., S.I.S., F.S., S.S., R.J.H., K.D.C.); and Interdisciplinary Stem Cell Institute, Department of Cardiology, University of Miami Miller School of Medicine, Miami, FL (J.M.H.)
| | - Prabhu Mathiyalagan
- From the Cardiovascular Research Center, Department of Cardiology, Icahn School of Medicine at Mount Sinai, New York, NY (J.M., D.K.C., P.A.G., P.M., J.F.M., S.I.S., F.S., S.S., R.J.H., K.D.C.); and Interdisciplinary Stem Cell Institute, Department of Cardiology, University of Miami Miller School of Medicine, Miami, FL (J.M.H.)
| | - Jack F Murphy
- From the Cardiovascular Research Center, Department of Cardiology, Icahn School of Medicine at Mount Sinai, New York, NY (J.M., D.K.C., P.A.G., P.M., J.F.M., S.I.S., F.S., S.S., R.J.H., K.D.C.); and Interdisciplinary Stem Cell Institute, Department of Cardiology, University of Miami Miller School of Medicine, Miami, FL (J.M.H.)
| | - Sophia I Salazar
- From the Cardiovascular Research Center, Department of Cardiology, Icahn School of Medicine at Mount Sinai, New York, NY (J.M., D.K.C., P.A.G., P.M., J.F.M., S.I.S., F.S., S.S., R.J.H., K.D.C.); and Interdisciplinary Stem Cell Institute, Department of Cardiology, University of Miami Miller School of Medicine, Miami, FL (J.M.H.)
| | - Francesca Stillitano
- From the Cardiovascular Research Center, Department of Cardiology, Icahn School of Medicine at Mount Sinai, New York, NY (J.M., D.K.C., P.A.G., P.M., J.F.M., S.I.S., F.S., S.S., R.J.H., K.D.C.); and Interdisciplinary Stem Cell Institute, Department of Cardiology, University of Miami Miller School of Medicine, Miami, FL (J.M.H.)
| | - Joshua M Hare
- From the Cardiovascular Research Center, Department of Cardiology, Icahn School of Medicine at Mount Sinai, New York, NY (J.M., D.K.C., P.A.G., P.M., J.F.M., S.I.S., F.S., S.S., R.J.H., K.D.C.); and Interdisciplinary Stem Cell Institute, Department of Cardiology, University of Miami Miller School of Medicine, Miami, FL (J.M.H.)
| | - Susmita Sahoo
- From the Cardiovascular Research Center, Department of Cardiology, Icahn School of Medicine at Mount Sinai, New York, NY (J.M., D.K.C., P.A.G., P.M., J.F.M., S.I.S., F.S., S.S., R.J.H., K.D.C.); and Interdisciplinary Stem Cell Institute, Department of Cardiology, University of Miami Miller School of Medicine, Miami, FL (J.M.H.)
| | - Roger J Hajjar
- From the Cardiovascular Research Center, Department of Cardiology, Icahn School of Medicine at Mount Sinai, New York, NY (J.M., D.K.C., P.A.G., P.M., J.F.M., S.I.S., F.S., S.S., R.J.H., K.D.C.); and Interdisciplinary Stem Cell Institute, Department of Cardiology, University of Miami Miller School of Medicine, Miami, FL (J.M.H.)
| | - Kevin D Costa
- From the Cardiovascular Research Center, Department of Cardiology, Icahn School of Medicine at Mount Sinai, New York, NY (J.M., D.K.C., P.A.G., P.M., J.F.M., S.I.S., F.S., S.S., R.J.H., K.D.C.); and Interdisciplinary Stem Cell Institute, Department of Cardiology, University of Miami Miller School of Medicine, Miami, FL (J.M.H.).
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Mayourian J, Sobie EA, Costa KD. An Introduction to Computational Modeling of Cardiac Electrophysiology and Arrhythmogenicity. Methods Mol Biol 2018; 1816:17-35. [PMID: 29987808 DOI: 10.1007/978-1-4939-8597-5_2] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Mathematical modeling is a powerful tool to study the complex and orchestrated biological process of cardiac electrical activity. By integrating experimental data from key components of cardiac electrophysiology, systems biology simulations can complement empirical findings, provide quantitative insight into physiological and pathophysiological mechanisms of action, and guide new hypotheses to better understand this complex biological system to develop novel cardiotherapeutic approaches. In this chapter, we briefly introduce in silico methods to describe the dynamics of physiological and pathophysiological single-cell and tissue-level cardiac electrophysiology. Using a "bottom-up" approach, we first describe the basis of ion channel mathematical models. Next, we discuss how the net flux of ions through such channels leads to changes in transmembrane voltage during cardiomyocyte action potentials. By applying these fundamentals, we describe how action potentials propagate in models of cardiac tissue. In addition, we provide case studies simulating single-cell and tissue-level arrhythmogenesis, as well as promising approaches to circumvent or overcome such adverse events. Overall, basic concepts and tools are discussed in this chapter as an accessible introduction to nonmathematicians to foster an understanding of electrophysiological modeling studies and help facilitate communication with dry lab colleagues and collaborators.
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Affiliation(s)
- Joshua Mayourian
- Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Eric A Sobie
- Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Kevin D Costa
- Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
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Dorobantu M, Popa-Fotea NM, Popa M, Rusu I, Micheu MM. Pursuing meaningful end-points for stem cell therapy assessment in ischemic cardiac disease. World J Stem Cells 2017; 9:203-218. [PMID: 29321822 PMCID: PMC5746641 DOI: 10.4252/wjsc.v9.i12.203] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2017] [Revised: 11/08/2017] [Accepted: 11/27/2017] [Indexed: 02/06/2023] Open
Abstract
Despite optimal interventional and medical therapy, ischemic heart disease is still an important cause of morbidity and mortality worldwide. Although not included in standard of care rehabilitation, stem cell therapy (SCT) could be a solution for prompting cardiac regeneration. Multiple studies have been published from the beginning of SCT until now, but overall no unanimous conclusion could be drawn in part due to the lack of appropriate end-points. In order to appreciate the impact of SCT, multiple markers from different categories should be considered: Structural, biological, functional, physiological, but also major adverse cardiac events or quality of life. Imaging end-points are among the most used - especially left ventricle ejection fraction (LVEF) measured through different methods. Other imaging parameters are infarct size, myocardial viability and perfusion. The impact of SCT on all of the aforementioned end-points is controversial and debatable. 2D-echocardiography is widely exploited, but new approaches such as tissue Doppler, strain/strain rate or 3D-echocardiography are more accurate, especially since the latter one is comparable with the MRI gold standard estimation of LVEF. Apart from the objective parameters, there are also patient-centered evaluations to reveal the benefits of SCT, such as quality of life and performance status, the most valuable from the patient point of view. Emerging parameters investigating molecular pathways such as non-coding RNAs or inflammation cytokines have a high potential as prognostic factors. Due to the disadvantages of current techniques, new imaging methods with labelled cells tracked along their lifetime seem promising, but until now only pre-clinical trials have been conducted in humans. Overall, SCT is characterized by high heterogeneity not only in preparation, administration and type of cells, but also in quantification of therapy effects.
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Affiliation(s)
- Maria Dorobantu
- Department of Cardiology, Clinical Emergency Hospital of Bucharest, Bucharest 014461, Romania
| | | | - Mihaela Popa
- Carol Davila, University of Medicine, "Carol Davila" University of Medicine and Pharmacy Bucharest, Bucharest 020022, Romania
| | - Iulia Rusu
- Carol Davila, University of Medicine, "Carol Davila" University of Medicine and Pharmacy Bucharest, Bucharest 020022, Romania
| | - Miruna Mihaela Micheu
- Department of Cardiology, Clinical Emergency Hospital of Bucharest, Bucharest 014461, Romania.
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Shafei AES, Ali MA, Ghanem HG, Shehata AI, Abdelgawad AA, Handal HR, Talaat KA, Ashaal AE, El-Shal AS. Mesenchymal stem cell therapy: A promising cell-based therapy for treatment of myocardial infarction. J Gene Med 2017; 19. [PMID: 29044850 DOI: 10.1002/jgm.2995] [Citation(s) in RCA: 111] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2017] [Revised: 10/07/2017] [Accepted: 10/07/2017] [Indexed: 12/12/2022] Open
Abstract
For decades, mesenchymal stem (MSCs) cells have been used for cardiovascular diseases as regenerative therapy. This review is an attempt to summarize the types of MSCs involved in myocardial infarction (MI) therapy, as well as its possible mechanisms effects, especially the paracrine one in MI focusing on the studies (human and animal) conducted within the last 10 years. Recently, reports showed that MSC therapy could have infarct-limiting effects after MI in both experimental and clinical trials. In this context, various types of MSCs can help cardiac regeneration by either revitalizing the cardiac stem cells or revascularizing the arteries and veins of the heart. Furthermore, MSCs could produce paracrine growth factors that increase the survival of nearby cardiomyocytes, as well as increase angiogenesis through recruitment of stem cell from bone marrow or inducing vessel growth from existing capillaries. Recent research suggests that the paracrine effects of MSCs could be mediated by extracellular vesicles including exosomes. Exosomal microRNAs (miRNAs) released by MSCs are promising therapeutic hotspot target for MI. This could be attributed to the role of miRNA in cardiac biology, including cardiac regeneration, stem cell differentiation, apoptosis, neovascularization, cardiac contractility and cardiac remodeling. Furthermore, gene-modified MSCs could be a recent promising therapy for MI to enhance the paracrine effects of MSCs, including better homing and effective cell targeted tissue regeneration. Although MSC therapy has achieved considerable attention and progress, there are critical challenges that remains to be overcome to achieve the most effective successful cell-based therapy in MI.
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Affiliation(s)
- Ayman El-Sayed Shafei
- Biomedical Research Department, Military Armed Forces College of Medicine, Cairo, Egypt
| | - Mahmoud Ahmed Ali
- Biomedical Research Department, Military Armed Forces College of Medicine, Cairo, Egypt
| | | | | | | | | | | | | | - Amal S El-Shal
- Medical Biochemistry & Molecular Biology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
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Jeong GJ, Oh JY, Kim YJ, Bhang SH, Jang HK, Han J, Yoon JK, Kwon SM, Lee TI, Kim BS. Therapeutic Angiogenesis via Solar Cell-Facilitated Electrical Stimulation. ACS APPLIED MATERIALS & INTERFACES 2017; 9:38344-38355. [PMID: 29043772 DOI: 10.1021/acsami.7b13322] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Abstract
Cell therapy has been suggested as a treatment modality for ischemic diseases, but the poor survival and engraftment of implanted cells limit its therapeutic efficacy. To overcome such limitation, we used electrical stimulation (ES) derived from a wearable solar cell for inducing angiogenesis in ischemic tissue. ES enhanced the secretion of angiogenic growth factors and the migration of mesenchymal stem cells (MSCs), myoblasts, endothelial progenitor cells, and endothelial cells in vitro. In a mouse ischemic hindlimb model, ES generated by a solar cell and applied to the ischemic region promoted migration of MSCs toward the ischemic site and upregulated expression of angiogenic paracrine factors (vascular endothelial, basic fibroblast, and hepatocyte growth factors; and stromal cell-derived factor-1α). Importantly, solar cell-generated ES promoted the formation of capillaries and arterioles at the ischemic region, attenuated muscle necrosis and fibrosis, and eventually prevented loss of the ischemic limb. Solar cell ES therapy showed higher angiogenic efficacy than conventional MSC therapy. This study shows the feasibility of using solar cell ES as a novel treatment for therapeutic angiogenesis.
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Affiliation(s)
| | - Jin Young Oh
- Department of Materials Science and Engineering, Yonsei University , Seoul 03722, Republic of Korea
| | - Yeon-Ju Kim
- Department of Physiology, School of Medicine, Pusan National University , Yangsan, 50612 Republic of Korea
| | - Suk Ho Bhang
- School of Chemical Engineering, Sungkyunkwan University , Suwon 16419, Republic of Korea
| | | | | | | | - Sang-Mo Kwon
- Department of Physiology, School of Medicine, Pusan National University , Yangsan, 50612 Republic of Korea
| | - Tae Il Lee
- Department of BioNano Technology, Gachon University , Seongnam 13120, Republic of Korea
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Baeza Garzón F, Pan Álvarez-Ossorio M, Romero Moreno MÁ, Martín Palanco V, Herrera Arroyo C, Suárez de Lezo Cruz Conde J. One Versus 2-stent Strategy for the Treatment of Bifurcation Lesions in the Context of a Coronary Chronic Total Occlusion. A Multicenter Registry. ACTA ACUST UNITED AC 2017; 71:344-350. [PMID: 29097079 DOI: 10.1016/j.rec.2017.07.018] [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: 01/08/2017] [Accepted: 07/12/2017] [Indexed: 11/19/2022]
Abstract
INTRODUCTION AND OBJECTIVES There is little evidence on the optimal strategy for bifurcation lesions in the context of a coronary chronic total occlusion (CTO). This study compared the procedural and mid-term outcomes of patients with bifurcation lesions in CTO treated with provisional stenting vs 2-stent techniques in a multicenter registry. METHODS Between January 2012 and June 2016, 922 CTO were recanalized at the 4 participating centers. Of these, 238 (25.8%) with a bifurcation lesion (side branch ≥ 2mm located proximally, distally, or within the occluded segment) were treated by a simple approach (n=201) or complex strategy (n=37). Propensity score matching was performed to account for selection bias between the 2 groups. Major adverse cardiac events (MACE) consisted of a composite of cardiac death, myocardial infarction, and clinically-driven target lesion revascularization. RESULTS Angiographic and procedural success were similar in the simple and complex groups (94.5% vs 97.3%; P=.48 and 85.6% vs 81.1%; P=.49). However, contrast volume, radiation dose, and fluoroscopy time were lower with the simple approach. At follow-up (25 months), the MACE rate was 8% in the simple and 10.8% in the complex group (P=.58). There was a trend toward a lower MACE-free survival in the complex group (80.1% vs 69.8%; P=.08). After propensity analysis, there were no differences between the groups regarding immediate and follow-up results. CONCLUSIONS Bifurcation lesions in CTO can be approached similarly to regular bifurcation lesions, for which provisional stenting is considered the technique of choice. After propensity score matching, there were no differences in procedural or mid-term clinical outcomes between the simple and complex strategies.
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Xu JY, Liu D, Zhong Y, Huang RC. Effects of timing on intracoronary autologous bone marrow-derived cell transplantation in acute myocardial infarction: a meta-analysis of randomized controlled trials. Stem Cell Res Ther 2017; 8:231. [PMID: 29037256 PMCID: PMC5644258 DOI: 10.1186/s13287-017-0680-5] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2017] [Revised: 09/19/2017] [Accepted: 09/22/2017] [Indexed: 01/27/2023] Open
Abstract
Background Several cell-based therapies for adjunctive treatment of acute myocardial infarction have been investigated in multiple clinical trials, but the timing of transplantation remains controversial. We conducted a meta-analysis of randomized controlled trials to investigate the effects of timing on bone marrow-derived cell (BMC) therapy in acute myocardial infarction (AMI). Methods A systematic literature search of PubMed, MEDLINE, and Cochrane Evidence-Based Medicine databases from January 2000 to June 2017 was performed on randomized controlled trials with at least a 3-month follow-up for patients with AMI undergoing emergency percutaneous coronary intervention (PCI) and receiving intracoronary BMC transfer thereafter. The defined end points were left ventricular (LV) ejection fraction, LV end-diastolic and end-systolic index. The data were analyzed to evaluate the effects of timing on BMC therapy. Results Thirty-four RCTs comprising a total of 2,307 patients were included; the results show that, compared to the control group, AMI patients who received BMC transplantation showed significantly improved cardiac function. BMC transplantation 3–7 days after PCI (+3.32%; 95% CI, 1.91 to 4.74; P < 0.00001) resulted in a significant increase of left ventricular ejection fraction (LVEF). As for the inhibitory effect on ventricular remodeling, BMC transplantation 3–7 days after PCI reduced LV end-diastolic indexes (–4.48; 95% CI, −7.98 to –0.98; P = 0.01) and LV end-systolic indexes (–6.73; 95% CI, –11.27 to –2.19; P = 0.004). However, in the groups who received BMC transplantation either within 24 hours or later than 7 days there was no significant effect on treatment outcome. In subgroup analysis, the group with LVEF ≤ 50% underwent a significant decrease in LV end-diastolic index after BMC transplantation (WMD = –3.29, 95% CI, –4.49 to –2.09; P < 0.00001); the decrease was even more remarkable in the LV end-systolic index after BMC transplantation in the group with LVEF ≤ 50% (WMD = –5.25, 95% CI, –9.30 to –1.20; P = 0.01), as well as in patients who received a dose of 10^7–10^8 cells (WMD = –12.99, 95% CI, –19.07 to –6.91; P < 0.0001). In the group with a follow-up of more than 12 months, this beneficial effect was significant and increased to a more pronounced effect of +3.58% (95% CI, 1.55 to 5.61; P = 0.0006) when compared with control. Conclusions In this meta-analysis, BMC transfer at 3 to 7 days post-AMI was superior to transfer within 24 hours or more than 7 days after AMI in improving LVEF and decreasing LV end-systolic dimensions or LV end-diastolic dimensions. It is more effective in patients with lower baseline LVEF (≤50%) and the effect can last more than 12 months. Electronic supplementary material The online version of this article (doi:10.1186/s13287-017-0680-5) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Jia-Ying Xu
- Department of Cardiology, The First Affiliated Hospital of Dalian Medical University, 222 Zhongshan Road, Dalian, 116011, People's Republic of China
| | - Dai Liu
- Department of Cardiology, The First Affiliated Hospital of Dalian Medical University, 222 Zhongshan Road, Dalian, 116011, People's Republic of China
| | - Yang Zhong
- Department of Cardiology, The First Affiliated Hospital of Dalian Medical University, 222 Zhongshan Road, Dalian, 116011, People's Republic of China.,Present address: Department of Cardiology, The Fifth People's Hospital of Dalian City, Dalian, People's Republic of China
| | - Rong-Chong Huang
- Department of Cardiology, The First Affiliated Hospital of Dalian Medical University, 222 Zhongshan Road, Dalian, 116011, People's Republic of China.
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Higuchi A, Ku NJ, Tseng YC, Pan CH, Li HF, Kumar SS, Ling QD, Chang Y, Alarfaj AA, Munusamy MA, Benelli G, Murugan K. Stem cell therapies for myocardial infarction in clinical trials: bioengineering and biomaterial aspects. J Transl Med 2017; 97:1167-1179. [PMID: 28869589 DOI: 10.1038/labinvest.2017.100] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2017] [Revised: 08/01/2017] [Accepted: 08/04/2017] [Indexed: 12/17/2022] Open
Abstract
Cardiovascular disease remains the leading cause of death and disability in advanced countries. Stem cell transplantation has emerged as a promising therapeutic strategy for acute and chronic ischemic cardiomyopathy. The current status of stem cell therapies for patients with myocardial infarction is discussed from a bioengineering and biomaterial perspective in this review. We describe (a) the current status of clinical trials of human pluripotent stem cells (hPSCs) compared with clinical trials of human adult or fetal stem cells, (b) the gap between fundamental research and application of human stem cells, (c) the use of biomaterials in clinical and pre-clinical studies of stem cells, and finally (d) trends in bioengineering to promote stem cell therapies for patients with myocardial infarction. We explain why the number of clinical trials using hPSCs is so limited compared with clinical trials using human adult and fetal stem cells such as bone marrow-derived stem cells.
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Affiliation(s)
- Akon Higuchi
- Department of Chemical and Materials Engineering, National Central University, Jhongli, Taoyuan, Taiwan.,Nano Medical Engineering Laboratory, RIKEN, Wako, Saitama, Japan.,Department of Botany and Microbiology, College of Science, King Saud University, Riyadh, Saudi Arabia.,Department of Chemical Engineering, R&D Center for Membrane Technology, Chung Yuan Christian University, Chungli, Taoyuan, Taiwan
| | - Nien-Ju Ku
- Department of Chemical and Materials Engineering, National Central University, Jhongli, Taoyuan, Taiwan
| | - Yeh-Chia Tseng
- Department of Chemical and Materials Engineering, National Central University, Jhongli, Taoyuan, Taiwan
| | - Chih-Hsien Pan
- Department of Chemical and Materials Engineering, National Central University, Jhongli, Taoyuan, Taiwan
| | - Hsing-Fen Li
- Department of Chemical and Materials Engineering, National Central University, Jhongli, Taoyuan, Taiwan
| | - S Suresh Kumar
- Department of Medical Microbiology and Parasitology, Universiti Putra Malaysia, Serdang, Selangor, Malaysia
| | - Qing-Dong Ling
- Cathay Medical Research Institute, Cathay General Hospital, Hsi-Chi City, Taipei, Taiwan.,Graduate Institute of Systems Biology and Bioinformatics, National Central University, Jhongli, Taoyuan, Taiwan
| | - Yung Chang
- Department of Chemical Engineering, R&D Center for Membrane Technology, Chung Yuan Christian University, Chungli, Taoyuan, Taiwan
| | - Abdullah A Alarfaj
- Department of Botany and Microbiology, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - Murugan A Munusamy
- Department of Botany and Microbiology, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - Giovanni Benelli
- Department of Agriculture, Food and Environment, University of Pisa, Via del Borghetto, Pisa, Italy.,The BioRobotics Institute, Scuola Superiore Sant'Anna, Pontedera, Pisa, Italy
| | - Kadarkarai Murugan
- Division of Entomology, Department of Zoology, School of Life Sciences, Bharathiar University, Coimbatore, Tamil Nadu, India.,Department of Zoology, Thiruvalluvar University, Vellore, Tamil Nadu, India
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50
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Regenerative Stem Cell Therapy Optimization via Tissue Engineering in Heart Failure with Reduced Ejection Fraction. Cardiovasc Eng Technol 2017; 8:515-526. [DOI: 10.1007/s13239-017-0325-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2017] [Accepted: 07/31/2017] [Indexed: 12/30/2022]
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