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Patel T, Mešić J, Meretzki S, Bronshtein T, Brlek P, Kivity V, Pancholy SB, Petrović M, Primorac D. Therapeutic Potential and Mechanisms of Mesenchymal Stem Cells in Coronary Artery Disease: Narrative Review. Int J Mol Sci 2025; 26:5414. [PMID: 40508220 PMCID: PMC12156323 DOI: 10.3390/ijms26115414] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2025] [Revised: 05/27/2025] [Accepted: 05/28/2025] [Indexed: 06/16/2025] Open
Abstract
Coronary artery disease (CAD) remains a leading cause of global morbidity and mortality despite advances in medical and interventional therapies. Mesenchymal stem cell (MSC) therapy has emerged as a promising regenerative approach for patients with refractory or non-revascularizable CAD. MSCs exhibit unique immunomodulatory, pro-angiogenic, and anti-fibrotic properties, primarily through paracrine mechanisms involving the secretion of cytokines, growth factors, and exosomal microRNAs. Clinical and preclinical studies have demonstrated improvements in myocardial perfusion, left ventricular ejection fraction (LVEF), and functional capacity following MSC-based interventions, particularly in patients with low baseline LVEF and heightened inflammation. Various MSC sources-including bone marrow, adipose tissue, and umbilical cord-offer distinct advantages, while delivery strategies such as intracoronary, intramyocardial, intravenous, and subcutaneous administration impact cell retention and efficacy. Advances in genetic modification, hypoxic preconditioning, and exosome-based therapies aim to enhance MSC survival and therapeutic potency. However, challenges persist regarding cell engraftment, cryopreservation effects, and inter-patient variability. Moving toward precision cell therapy, future approaches may involve stratifying patients by inflammatory status, ischemic burden, and comorbidities to optimize treatment outcomes. MSCs may not yet replace conventional therapies but are increasingly positioned to complement them within a personalized, regenerative framework for CAD management.
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Affiliation(s)
- Tejas Patel
- Apex Heart Institute, Ahmedabad 380059, India
| | - Jana Mešić
- St. Catherine Specialty Hospital, 10000 Zagreb, Croatia
| | | | | | - Petar Brlek
- St. Catherine Specialty Hospital, 10000 Zagreb, Croatia
- School of Medicine, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia
- Faculty of Science, Department of Molecular Biology, University of Zagreb, 10000 Zagreb, Croatia
| | | | | | | | - Dragan Primorac
- St. Catherine Specialty Hospital, 10000 Zagreb, Croatia
- School of Medicine, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia
- School of Medicine, University of Split, 21000 Split, Croatia
- Eberly College of Science, The Pennsylvania State University, State College, University Park, PA 16802, USA
- Henry C. Lee College of Criminal Justice and Forensic Sciences, University of New Haven, New Haven, CT 06516, USA
- Regiomed Kliniken, 96450 Coburg, Germany
- School of Medicine, University of Rijeka, 51000 Rijeka, Croatia
- Faculty of Dental Medicine and Health, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia
- National Forensic Sciences University, Gandhinagar 382007, India
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Khalili MR, Ahmadloo S, Mousavi SA, Joghataei MT, Brouki Milan P, Naderi Gharahgheshlagh S, Mohebi SL, Haramshahi SMA, Hosseinpour Sarmadi V. Navigating mesenchymal stem cells doses and delivery routes in heart disease trials: A comprehensive overview. Regen Ther 2025; 29:117-127. [PMID: 40162019 PMCID: PMC11952810 DOI: 10.1016/j.reth.2025.02.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2025] [Revised: 02/13/2025] [Accepted: 02/27/2025] [Indexed: 04/02/2025] Open
Abstract
In recent years, various clinical trials have been designed and implemented using mesenchymal stem cells (MSCs) for the treatment of heart diseases. Clinical trials exploring MSC-based treatments have proliferated, yet the lack of standardized protocols for MSC administration remains a significant challenge. Despite the growing popularity of MSC trials, questions persist regarding optimal dosing, administration routes, and frequency to achieve safety and efficacy, particularly in the context of cardiac regeneration. The current study has reviewed the clinical trials that have used MSCs for the treatment of heart diseases since 2009. The findings reveal diverse transplantation methods and varying MSCs quantities, highlighting the absence of a universal guideline for MSCs utilization in heart disease clinical trials.
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Affiliation(s)
- Mohammad Reza Khalili
- Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Tehran, Iran
| | - Salma Ahmadloo
- Institute for Cognitive and Brain Science, Shahid Beheshti University, Tehran, Iran
| | - Seyed Amin Mousavi
- Department of Plastic and Reconstructive Surgery, Hazrat Fatemeh Hospital, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | | | - Peiman Brouki Milan
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran
- Department of Tissue Engineering and Regenerative Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
| | | | - Seyedeh Lena Mohebi
- Institutes of Regenerative Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Seyed Mohammad Amin Haramshahi
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran
- Department of Tissue Engineering and Regenerative Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Vahid Hosseinpour Sarmadi
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran
- Department of Tissue Engineering and Regenerative Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
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Le NT, Dunleavy MW, Zhou W, Bhatia SS, Kumar RD, Woo ST, Ramirez-Pulido G, Ramakrishnan KS, El-Hashash AH. Stem Cell Therapy for Myocardial Infarction Recovery: Advances, Challenges, and Future Directions. Biomedicines 2025; 13:1209. [PMID: 40427036 PMCID: PMC12109359 DOI: 10.3390/biomedicines13051209] [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: 03/31/2025] [Revised: 05/01/2025] [Accepted: 05/06/2025] [Indexed: 05/29/2025] Open
Abstract
Myocardial infarction (MI) is a leading cause of morbidity worldwide, resulting from ischemic damage and necrosis to cardiomyocytes. While the standard treatment regimen for MI can be successful in restoring coronary perfusion, it typically does not resolve myocardial damage, which can leave patients particularly vulnerable to complications such as heart failure or electrical conduction abnormalities. Stem cell therapies offer a promising novel approach aimed at restoring cardiac function and decreasing the incidence of functional complications after an MI. This review used a literature search to evaluate the current landscape of stem cell therapy for post-MI recovery and focuses on the stem cell candidates for MI recovery therapy, delivery methods of such treatment, and their effectiveness. Both preclinical and clinical trials have demonstrated the safety of stem cells, but have struggled with limited cell retention, inconsistent efficacy, and survival. Mechanisms are employed by stem cells to promote regeneration, such as paracrine signaling, angiogenesis, and structural remodeling, in addition to the various stem cell delivery methods, including intracoronary infusion, direct myocardial injection, and intravenous administration. Furthermore, some strategies to combat past challenges in this field are discussed; for instance, extracellular vesicles, bioengineered patches, hydrogels, gene editing, and bioprinting. This article will provide a framework for future research in stem cell therapies and highlight the current progress in the field.
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Affiliation(s)
- Nicholas T. Le
- Department of Biology, College Station Campus, Texas A&M University, College Station, TX 77840, USA; (M.W.D.); (S.S.B.); (R.D.K.); (S.T.W.); (K.S.R.)
| | - Matthew W. Dunleavy
- Department of Biology, College Station Campus, Texas A&M University, College Station, TX 77840, USA; (M.W.D.); (S.S.B.); (R.D.K.); (S.T.W.); (K.S.R.)
| | - William Zhou
- Department of Health Promotion and Behavioral Sciences, University of Texas at Austin, Austin, TX 78712, USA;
| | - Sumrithbir S. Bhatia
- Department of Biology, College Station Campus, Texas A&M University, College Station, TX 77840, USA; (M.W.D.); (S.S.B.); (R.D.K.); (S.T.W.); (K.S.R.)
| | - Rebecca D. Kumar
- Department of Biology, College Station Campus, Texas A&M University, College Station, TX 77840, USA; (M.W.D.); (S.S.B.); (R.D.K.); (S.T.W.); (K.S.R.)
| | - Suyin T. Woo
- Department of Biology, College Station Campus, Texas A&M University, College Station, TX 77840, USA; (M.W.D.); (S.S.B.); (R.D.K.); (S.T.W.); (K.S.R.)
| | | | - Kaushik S. Ramakrishnan
- Department of Biology, College Station Campus, Texas A&M University, College Station, TX 77840, USA; (M.W.D.); (S.S.B.); (R.D.K.); (S.T.W.); (K.S.R.)
| | - Ahmed H. El-Hashash
- Department of Biology, Elizabeth City State University Campus of the University of North Carolina, Elizabeth City, NC 27909, USA
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Seyihoglu B, Orhan I, Okudur N, Aygun HK, Bhupal M, Yavuz Y, Can A. 20 years of treating ischemic cardiomyopathy with mesenchymal stromal cells: a meta-analysis and systematic review. Cytotherapy 2024; 26:1443-1457. [PMID: 39078351 DOI: 10.1016/j.jcyt.2024.07.004] [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: 01/19/2024] [Revised: 06/17/2024] [Accepted: 07/01/2024] [Indexed: 07/31/2024]
Abstract
This meta-analysis and systematic review compiles comparative data from 2004 to 2024, investigating the safety and efficacy of mesenchymal stem/stromal cells (MSCs) derived from various tissues for the treatment of ischemic cardiomyopathy (ICM) and associated heart failure. In addition, this review highlights the limitations of these interventions and provides valuable insights for future therapeutic approaches. Relevant articles were retrieved from the PubMed® database using targeted keywords. Our inclusion criteria included clinical trials with patients over 18 years of age, case reports and pilot studies. Animal experiments, in vitro studies, correlational and longitudinal studies, and study designs and protocols were excluded. Forty-nine original articles resulted in follow-up reports of 45 trials. MSCs from bone marrow, umbilical cord and adipose tissue were moderately well tolerated. Of the 1408 participants who received MSCs, 33 trials (67.3%) reported the occurrence of death or serious adverse events. These events resulted in 80 deaths (52% of reported cases) following MSC administration. Importantly, 41.3% of these deaths (n = 33) were not considered to be related to the intervention itself, while 40% of these deaths had no reported cause. As the primary outcome, the mean increase in left ventricular ejection fraction (LVEF) from baseline was 5.75% (95% CI: 3.38% -8.11%, p < 0.0001, I2 = 90,9%) in the randomized controlled trials only (n = 24) within the treatment groups and 3.19% (95% CI: 1.63% to 4.75%, p < 0.0001, I2 = 74,17%) in the control groups after the intervention. When the above results were compared using the standardized mean difference (SDM), a significance in favor of the treatment group was also found (SDM = 0.41; 95% CI: 0.19-0.64, p < 0.001, I2 = 71%). Although improvements were also seen in the control groups, 33.3% (n = 15) of the studies showed no significant difference between the control and treatment groups. The 6-minute walking test (6MWT) and New York Heart Association (NYHA) class scores, used for assessing exercise tolerance and quality of life (QoL), respectively, further supported the improvements in the treatment group. These improvements were noted as 62.5% (n = 10) for the 6MWT and 54.5% (n = 12) for the NYHA class scores. According to the risk of bias analysis, 4 trials were of good quality (11.8%), 15 were of fair quality (44.1%), and 15 were of poor quality (44.1%). Major limitations of these studies included small sample size, diagnostic challenges/lack, uncertain cell dosage and potential bias in patient selection. Despite the ongoing debate surrounding cell administration for ICM, there are supporting signs of improved clinical and laboratory outcomes, as well as improved QoL in the MSC-treated groups. However, it is important to recognize the limitations of each study, highlighting the need for larger, controlled trials to validate these findings.
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Affiliation(s)
| | - Inci Orhan
- Ankara University School of Medicine, Sihhiye, Ankara, Türkiye
| | - Nil Okudur
- Ankara University School of Medicine, Sihhiye, Ankara, Türkiye
| | | | - Melissa Bhupal
- Ankara University School of Medicine, Sihhiye, Ankara, Türkiye
| | - Yasemin Yavuz
- Department of Biostatistics, Ankara University School of Medicine, Sihhiye, Ankara 06410, Türkiye
| | - Alp Can
- Department of Histology and Embryology Laboratory for Stem Cells and Reproductive Cell Biology, Ankara University School of Medicine, Sihhiye, Ankara 06410, Türkiye.
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Yuce K. The Application of Mesenchymal Stem Cells in Different Cardiovascular Disorders: Ways of Administration, and the Effectors. Stem Cell Rev Rep 2024; 20:1671-1691. [PMID: 39023739 DOI: 10.1007/s12015-024-10765-9] [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] [Accepted: 07/11/2024] [Indexed: 07/20/2024]
Abstract
The heart is an organ with a low ability to renew and repair itself. MSCs have cell surface markers such as CD45-, CD34-, CD31-, CD4+, CD11a+, CD11b+, CD15+, CD18+, CD25+, CD49d+, CD50+, CD105+, CD73+, CD90+, CD9+, CD10+, CD106+, CD109+, CD127+, CD120a+, CD120b+, CD124+, CD126+, CD140a+, CD140b+, adherent properties and the ability to differentiate into cells such as adipocytes, osteoblasts and chondrocytes. Autogenic, allogeneic, normal, pretreated and genetically modified MSCs and secretomes are used in preclinical and clinical studies. MSCs and their secretomes (the total released molecules) generally have cardioprotective effects. Studies on cardiovascular diseases using MSCs and their secretomes include myocardial infraction/ischemia, fibrosis, hypertrophy, dilated cardiomyopathy and atherosclerosis. Stem cells or their secretomes used for this purpose are administered to the heart via intracoronary (Antegrade intracoronary and retrograde coronary venous injection), intramyocardial (Transendocardial and epicardial injection) and intravenous routes. The protective effects of MSCs and their secretomes on the heart are generally attributed to their differentiation into cardiomyocytes and endothelial cells, their immunomodulatory properties, paracrine effects, increasing blood vessel density, cardiac remodeling, and ejection fraction and decreasing apoptosis, the size of the wound, end-diastolic volume, end-systolic volume, ventricular myo-mass, fibrosis, matrix metalloproteins, and oxidative stress. The present review aims to assist researchers and physicians in selecting the appropriate cell type, secretomes, and technique to increase the chance of success in designing therapeutic strategies against cardiovascular diseases.
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Affiliation(s)
- Kemal Yuce
- Physiology, Department of Basic Medical Sciences, Medicine Faculty, Selcuk University, Konya, Türkiye.
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6
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Safwan M, Bourgleh MS, Aldoush M, Haider KH. Tissue-source effect on mesenchymal stem cells as living biodrugs for heart failure: Systematic review and meta-analysis. World J Cardiol 2024; 16:469-483. [PMID: 39221190 PMCID: PMC11362808 DOI: 10.4330/wjc.v16.i8.469] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Revised: 06/24/2024] [Accepted: 07/23/2024] [Indexed: 08/26/2024] Open
Abstract
BACKGROUND Mesenchymal stem cells (MSCs), as living biodrugs, have entered advanced phases of clinical assessment for cardiac function restoration in patients with myocardial infarction and heart failure. While MSCs are available from diverse tissue sources, bone-marrow-derived MSCs (BM-MSCs) remain the most well-studied cell type, besides umbilical-cord-derived MSCs (UC-MSCs). The latter offers advantages, including noninvasive availability without ethical considerations. AIM To compare the safety and efficacy of BM-MSCs and UC-MSCs in terms of left ventricular ejection fraction (LVEF), 6-min walking distance (6MWD), and major adverse cardiac events (MACEs). METHODS Five databases were systematically searched to identify randomized controlled trials (RCTs). Thirteen RCTs (693 patients) were included using predefined eligibility criteria. Weighted mean differences and odds ratio (OR) for the changes in the estimated treatment effects. RESULTS UC-MSCs significantly improved LVEF vs controls by 5.08% [95% confidence interval (CI): 2.20%-7.95%] at 6 mo and 2.78% (95%CI: 0.86%-4.70%) at 12 mo. However, no significant effect was observed for BM-MSCs vs controls. No significant changes were observed in the 6MWD with either of the two cell types. Also, no differences were observed for MACEs, except rehospitalization rates, which were lower only with BM-MSCs (odds ratio 0.48, 95%CI: 0.24-0.97) vs controls. CONCLUSION UC-MSCs significantly improved LVEF compared with BM-MSCs. Their advantageous characteristics position them as a promising alternative to MSC-based therapy.
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Affiliation(s)
- Moaz Safwan
- Department of Basic Sciences, Sulaiman Al Rajhi University, Al Bukairiyah 51941, Saudi Arabia
| | - Mariam Safwan Bourgleh
- Department of Basic Sciences, Sulaiman Al Rajhi University, Al Bukairiyah 51941, Saudi Arabia
| | - Mohamed Aldoush
- Department of Basic Sciences, Sulaiman Al Rajhi University, Al Bukairiyah 51941, Saudi Arabia
| | - Khawaja Husnain Haider
- Department of Basic Sciences, Sulaiman Al Rajhi University, Al Bukairiyah 51941, Saudi Arabia.
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Seow KS, Ling APK. Mesenchymal stem cells as future treatment for cardiovascular regeneration and its challenges. ANNALS OF TRANSLATIONAL MEDICINE 2024; 12:73. [PMID: 39118948 PMCID: PMC11304428 DOI: 10.21037/atm-23-1936] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Accepted: 12/04/2023] [Indexed: 08/10/2024]
Abstract
Cardiovascular diseases (CVDs), particularly stroke and myocardial infarction (MI) contributed to the leading cause of death annually among the chronic diseases globally. Despite the advancement of technology, the current available treatments mainly served as palliative care but not treating the diseases. However, the discovery of mesenchymal stem cells (MSCs) had gained a consideration to serve as promising strategy in treating CVDs. Recent evidence also showed that MSCs are the strong candidate to be used as stem cell therapy involving cardiovascular regeneration due to its cardiomyogenesis, anti-inflammatory and immunomodulatory properties, antifibrotic effects and neovascularization capacity. Besides, MSCs could be used for cellular cardiomyoplasty with its transdifferentiation of MSCs into cardiomyocytes, paracrine effects, microvesicles and exosomes as well as mitochondrial transfer. The safety and efficacy of utilizing MSCs have been described in well-established preclinical and clinical studies in which the accomplishment of MSCs transplantation resulted in further improvement of the cardiac function. Tissue engineering could enhance the desired properties and therapeutic effects of MSCs in cardiovascular regeneration by genome-editing, facilitating the cell delivery and retention, biomaterials-based scaffold, and three-dimensional (3D)-bioprinting. However, there are still obstacles in the use of MSCs due to the complexity and versatility of MSCs, low retention rate, route of administration and the ethical and safety issues of the use of MSCs. The aim of this review is to highlight the details of therapeutic properties of MSCs in treating CVDs, strategies to facilitate the therapeutic effects of MSCs through tissue engineering and the challenges faced using MSCs. A comprehensive review has been done through PubMed and National Center for Biotechnology Information (NCBI) from the year of 2010 to 2021 based on some specific key terms such as 'mesenchymal stem cells in cardiovascular disease', 'mesenchymal stem cells in cardiac regeneration', 'mesenchymal stem cells facilitate cardiac repairs', 'tissue engineering of MSCs' to include relevant literature in this review.
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Affiliation(s)
- Ke Sin Seow
- Division of Applied Biomedical Sciences and Biotechnology, School of Health Sciences, International Medical University, Kuala Lumpur, Malaysia
| | - Anna Pick Kiong Ling
- Division of Applied Biomedical Sciences and Biotechnology, School of Health Sciences, International Medical University, Kuala Lumpur, Malaysia
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Barrère-Lemaire S, Vincent A, Jorgensen C, Piot C, Nargeot J, Djouad F. Mesenchymal stromal cells for improvement of cardiac function following acute myocardial infarction: a matter of timing. Physiol Rev 2024; 104:659-725. [PMID: 37589393 DOI: 10.1152/physrev.00009.2023] [Citation(s) in RCA: 29] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 07/05/2023] [Accepted: 08/16/2023] [Indexed: 08/18/2023] Open
Abstract
Acute myocardial infarction (AMI) is the leading cause of cardiovascular death and remains the most common cause of heart failure. Reopening of the occluded artery, i.e., reperfusion, is the only way to save the myocardium. However, the expected benefits of reducing infarct size are disappointing due to the reperfusion paradox, which also induces specific cell death. These ischemia-reperfusion (I/R) lesions can account for up to 50% of final infarct size, a major determinant for both mortality and the risk of heart failure (morbidity). In this review, we provide a detailed description of the cell death and inflammation mechanisms as features of I/R injury and cardioprotective strategies such as ischemic postconditioning as well as their underlying mechanisms. Due to their biological properties, the use of mesenchymal stromal/stem cells (MSCs) has been considered a potential therapeutic approach in AMI. Despite promising results and evidence of safety in preclinical studies using MSCs, the effects reported in clinical trials are not conclusive and even inconsistent. These discrepancies were attributed to many parameters such as donor age, in vitro culture, and storage time as well as injection time window after AMI, which alter MSC therapeutic properties. In the context of AMI, future directions will be to generate MSCs with enhanced properties to limit cell death in myocardial tissue and thereby reduce infarct size and improve the healing phase to increase postinfarct myocardial performance.
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Affiliation(s)
- Stéphanie Barrère-Lemaire
- Institut de Génomique Fonctionnelle, Université de Montpellier, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Montpellier, France
- LabEx Ion Channel Science and Therapeutics, Université de Nice, Nice, France
| | - Anne Vincent
- Institut de Génomique Fonctionnelle, Université de Montpellier, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Montpellier, France
- LabEx Ion Channel Science and Therapeutics, Université de Nice, Nice, France
| | - Christian Jorgensen
- Institute of Regenerative Medicine and Biotherapies, Université de Montpellier, Institut National de la Santé et de la Recherche Médicale, Montpellier, France
- Centre Hospitalier Universitaire Montpellier, Montpellier, France
| | - Christophe Piot
- Département de Cardiologie Interventionnelle, Clinique du Millénaire, Montpellier, France
| | - Joël Nargeot
- Institut de Génomique Fonctionnelle, Université de Montpellier, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Montpellier, France
- LabEx Ion Channel Science and Therapeutics, Université de Nice, Nice, France
| | - Farida Djouad
- Institute of Regenerative Medicine and Biotherapies, Université de Montpellier, Institut National de la Santé et de la Recherche Médicale, Montpellier, France
- Centre Hospitalier Universitaire Montpellier, Montpellier, France
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Li Y, Song D, Yu Z, Zhang Y, Liu Z, Yan T. Effect and mechanism of hypoxia on differentiation of porcine-induced pluripotent stem cells into vascular endothelial cells. In Vitro Cell Dev Biol Anim 2024; 60:9-22. [PMID: 38148354 DOI: 10.1007/s11626-023-00833-8] [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: 08/31/2023] [Accepted: 11/14/2023] [Indexed: 12/28/2023]
Abstract
Pigs are similar to humans in organ size and physiological function, and are considered as good models for studying cardiovascular diseases. The study of porcine-induced pluripotent stem cells (piPSC) differentiating into vascular endothelial cells (EC) is expected to open up a new way of obtaining high-quality seed cells. Given that the hypoxic environment has an important role in the differentiation process of vascular EC, this work intends to establish a hypoxia-induced differentiation system of piPSC into vascular EC. There is evidence that the hypoxia microenvironment in the initial stage could significantly improve differentiation efficiency. Further study suggests that the hypoxia culture system supports a combined effect of hypoxia inducible factors and their associated regulatory molecules, such as HIF-1α, VEGFA, FGF2, LDH-A, and PDK1, which can efficiently promote the lineage-specific differentiation of piPSC into EC. Most notably, the high level of ETV2 after 4 d of hypoxic treatment indicates that it possibly plays an important role in the promoting process of EC differentiation. The research is expected to help the establishment of new platforms for piPSC directional induction research, so as to obtain adequate seed cells with ideal phenotype and functionality.
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Affiliation(s)
- Yimei Li
- Key Laboratory of Animal Cellular and Genetic Engineering of Heilongjiang Province, College of Life Science, Northeast Agricultural University, Harbin, 150030, Heilongjiang, China
- College of Life Science, Northeast Agricultural University, Harbin, 150030, China
| | - Danyang Song
- Key Laboratory of Animal Cellular and Genetic Engineering of Heilongjiang Province, College of Life Science, Northeast Agricultural University, Harbin, 150030, Heilongjiang, China
- College of Life Science, Northeast Agricultural University, Harbin, 150030, China
| | - Zhuoran Yu
- Key Laboratory of Animal Cellular and Genetic Engineering of Heilongjiang Province, College of Life Science, Northeast Agricultural University, Harbin, 150030, Heilongjiang, China
- College of Life Science, Northeast Agricultural University, Harbin, 150030, China
| | - Yu Zhang
- Key Laboratory of Animal Cellular and Genetic Engineering of Heilongjiang Province, College of Life Science, Northeast Agricultural University, Harbin, 150030, Heilongjiang, China
- School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an 710061, China
| | - Zhonghua Liu
- Key Laboratory of Animal Cellular and Genetic Engineering of Heilongjiang Province, College of Life Science, Northeast Agricultural University, Harbin, 150030, Heilongjiang, China
- College of Life Science, Northeast Agricultural University, Harbin, 150030, China
| | - Tingsheng Yan
- Key Laboratory of Animal Cellular and Genetic Engineering of Heilongjiang Province, College of Life Science, Northeast Agricultural University, Harbin, 150030, Heilongjiang, China.
- College of Life Science, Northeast Agricultural University, Harbin, 150030, China.
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10
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Bhaskara M, Anjorin O, Wang M. Mesenchymal Stem Cell-Derived Exosomal microRNAs in Cardiac Regeneration. Cells 2023; 12:2815. [PMID: 38132135 PMCID: PMC10742005 DOI: 10.3390/cells12242815] [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: 11/15/2023] [Revised: 12/01/2023] [Accepted: 12/05/2023] [Indexed: 12/23/2023] Open
Abstract
Mesenchymal stem cell (MSC)-based therapy is one of the most promising modalities for cardiac repair. Accumulated evidence suggests that the therapeutic value of MSCs is mainly attributable to exosomes. MSC-derived exosomes (MSC-Exos) replicate the beneficial effects of MSCs by regulating various cellular responses and signaling pathways implicated in cardiac regeneration and repair. miRNAs constitute an important fraction of exosome content and are key contributors to the biological function of MSC-Exo. MSC-Exo carrying specific miRNAs provides anti-apoptotic, anti-inflammatory, anti-fibrotic, and angiogenic effects within the infarcted heart. Studying exosomal miRNAs will provide an important insight into the molecular mechanisms of MSC-Exo in cardiac regeneration and repair. This significant information can help optimize cell-free treatment and overcome the challenges associated with MSC-Exo therapeutic application. In this review, we summarize the characteristics and the potential mechanisms of MSC-derived exosomal miRNAs in cardiac repair and regeneration.
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Affiliation(s)
| | | | - Meijing Wang
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA
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Amini H, Namjoo AR, Narmi MT, Mardi N, Narimani S, Naturi O, Khosrowshahi ND, Rahbarghazi R, Saghebasl S, Hashemzadeh S, Nouri M. Exosome-bearing hydrogels and cardiac tissue regeneration. Biomater Res 2023; 27:99. [PMID: 37803483 PMCID: PMC10559618 DOI: 10.1186/s40824-023-00433-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Accepted: 09/18/2023] [Indexed: 10/08/2023] Open
Abstract
BACKGROUND In recent years, cardiovascular disease in particular myocardial infarction (MI) has become the predominant cause of human disability and mortality in the clinical setting. The restricted capacity of adult cardiomyocytes to proliferate and restore the function of infarcted sites is a challenging issue after the occurrence of MI. The application of stem cells and byproducts such as exosomes (Exos) has paved the way for the alleviation of cardiac tissue injury along with conventional medications in clinics. However, the short lifespan and activation of alloreactive immune cells in response to Exos and stem cells are the main issues in patients with MI. Therefore, there is an urgent demand to develop therapeutic approaches with minimum invasion for the restoration of cardiac function. MAIN BODY Here, we focused on recent data associated with the application of Exo-loaded hydrogels in ischemic cardiac tissue. Whether and how the advances in tissue engineering modalities have increased the efficiency of whole-based and byproducts (Exos) therapies under ischemic conditions. The integration of nanotechnology and nanobiology for designing novel smart biomaterials with therapeutic outcomes was highlighted. CONCLUSION Hydrogels can provide suitable platforms for the transfer of Exos, small molecules, drugs, and other bioactive factors for direct injection into the damaged myocardium. Future studies should focus on the improvement of physicochemical properties of Exo-bearing hydrogel to translate for the standard treatment options.
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Affiliation(s)
- Hassan Amini
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of General and Vascular Surgery, Tabriz University of Medical Sciences, Tabriz, 51548/53431, Iran
| | - Atieh Rezaei Namjoo
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Maryam Taghavi Narmi
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Narges Mardi
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Samaneh Narimani
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ozra Naturi
- Department of Organic and Biochemistry, Faculty of Chemistry, University of Tabriz, Tabriz, Iran
| | - Nafiseh Didar Khosrowshahi
- Stem Cell and Tissue Engineering Research Laboratory, Sahand University of Technology, Tabriz, 51335-1996, Iran
| | - Reza Rahbarghazi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
- Department of Applied Cell Sciences, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, 51548/53431, Iran.
| | - Solmaz Saghebasl
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
- Department of Applied Cell Sciences, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, 51548/53431, Iran.
| | - Shahriar Hashemzadeh
- Department of General and Vascular Surgery, Tabriz University of Medical Sciences, Tabriz, 51548/53431, Iran.
| | - Mohammad Nouri
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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12
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Ala M. The beneficial effects of mesenchymal stem cells and their exosomes on myocardial infarction and critical considerations for enhancing their efficacy. Ageing Res Rev 2023; 89:101980. [PMID: 37302757 DOI: 10.1016/j.arr.2023.101980] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 04/17/2023] [Accepted: 06/08/2023] [Indexed: 06/13/2023]
Abstract
Mesenchymal stem cells (MSCs) are multipotent stromal cells with regenerative, anti-inflammatory, and immunomodulatory properties. MSCs and their exosomes significantly improved structural and functional alterations after myocardial infarction (MI) in preclinical studies and clinical trials. By reprograming intracellular signaling pathways, MSCs attenuate inflammatory response, oxidative stress, apoptosis, pyroptosis, and endoplasmic reticulum (ER) stress and improve angiogenesis, mitochondrial biogenesis, and myocardial remodeling after MI. MSC-derived exosomes contain a mixture of non-coding RNAs, growth factors, anti-inflammatory mediators, and anti-fibrotic factors. Although primary results from clinical trials were promising, greater efficacies can be achieved by controlling several modifiable factors. The optimum timing of transplantation, route of administration, origin of MSCs, number of doses, and number of cells per dose need to be further investigated by future studies. Newly, highly effective MSC delivery systems have been developed to improve the efficacy of MSCs and their exosomes. Moreover, MSCs can be more efficacious after being pretreated with non-coding RNAs, growth factors, anti-inflammatory or inflammatory mediators, and hypoxia. Similarly, viral vector-mediated overexpression of particular genes can augment the protective effects of MSCs on MI. Therefore, future clinical trials must consider these advances in preclinical studies to properly reflect the efficacy of MSCs or their exosomes for MI.
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Affiliation(s)
- Moein Ala
- Experimental Medicine Research Center, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
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13
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Kędziora A, Konstanty-Kalandyk J, Litwinowicz R, Mazur P, Kapelak B, Piątek J. Hybrid techniques for myocardial regeneration: state of the art and future perspectives. ADVANCES IN INTERVENTIONAL CARDIOLOGY 2022; 18:360-365. [PMID: 36967853 PMCID: PMC10031663 DOI: 10.5114/aic.2022.121124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Accepted: 11/01/2022] [Indexed: 11/18/2022] Open
Abstract
Myocardium has a limited proliferative capacity, and adult hearts are considered incapable of regenerating after injury. A significant loss in the viable myocardium eventually diminishes the heart's ability to contract synchronously, leading to heart failure. Despite the development in interventional and pharmacological treatment for ischemic heart disease and heart failure, there is a significant number of highly symptomatic patients. For these individuals, treatments that stimulate myocardial regeneration can offer alleviation of dyspnea and angina and improvement in quality of life. Stem cells are known to promote neovascularization and endothelial repair. Various stem cell lines have been investigated over the years to establish those with the highest potential to differentiate into cardiomyocytes, including bone marrow-derived mononuclear cells, mesenchymal stromal cells, CD34+, CD133+, endothelial progenitor cells, and adipose-derived mesenchymal stromal cells. Stem cell studies were based on several delivery pathways: infusion into coronary vessels, direct injection into the injured region of the myocardium, and delivery within the novel bioengineered scaffolds. Acellular materials have also been investigated over the years. They demonstrate the therapeutic potential to promote angiogenesis and release of growth factors to improve the restoration of critical components of the extracellular matrix. This review summarizes hybrid cardiac regeneration treatments that combine novel bioengineering techniques with delivery approaches that cardiac surgeons can provide.
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Affiliation(s)
- Anna Kędziora
- Department of Cardiovascular Surgery and Transplantology, John Paul II Hospital, Krakow, Poland
- Jagiellonian University Medical College, Krakow, Poland
| | - Janusz Konstanty-Kalandyk
- Department of Cardiovascular Surgery and Transplantology, John Paul II Hospital, Krakow, Poland
- Jagiellonian University Medical College, Krakow, Poland
| | - Radosław Litwinowicz
- Jagiellonian University Medical College, Krakow, Poland
- Department of Cardiac Surgery, Regional Specialist Hospital, Grudziadz, Poland
| | - Piotr Mazur
- Department of Cardiovascular Surgery and Transplantology, John Paul II Hospital, Krakow, Poland
- Jagiellonian University Medical College, Krakow, Poland
- Department of Cardiac Surgery, Leipzig Heart Center, Leipzig, Germany
- Department of Cardiovascular Surgery, Mayo Clinic, Rochester MIN, USA
| | - Bogusław Kapelak
- Department of Cardiovascular Surgery and Transplantology, John Paul II Hospital, Krakow, Poland
- Jagiellonian University Medical College, Krakow, Poland
| | - Jacek Piątek
- Department of Cardiovascular Surgery and Transplantology, John Paul II Hospital, Krakow, Poland
- Jagiellonian University Medical College, Krakow, Poland
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14
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Tekieli Ł, Szot W, Kwiecień E, Mazurek A, Borkowska E, Czyż Ł, Dąbrowski M, Kozynacka A, Skubera M, Podolec P, Majka M, Kostkiewicz M, Musiałek P. Single-photon emission computed tomography as a fundamental tool in evaluation of myocardial reparation and regeneration therapies. ADVANCES IN INTERVENTIONAL CARDIOLOGY 2022; 18:326-339. [PMID: 36967839 PMCID: PMC10031666 DOI: 10.5114/aic.2023.124403] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2022] [Accepted: 06/14/2022] [Indexed: 01/26/2023] Open
Abstract
Despite unquestionable progress in interventional and pharmacologic therapies of ischemic heart disease, the number of patients with chronic ischemic heart failure is increasing and the prognosis remains poor. Repair/restoration of functional myocardium through progenitor cell-mediated (PCs) healing and renovation of injured myocardium is one of the pivotal directions in biomedical research. PCs release numerous pro-angiogenic and anti-apoptotic factors. Moreover, they have self-renewal capability and may differentiate into specialized cells that include endothelial cells and cardiomyocytes. Uptake and homing of PCs in the zone(s) of ischaemic injury (i.e., their effective transplantation to the target zone) is an essential pre-requisite for any potential therapeutic effect; thus effective cell tracking is fundamental in pre-clinical and early clinical studies. Another crucial requirement in rigorous research is quantification of the infarct zone, including the amount of non-perfused and hypo-perfused myocardium. Quantitative and reproducible evaluation of global and regional myocardial contractility and left ventricular remodeling is particularly relevant in clinical studies. Using SPECT, our earlier work has addressed several critical questions in cardiac regenerative medicine including optimizing transcoronary cell delivery, determination of the zone(s) of myocardial cell uptake, and late functional improvement in relation to the magnitude of cell uptake. Here, we review the role of single-photon emission computed tomography (SPECT), a technique that offers high-sensitivity, quantitative cell tracking on top of its ability to evaluate myocardial perfusion and function on both cross-sectional and longitudinal bases. SPECT, with its direct relevance to routine clinical practice, is a fundamental tool in evaluation of myocardial reparation and regeneration therapies.
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Affiliation(s)
- Łukasz Tekieli
- Department of Cardiac and Vascular Diseases, John Paul II Hospital, Jagiellonian University, Krakow, Poland
- Department of Interventional Cardiology, John Paul II Hospital, Jagiellonian University, Krakow, Poland
| | - Wojciech Szot
- Department of Radiology, John Paul II Hospital, Krakow, Poland
| | - Ewa Kwiecień
- Department of Cardiac and Vascular Diseases, John Paul II Hospital, Jagiellonian University, Krakow, Poland
| | - Adam Mazurek
- Department of Cardiac and Vascular Diseases, John Paul II Hospital, Jagiellonian University, Krakow, Poland
| | - Eliza Borkowska
- Department of Radiology, John Paul II Hospital, Krakow, Poland
| | - Łukasz Czyż
- Department of Cardiac and Vascular Diseases, John Paul II Hospital, Jagiellonian University, Krakow, Poland
| | - Maciej Dąbrowski
- Department of Interventional Cardiology and Angiology, National Institute of Cardiology, Warsaw, Poland
| | - Anna Kozynacka
- Department of Coronary Artery Disease and Heart Failure, John Paul II Hospital, Jagiellonian University, Krakow, Poland
| | - Maciej Skubera
- Department of Cardiac and Vascular Diseases, John Paul II Hospital, Jagiellonian University, Krakow, Poland
| | - Piotr Podolec
- Department of Cardiac and Vascular Diseases, John Paul II Hospital, Jagiellonian University, Krakow, Poland
| | - Marcin Majka
- Department of Transplantation, Jagiellonian University, Krakow, Poland
| | | | - Piotr Musiałek
- Department of Cardiac and Vascular Diseases, John Paul II Hospital, Jagiellonian University, Krakow, Poland
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Kim YS, Kim M, Cho DI, Lim SY, Jun JH, Kim MR, Kang BG, Eom GH, Kang G, Yoon S, Ahn Y. PSME4 Degrades Acetylated YAP1 in the Nucleus of Mesenchymal Stem Cells. Pharmaceutics 2022; 14:pharmaceutics14081659. [PMID: 36015285 PMCID: PMC9415559 DOI: 10.3390/pharmaceutics14081659] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 08/04/2022] [Accepted: 08/05/2022] [Indexed: 11/16/2022] Open
Abstract
Intensive research has focused on minimizing the infarct area and stimulating endogenous regeneration after myocardial infarction. Our group previously elucidated that apicidin, a histone deacetylase (HDAC) inhibitor, robustly accelerates the cardiac commitment of naïve mesenchymal stem cells (MSCs) through acute loss of YAP1. Here, we propose the novel regulation of YAP1 in MSCs. We found that acute loss of YAP1 after apicidin treatment resulted in the mixed effects of transcriptional arrest and proteasomal degradation. Subcellular fractionation revealed that YAP1 was primarily localized in the cytoplasm. YAP1 was acutely relocalized into the nucleus and underwent proteasomal degradation. Interestingly, phosphor-S127 YAP1 was shuttled into the nucleus, suggesting that a mechanism other than phosphorylation governed the subcellular localization of YAP1. Apicidin successfully induced acetylation and subsequent dissociation of YAP1 from 14-3-3, an essential molecule for cytoplasmic restriction. HDAC6 regulated both acetylation and subcellular localization of YAP1. An acetylation-dead mutant of YAP1 retarded nuclear redistribution upon apicidin treatment. We failed to acquire convincing evidence for polyubiquitination-dependent degradation of YAP1, suggesting that a polyubiquitination-independent regulator determined YAP1 fate. Nuclear PSME4, a subunit of the 26 S proteasome, recognized and degraded acetyl YAP1 in the nucleus. MSCs from PSME4-null mice were injected into infarcted heart, and aberrant sudden death was observed. Injection of immortalized human MSCs after knocking down PSME4 failed to improve either cardiac function or the fibrotic scar area. Our data suggest that acetylation-dependent proteasome subunit PSME4 clears acetyl-YAP1 in response to apicidin treatment in the nucleus of MSCs.
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Affiliation(s)
- Yong Sook Kim
- Biomedical Research Institute, Chonnam National University Hospital, Gwangju 61469, Korea
| | - Mira Kim
- Department of Pharmacology, Chonnam National University Medical School, Hwasun 58128, Korea
| | - Dong Im Cho
- Biomedical Research Institute, Chonnam National University Hospital, Gwangju 61469, Korea
| | - Soo Yeon Lim
- Biomedical Research Institute, Chonnam National University Hospital, Gwangju 61469, Korea
| | - Ju Hee Jun
- Biomedical Research Institute, Chonnam National University Hospital, Gwangju 61469, Korea
| | - Mi Ra Kim
- Biomedical Research Institute, Chonnam National University Hospital, Gwangju 61469, Korea
| | - Bo Gyeong Kang
- Biomedical Research Institute, Chonnam National University Hospital, Gwangju 61469, Korea
| | - Gwang Hyeon Eom
- Department of Pharmacology, Chonnam National University Medical School, Hwasun 58128, Korea
| | - Gaeun Kang
- Division of Clinical Pharmacology, Chonnam National University Hospital, Gwangju 61469, Korea
- Correspondence: (G.K.); (S.Y.); (Y.A.)
| | - Somy Yoon
- College of Pharmacy, Chonnam National University, Gwangju 61186, Korea
- Correspondence: (G.K.); (S.Y.); (Y.A.)
| | - Youngkeun Ahn
- Department of Cardiology, Chonnam National University Hospital, Gwangju 61469, Korea
- Correspondence: (G.K.); (S.Y.); (Y.A.)
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16
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Pournemati B, Tabesh H, Jenabi A, Mehdinavaz Aghdam R, Hossein Rezayan A, Poorkhalil A, Ahmadi Tafti SH, Mottaghy K. Injectable conductive nanocomposite hydrogels for cardiac tissue engineering: Focusing on carbon and metal-based nanostructures. Eur Polym J 2022. [DOI: 10.1016/j.eurpolymj.2022.111336] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
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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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18
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Wang M, Yan L, Li Q, Yang Y, Turrentine M, March K, Wang IW. Mesenchymal stem cell secretions improve donor heart function following ex vivo cold storage. J Thorac Cardiovasc Surg 2022; 163:e277-e292. [PMID: 32981709 PMCID: PMC7921217 DOI: 10.1016/j.jtcvs.2020.08.095] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Revised: 08/15/2020] [Accepted: 08/24/2020] [Indexed: 12/20/2022]
Abstract
OBJECTIVES Heart transplantation is the gold standard of treatments for end-stage heart failure, but its use is limited by extreme shortage of donor organs. The time "window" between procurement and transplantation sets the stage for myocardial ischemia/reperfusion injury, which constrains the maximal storage time and lowers use of donor organs. Given mesenchymal stem cell (MSC)-derived paracrine protection, we aimed to evaluate the efficacy of MSC-conditioned medium (CM) and extracellular vesicles (EVs) when added to ex vivo preservation solution on ameliorating ischemia/reperfusion-induced myocardial damage in donor hearts. METHODS Mouse donor hearts were stored at 0°C-4°C of <1-hour cold ischemia (<1hr-I), 6hr-I + vehicle, 6hr-I + MSC-CM, 6hr-I + MSC-EVs, and 6hr-I + MSC-CM from MSCs treated with exosome release inhibitor. The hearts were then heterotopically implanted into recipient mice. At 24 hours postsurgery, myocardial function was evaluated. Heart tissue was collected for analysis of histology, apoptotic cell death, microRNA (miR)-199a-3p expression, and myocardial cytokine production. RESULTS Six-hour cold ischemia significantly impaired myocardial function, increased cell death, and reduced miR-199a-3p in implanted hearts versus <1hr-I. MSC-CM or MSC-EVs in preservation solution reversed the detrimental effects of prolong cold ischemia on donor hearts. Exosome-depleted MSC-CM partially abolished MSC secretome-mediated cardioprotection in implanted hearts. MiR-199a-3p was highly enriched in MSC-EVs. MSC-CM and MSC-EVs increased cold ischemia-downregulated miR-199a-3p in donor hearts, whereas exosome-depletion neutralized this effect. CONCLUSIONS MSC-CM and MSC-EVs confer improved myocardial preservation in donor hearts during prolonged cold static storage and MSC-EVs can be used for intercellular transport of miRNAs in heart transplantation.
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Affiliation(s)
- Meijing Wang
- Division of Cardiothoracic Surgery, Department of Surgery, IU School of Medicine, Indianapolis, Ind.
| | - Liangliang Yan
- Division of Cardiothoracic Surgery, Department of Surgery, IU School of Medicine, Indianapolis, Ind; Department of Cardiovascular Surgery, Fujian Medical University Union Hospital, Fujian, China
| | - Qianzhen Li
- Division of Cardiothoracic Surgery, Department of Surgery, IU School of Medicine, Indianapolis, Ind; Department of Cardiovascular Surgery, Fujian Medical University Union Hospital, Fujian, China; Division of Cardiovascular Medicine, Department of Medicine, IU School of Medicine, Indianapolis, Ind
| | - Yang Yang
- Division of Cardiothoracic Surgery, Department of Surgery, IU School of Medicine, Indianapolis, Ind
| | - Mark Turrentine
- Division of Cardiothoracic Surgery, Department of Surgery, IU School of Medicine, Indianapolis, Ind
| | - Keith March
- Division of Cardiovascular Medicine, Department of Medicine, IU School of Medicine, Indianapolis, Ind; Division of Cardiovascular Medicine, Center for Regenerative Medicine, University of Florida, Gainesville, Fla
| | - I-Wen Wang
- Division of Cardiothoracic Surgery, Department of Surgery, IU School of Medicine, Indianapolis, Ind; Methodist Hospital, IU Health, IU School of Medicine, Indianapolis, Ind.
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Poomani MS, Mariappan I, Perumal R, Regurajan R, Muthan K, Subramanian V. Mesenchymal Stem Cell (MSCs) Therapy for Ischemic Heart Disease: A Promising Frontier. Glob Heart 2022; 17:19. [PMID: 35342702 PMCID: PMC8916054 DOI: 10.5334/gh.1098] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Accepted: 01/26/2022] [Indexed: 01/07/2023] Open
Abstract
Although tremendous progress has been made in conventional treatment for ischemic heart disease, it still remains a major cause of death and disability. Cell-based therapeutics holds an exciting frontier of research for complete cardiac recuperation. The capacity of diverse stem and progenitor cells to stimulate cardiac renewal has been analysed, with promising results in both pre-clinical and clinical trials. Mesenchymal stem cells have been ascertained to have regenerative ability via a variety of mechanisms, including differentiation from the mesoderm lineage, immunomodulatory properties, and paracrine effects. Also, their availability, maintenance, and ability to replenish endogenous stem cell niches have rendered them suitable for front-line research. This review schemes to outline the use of mesenchymal stem cell therapeutics for ischemic heart disease, their characteristics, the potent mechanisms of mesenchymal stem cell-based heart regeneration, and highlight preclinical data. Additionally, we discuss the results of the clinical trials to date as well as ongoing clinical trials on ischemic heart disease.
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Affiliation(s)
- Merlin Sobia Poomani
- Department of Biotechnology, Manonmaniam Sundaranar University, Tirunelveli 627012, Tamil Nadu, India
| | - Iyyadurai Mariappan
- Department of Biotechnology, Manonmaniam Sundaranar University, Tirunelveli 627012, Tamil Nadu, India
| | | | - Rathika Regurajan
- Center for Marine Science and Technology, Manonmaniam Sundaranar University, Tirunelveli 627012 Tamil Nadu, India
| | - Krishnaveni Muthan
- Center for Marine Science and Technology, Manonmaniam Sundaranar University, Tirunelveli 627012 Tamil Nadu, India
| | - Venkatesh Subramanian
- Department of Biotechnology, Manonmaniam Sundaranar University, Tirunelveli 627012, Tamil Nadu, India
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Gokce C, Gurcan C, Delogu LG, Yilmazer A. 2D Materials for Cardiac Tissue Repair and Regeneration. Front Cardiovasc Med 2022; 9:802551. [PMID: 35224044 PMCID: PMC8873146 DOI: 10.3389/fcvm.2022.802551] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Accepted: 01/13/2022] [Indexed: 12/12/2022] Open
Abstract
Cardiovascular diseases (CVDs) have a massive impact on human health. Due to the limited regeneration capacity of adult heart tissue, CVDs are the leading cause of death and disability worldwide. Even though there are surgical and pharmacological treatments for CVDs, regenerative strategies are the most promising approaches and have the potential to benefit millions of people. As in any other tissue engineering approach, the repair and regeneration of damaged cardiac tissues generally involve scaffolds made up of biodegradable and biocompatible materials, cellular components such as stem cells, and growth factors. This review provides an overview of biomaterial-based tissue engineering approaches for CVDs with a specific focus on the potential of 2D materials. It is essential to consider both physicochemical and immunomodulatory properties for evaluating the applicability of 2D materials in cardiac tissue repair and regeneration. As new members of the 2D materials will be explored, they will quickly become part of cardiac tissue engineering technologies.
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Affiliation(s)
- Cemile Gokce
- Department of Biomedical Engineering, Ankara University, Ankara, Turkey
| | - Cansu Gurcan
- Department of Biomedical Engineering, Ankara University, Ankara, Turkey
- Stem Cell Institute, Ankara University, Ankara, Turkey
| | | | - Acelya Yilmazer
- Department of Biomedical Engineering, Ankara University, Ankara, Turkey
- Stem Cell Institute, Ankara University, Ankara, Turkey
- *Correspondence: Acelya Yilmazer
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Zou D, Vigen M, Putnam AJ, Cao C, Tarlé SA, Guinn T, Kaigler D. Phenotypic, trophic, and regenerative properties of mesenchymal stem cells from different osseous tissues. Cell Tissue Res 2022; 388:75-88. [DOI: 10.1007/s00441-021-03563-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Accepted: 11/16/2021] [Indexed: 12/18/2022]
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22
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Modulation of Mesenchymal Stem Cells for Enhanced Therapeutic Utility in Ischemic Vascular Diseases. Int J Mol Sci 2021; 23:ijms23010249. [PMID: 35008675 PMCID: PMC8745455 DOI: 10.3390/ijms23010249] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 12/23/2021] [Accepted: 12/24/2021] [Indexed: 12/12/2022] Open
Abstract
Mesenchymal stem cells are multipotent stem cells isolated from various tissue sources, including but not limited to bone marrow, adipose, umbilical cord, and Wharton Jelly. Although cell-mediated mechanisms have been reported, the therapeutic effect of MSCs is now recognized to be primarily mediated via paracrine effects through the secretion of bioactive molecules, known as the “secretome”. The regenerative benefit of the secretome has been attributed to trophic factors and cytokines that play neuroprotective, anti-angiogenic/pro-angiogenic, anti-inflammatory, and immune-modulatory roles. The advancement of autologous MSCs therapy can be hindered when introduced back into a hostile/disease environment. Barriers include impaired endogenous MSCs function, limited post-transplantation cell viability, and altered immune-modulatory efficiency. Although secretome-based therapeutics have gained popularity, many translational hurdles, including the heterogeneity of MSCs, limited proliferation potential, and the complex nature of the secretome, have impeded the progress. This review will discuss the experimental and clinical impact of restoring the functional capabilities of MSCs prior to transplantation and the progress in secretome therapies involving extracellular vesicles. Modulation and utilization of MSCs–secretome are most likely to serve as an effective strategy for promoting their ultimate success as therapeutic modulators.
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Bagno LL, Salerno AG, Balkan W, Hare JM. Mechanism of Action of Mesenchymal Stem Cells (MSCs): impact of delivery method. Expert Opin Biol Ther 2021; 22:449-463. [PMID: 34882517 DOI: 10.1080/14712598.2022.2016695] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
INTRODUCTION Mesenchymal stromal cells (MSCs; AKA mesenchymal stem cells) stimulate healing and reduce inflammation. Promising therapeutic responses are seen in many late-phase clinical trials, but others have not satisfied their primary endpoints, making translation of MSCs into clinical practice difficult. These inconsistencies may be related to the route of MSC delivery, lack of product optimization, or varying background therapies received in clinical trials over time. AREAS COVERED Here we discuss the different routes of MSC delivery, highlighting the proposed mechanism(s) of therapeutic action as well as potential safety concerns. PubMed search criteria used: MSC plus: local administration; routes of administration; delivery methods; mechanism of action; therapy in different diseases. EXPERT OPINION Direct injection of MSCs using a controlled local delivery approach appears to have benefits in certain disease states, but further studies are required to make definitive conclusions regarding the superiority of one delivery method over another.
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Affiliation(s)
- Luiza L Bagno
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Alessandro G Salerno
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Wayne Balkan
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA.,Department of Medicine, University of Miami Miller School of Medicine, Miami
| | - Joshua M Hare
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA.,Department of Medicine, University of Miami Miller School of Medicine, Miami
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24
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Attar A, Bahmanzadegan Jahromi F, Kavousi S, Monabati A, Kazemi A. Mesenchymal stem cell transplantation after acute myocardial infarction: a meta-analysis of clinical trials. Stem Cell Res Ther 2021; 12:600. [PMID: 34876213 PMCID: PMC8650261 DOI: 10.1186/s13287-021-02667-1] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Accepted: 11/18/2021] [Indexed: 12/17/2022] Open
Abstract
Background Trials investigating the role of mesenchymal stem cells (MSCs) in increasing ejection fraction (LVEF) after acute myocardial infarction (AMI) have raised some controversies. This study was conducted to find whether transplantation of MSCs after AMI can help improve myocardial performance indices or clinical outcomes. Methods Randomized trials which evaluated transplantation of MSCs after AMI were enrolled. The primary outcome was LVEF change. We also assessed the role of cell origin, cell number, transplantation time interval after AMI, and route of cell delivery on the primary outcome. Results Thirteen trials including 956 patients (468 and 488 in the intervention and control arms) were enrolled. After excluding the biased data, LVEF was significantly increased compared to the baseline among those who received MSC (WMD = 3.78%, 95% CI: 2.14 to 5.42, p < 0.001, I2 = 90.2%) with more pronounced effect if the transplantation occurred within the first week after AMI (MD = 5.74%, 95%CI: 4.297 to 7.183; I2 = 79.2% p < 0.001). The efficacy of trans-endocardial injection was similar to that of intracoronary infusion (4% [95%CI: 2.741 to 5.259, p < 0.001] vs. 3.565% [95%CI: 1.912 to 5.218, p < 0.001], respectively). MSC doses of lower and higher than 107 cells did not improve LVEF differently (5.24% [95%CI: 2.06 to 8.82, p = 0.001] vs. 3.19% [95%CI: 0.17 to 6.12, p = 0.04], respectively).
Conclusion Transplantation of MSCs after AMI significantly increases LVEF, showing a higher efficacy if done in the first week. Further clinical studies should be conducted to investigate long-term clinical outcomes such as heart failure and cardiovascular mortality. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-021-02667-1.
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Affiliation(s)
- Armin Attar
- Department of Cardiovascular Medicine, TAHA Clinical Trial Group, School of Medicine, Shiraz University of Medical Sciences, Zand Street, Shiraz, Iran.
| | | | - Shahin Kavousi
- Students' Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Ahmad Monabati
- Hematology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.,Department of Pathology, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Asma Kazemi
- Nutrition Research Center, Shiraz University of Medical Sciences, PO Box 71645-111, Shiraz, Iran.
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25
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Paracrine Regulation of Alveolar Epithelial Damage and Repair Responses by Human Lung-Resident Mesenchymal Stromal Cells. Cells 2021; 10:cells10112860. [PMID: 34831082 PMCID: PMC8616441 DOI: 10.3390/cells10112860] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 10/17/2021] [Accepted: 10/21/2021] [Indexed: 11/17/2022] Open
Abstract
COPD is characterized by irreversible lung tissue damage. We hypothesized that lung-derived mesenchymal stromal cells (LMSCs) reduce alveolar epithelial damage via paracrine processes, and may thus be suitable for cell-based strategies in COPD. We aimed to assess whether COPD-derived LMSCs display abnormalities. LMSCs were isolated from lung tissue of severe COPD patients and non-COPD controls. Effects of LMSC conditioned-medium (CM) on H2O2-induced, electric field- and scratch-injury were studied in A549 and NCI-H441 epithelial cells. In organoid models, LMSCs were co-cultured with NCI-H441 or primary lung cells. Organoid number, size and expression of alveolar type II markers were assessed. Pre-treatment with LMSC-CM significantly attenuated oxidative stress-induced necrosis and accelerated wound repair in A549. Co-culture with LMSCs supported organoid formation in NCI-H441 and primary epithelial cells, resulting in significantly larger organoids with lower type II-marker positivity in the presence of COPD-derived versus control LMSCs. Similar abnormalities developed in organoids from COPD compared to control-derived lung cells, with significantly larger organoids. Collectively, this indicates that LMSCs' secretome attenuates alveolar epithelial injury and supports epithelial repair. Additionally, LMSCs promote generation of alveolar organoids, with abnormalities in the supportive effects of COPD-derived LMCS, reflective of impaired regenerative responses of COPD distal lung cells.
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26
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Pan Q, Xu J, Wen CJ, Xiong YY, Gong ZT, Yang YJ. Nanoparticles: Promising Tools for the Treatment and Prevention of Myocardial Infarction. Int J Nanomedicine 2021; 16:6719-6747. [PMID: 34621124 PMCID: PMC8491866 DOI: 10.2147/ijn.s328723] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Accepted: 09/17/2021] [Indexed: 12/12/2022] Open
Abstract
Despite several recent advances, current therapy and prevention strategies for myocardial infarction are far from satisfactory, owing to limitations in their applicability and treatment effects. Nanoparticles (NPs) enable the targeted and stable delivery of therapeutic compounds, enhance tissue engineering processes, and regulate the behaviour of transplants such as stem cells. Thus, NPs may be more effective than other mechanisms, and may minimize potential adverse effects. This review provides evidence for the view that function-oriented systems are more practical than traditional material-based systems; it also summarizes the latest advances in NP-based strategies for the treatment and prevention of myocardial infarction.
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Affiliation(s)
- Qi Pan
- State Key Laboratory of Cardiovascular Disease, Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China
| | - Jing Xu
- State Key Laboratory of Cardiovascular Disease, Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China
| | - Cen-Jin Wen
- Department of Cardiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China
| | - Yu-Yan Xiong
- State Key Laboratory of Cardiovascular Disease, Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China
| | - Zhao-Ting Gong
- State Key Laboratory of Cardiovascular Disease, Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China
| | - Yue-Jin Yang
- State Key Laboratory of Cardiovascular Disease, Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China
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27
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Abu-El-Rub E, Khasawneh RR, Almahasneh F, Altaany Z, Bataineh N, Zegallai H, Sekaran S. Mesenchymal stem cells and COVID-19: What they do and what they can do. World J Stem Cells 2021; 13:1318-1337. [PMID: 34630865 PMCID: PMC8474724 DOI: 10.4252/wjsc.v13.i9.1318] [Citation(s) in RCA: 2] [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: 03/14/2021] [Revised: 06/15/2021] [Accepted: 08/27/2021] [Indexed: 02/06/2023] Open
Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or coronavirus disease 2019 (COVID-19) pandemic has exhausted the health systems in many countries with thousands cases diagnosed daily. The currently used treatment guideline is to manage the common symptoms like fever and cough, but doesn't target the virus itself or halts serious complications arising from this viral infection. Currently, SARS-CoV-2 exhibits many genetic modulations which have been associated with the appearance of highly contagious strains. The number of critical cases of COVID-19 increases markedly, and many of the infected people die as a result of respiratory failure and multiple organ dysfunction. The regenerative potential of mesenchymal stem cells (MSCs) has been extensively studied and confirmed. The impressive immunomodulation and anti-inflammatory activity of MSCs have been recognized as a golden opportunity for the treatment of COVID-19 and its associated complications. Moreover, MSCs regenerative and repairing abilities have been corroborated by many studies with positive outcomes and high recovery rates. Based on that, MSCs infusion could be an effective mechanism in managing and stemming the serious complications and multiple organ failure associated with COVID-19. In the present review, we discuss the commonly reported complications of COVID-19 viral infection and the established and anticipated role of MSCs in managing these complications.
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Affiliation(s)
- Ejlal Abu-El-Rub
- Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg R2H2A6, Canada
- Department of Physiology and Pathophysiology, Basic Medical Sciences, Yarmouk University, IRBID 21163, Jordan.
| | - Ramada R Khasawneh
- Department of Anatomy and Histology, Basic Medical Sciences, Yarmouk University, IRBID 21163, Jordan
| | - Fatimah Almahasneh
- Department of Physiology and Pharmacology, Basic Medical Sciences, Yarmouk University, IRBID 21163, Jordan
| | - Zaid Altaany
- Department of Biochemistry and Genetics, Basic Medical Sciences, Yarmouk University, IRBID 21163, Jordan
| | - Nesreen Bataineh
- Department of Pathology, Basic Medical Sciences, Yarmouk University, IRBID 21163, Jordan
| | - Hana Zegallai
- Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg R2H2A6, Canada
| | - Saravanan Sekaran
- Department of Pharmacology, Saveetha Dental College and Hospitals to be University, Chennai 600077, India
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Oxygen Delivery Approaches to Augment Cell Survival After Myocardial Infarction: Progress and Challenges. Cardiovasc Toxicol 2021; 22:207-224. [PMID: 34542796 DOI: 10.1007/s12012-021-09696-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2021] [Accepted: 09/11/2021] [Indexed: 10/20/2022]
Abstract
Myocardial infarction (MI), triggered by blockage of a coronary artery, remains the most common cause of death worldwide. After MI, the capability of providing sufficient blood and oxygen significantly decreases in the heart. This event leads to depletion of oxygen from cardiac tissue and consequently leads to massive cardiac cell death due to hypoxemia. Over the past few decades, many studies have been carried out to discover acceptable approaches to treat MI. However, very few have addressed the crucial role of efficient oxygen delivery to the injured heart. Thus, various strategies were developed to increase the delivery of oxygen to cardiac tissue and improve its function. Here, we have given an overall discussion of the oxygen delivery mechanisms and how the current technologies are employed to treat patients suffering from MI, including a comprehensive view on three major technical approaches such as oxygen therapy, hemoglobin-based oxygen carriers (HBOCs), and oxygen-releasing biomaterials (ORBs). Although oxygen therapy and HBOCs have shown promising results in several animal and clinical studies, they still have a few drawbacks which limit their effectiveness. More recent studies have investigated the efficacy of ORBs which may play a key role in the future of oxygenation of cardiac tissue. In addition, a summary of conducted studies under each approach and the remaining challenges of these methods are discussed.
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29
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Botleroo RA, Bhandari R, Ahmed R, Kareem R, Gyawali M, Venkatesan N, Ogeyingbo OD, Elshaikh AO. Stem Cell Therapy for the Treatment of Myocardial Infarction: How Far Are We Now? Cureus 2021; 13:e17022. [PMID: 34522503 PMCID: PMC8425504 DOI: 10.7759/cureus.17022] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2021] [Accepted: 08/09/2021] [Indexed: 12/26/2022] Open
Abstract
Myocardial infarction is one of the leading causes of death worldwide. Poor functional recovery of the myocardium is noticed after an event of myocardial infarction. Researchers and clinicians around the world have been engaged to regenerate the damaged human heart for a long time. Stem cell therapy is an exciting newer therapy to treat cardiovascular diseases. Various types of stem cells have been used to revive the damaged myocardium after myocardial infarction, and they have overall demonstrated safety and moderate efficacy. The specific mechanisms by which these cells help in improving cardiac function are still not completely known. There is growing evidence that intracoronary bone marrow cell transplantation in patients with myocardial infarction beneficially affects the remodeling of the damaged myocardium. Our systematic review article aims to assess the effects and the future of stem cell therapy in patients with myocardial Infarction. We searched articles in PubMed, ScienceDirect, and Google Scholar. Thirty-one studies that included 2171 patients in total were analyzed. Most of these studies showed stem cell therapy is safe and well tolerated in patients, and modest improvements are seen in left ventricular functions with no major adverse effects. However, some studies showed no positive and clinically significant outcomes. So, more high-quality studies on a larger scale are required to support and confirm its efficacy in remodeling damaged myocardium after myocardial infarction. We should also perform studies to determine the timing of cell delivery that is best suited for stem cell therapy.
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Affiliation(s)
- Rinky A Botleroo
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Renu Bhandari
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA.,Internal Medicine, Manipal College of Medical Sciences, Pokhara, NPL
| | - Rowan Ahmed
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Roaa Kareem
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Mallika Gyawali
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Nanditha Venkatesan
- Internal Medicine, All India Institute of Medical Sciences, Raipur, IND.,Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Opemipo D Ogeyingbo
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA.,Internal Medicine, Saint James School of Medicine, Park Ridge, USA.,Public Health, Walden University, Minneapolis, USA
| | - Abeer O Elshaikh
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
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30
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Arjmand B, Abedi M, Arabi M, Alavi-Moghadam S, Rezaei-Tavirani M, Hadavandkhani M, Tayanloo-Beik A, Kordi R, Roudsari PP, Larijani B. Regenerative Medicine for the Treatment of Ischemic Heart Disease; Status and Future Perspectives. Front Cell Dev Biol 2021; 9:704903. [PMID: 34568321 PMCID: PMC8461329 DOI: 10.3389/fcell.2021.704903] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Accepted: 07/19/2021] [Indexed: 12/20/2022] Open
Abstract
Cardiovascular disease is now the leading cause of adult death in the world. According to new estimates from the World Health Organization, myocardial infarction (MI) is responsible for four out of every five deaths due to cardiovascular disease. Conventional treatments of MI are taking aspirin and nitroglycerin as intermediate treatments and injecting antithrombotic agents within the first 3 h after MI. Coronary artery bypass grafting and percutaneous coronary intervention are the most common long term treatments. Since none of these interventions will fully regenerate the infarcted myocardium, there is value in pursuing more innovative therapeutic approaches. Regenerative medicine is an innovative interdisciplinary method for rebuilding, replacing, or repairing the missed part of different organs in the body, as similar as possible to the primary structure. In recent years, regenerative medicine has been widely utilized as a treatment for ischemic heart disease (one of the most fatal factors around the world) to repair the lost part of the heart by using stem cells. Here, the development of mesenchymal stem cells causes a breakthrough in the treatment of different cardiovascular diseases. They are easily obtainable from different sources, and expanded and enriched easily, with no need for immunosuppressing agents before transplantation, and fewer possibilities of genetic abnormality accompany them through multiple passages. The production of new cardiomyocytes can result from the transplantation of different types of stem cells. Accordingly, due to its remarkable benefits, stem cell therapy has received attention in recent years as it provides a drug-free and surgical treatment for patients and encourages a more safe and feasible cardiac repair. Although different clinical trials have reported on the promising benefits of stem cell therapy, there is still uncertainty about its mechanism of action. It is important to conduct different preclinical and clinical studies to explore the exact mechanism of action of the cells. After reviewing the pathophysiology of MI, this study addresses the role of tissue regeneration using various materials, including different types of stem cells. It proves some appropriate data about the importance of ethical problems, which leads to future perspectives on this scientific method.
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Affiliation(s)
- Babak Arjmand
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
- Metabolomics and Genomics Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Mina Abedi
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Maryam Arabi
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Sepideh Alavi-Moghadam
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Mahdieh Hadavandkhani
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Akram Tayanloo-Beik
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Ramin Kordi
- Sports Medicine Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Peyvand Parhizkar Roudsari
- Metabolomics and Genomics Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Bagher Larijani
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
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Saheli M, Pirhajati Mahabadi V, Mesbah-Namin SA, Seifalian A, Bagheri-Hosseinabadi Z. DNA methyltransferase inhibitor 5-azacytidine in high dose promotes ultrastructural maturation of cardiomyocyte. Stem Cell Investig 2021; 7:22. [PMID: 33437842 DOI: 10.21037/sci-2020-007] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2020] [Accepted: 12/01/2020] [Indexed: 01/26/2023]
Abstract
Background The adult human heart muscle cells, cardiomyocytes are not capable of regenerate after injury. Stem cells are a powerful means for future regenerative medicine because of their capacity for self-renewal and multipotency. Several studies have reported the cardiogenic potential in human adipose tissue-derived stem cells (ADSCs) differentiation, but there is still no efficient protocol for the induction of cardiac differentiation by 5-azacytidine (5-Aza). The present study involves characterization and mainly, the ultrastructure of ADSCs derived cardiomyocyte-like cells. Methods The cultured ADSCs were treated with 50 µM 5-Aza for 24 hours, followed by a 10-week extension. At different time points, cardiomyocyte-like cells were assessed by qRT-PCR and were evaluated by transmission electron microscopy at 10th week. Results The expression of cardiac-specific markers entailing cardiac troponin I (cTnI), connexin 43, myosin light chain-2v (Mlc-2v), increased over 10 weeks and the highest expression was at 10th week. The expression of the β-myosin heavy chain (β-MHC) increased significantly over 5 weeks and then decreased. At the ultrastructural level myofibrils, transverse tubules (T-tubules), sarcoplasmic reticular membrane, and intercalated discs were present. Conclusions These data suggest that treatment with 5-Aza in high dose could promote differentiation of ADSCs into cardiomyocyte-like cells. These differentiated cells could be used for regeneration of damaged cardiomyocytes with the 3D scaffold for delivery of the cells.
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Affiliation(s)
- Mona Saheli
- Department of Anatomical Sciences, Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Vahid Pirhajati Mahabadi
- Neuroscience Research Center, Vice-Chancellor for Research and Technology, Iran University of Medical Sciences, Tehran, Iran.,Cellular and Molecular Research Center, Vice-Chancellor for Research and Technology, Iran university of Medical Sciences, Tehran, Iran
| | - Seyed Alireza Mesbah-Namin
- Department of Clinical Biochemistry, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Alexander Seifalian
- Nanotechnology and Regenerative Medicine Commercialisation Centre (NanoRegMed Ltd.), London BioScience Innovation Centre, London, UK
| | - Zahra Bagheri-Hosseinabadi
- Department of Clinical Biochemistry, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran.,Physiology Research Center, Kerman University of Medical Sciences, Kerman, Iran
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32
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Niada S, Giannasi C, Magagnotti C, Andolfo A, Brini AT. Proteomic analysis of extracellular vesicles and conditioned medium from human adipose-derived stem/stromal cells and dermal fibroblasts. J Proteomics 2020; 232:104069. [PMID: 33309826 DOI: 10.1016/j.jprot.2020.104069] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Revised: 10/23/2020] [Accepted: 11/29/2020] [Indexed: 12/19/2022]
Abstract
Conditioned medium (CM) and extracellular vesicles (EV) from Adipose-derived Stem/stromal cells (ASC) and Dermal fibroblasts (DF) represent promising tools for therapeutic applications. Which one should be preferred is still under debate and no direct comparison of their proteome has been reported yet. Here, we apply quantitative proteomics to explore the protein composition of CM and EV from the two cell types. Data are available via ProteomeXchange (identifier PXD020219). We identified 1977 proteins by LC-MS/MS proteomic analysis. Unsupervised clustering analysis and PCA recognized CM and EV as separate groups. We identified 68 and 201 CM and EV specific factors. CM were enriched in proteins of endoplasmic reticulum, Golgi apparatus and lysosomes, whereas EV contained a large amount of GTPases, ribosome and translation factors. The analysis of ASC and DF secretomes revealed the presence of cell type-specific proteins. ASC-CM and -EV carried factors involved in ECM organization and immunological regulation, respectively. Conversely, DF-CM and -EV were enriched in epithelium development associated factors and -EV in Wnt signaling factors. In conclusion, this analysis provides evidence of a different protein composition between CM and EV and of the presence of cell type-specific bioactive mediators suggesting their specific future use as advanced therapy medicinal products. SIGNIFICANCE: The use of cell secretome presents several advantages over cell therapy such as the lower risks associated to the administration step and the avoidance of any potential risk of malignant transformation. The main secretome preparations consist in concentrated conditioned medium (CM) and extracellular vesicles (EV). Both of them showed well-documented therapeutic potentials. However, it is still not clear in which case it should be better to use one preparation over the other and an exhaustive comparison between their proteome has not been performed yet. The choice of the cell source is another relevant aspect that still needs to be addressed. In order to shed light on these questions we explored the protein composition of CM and EV obtained from Adipose-derived Stem/stromal Cells (ASC) and Dermal Fibroblasts (DF), by a comprehensive quantitative proteomics approach. The analysis showed a clear distinction between CM and EV proteome. CM were enriched in proteins of endoplasmic reticulum, Golgi apparatus and lysosomes, whereas EV contained a large amount of GTPases, ribosome and translation-related factors. Furthermore, the analysis of ASC and DF secretomes revealed specific biological processes for the different cell products. ASC secretome presented factors involved in ECM organization (hyaluronan and glycosaminoglycan metabolism) and immunological regulation (e.g. macrophage and IkB/NFkB signaling regulation), respectively. On the other hand, DF-CM and -EV were both enriched in epithelium development associated factors, whilst DF-CM in proteins involved in cellular processes regulation and -EV in Wnt signaling factors. In conclusion, our study shed a light on the different protein composition of CM and EV of two promising cell types, spanning from basic processes involved in secretion to specific pathways supporting their therapeutic potential and their possible future use as advanced therapy medicinal products.
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Affiliation(s)
| | | | - Cinzia Magagnotti
- Proteomics and Metabolomics Facility (ProMeFa), IRCCS San Raffaele Scientific Institute, Milan, Italy.
| | - Annapaola Andolfo
- Proteomics and Metabolomics Facility (ProMeFa), IRCCS San Raffaele Scientific Institute, Milan, Italy.
| | - Anna Teresa Brini
- IRCCS Istituto Ortopedico Galeazzi, Milan, Italy; Department of Biomedical, Surgical and Dental Sciences, Università degli Studi di Milano, Milan, Italy.
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33
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Ellison-Hughes GM, Colley L, O'Brien KA, Roberts KA, Agbaedeng TA, Ross MD. The Role of MSC Therapy in Attenuating the Damaging Effects of the Cytokine Storm Induced by COVID-19 on the Heart and Cardiovascular System. Front Cardiovasc Med 2020; 7:602183. [PMID: 33363221 PMCID: PMC7756089 DOI: 10.3389/fcvm.2020.602183] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Accepted: 11/17/2020] [Indexed: 01/08/2023] Open
Abstract
The global pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes coronavirus disease 2019 (COVID-19) has led to 47 m infected cases and 1. 2 m (2.6%) deaths. A hallmark of more severe cases of SARS-CoV-2 in patients with acute respiratory distress syndrome (ARDS) appears to be a virally-induced over-activation or unregulated response of the immune system, termed a "cytokine storm," featuring elevated levels of pro-inflammatory cytokines such as IL-2, IL-6, IL-7, IL-22, CXCL10, and TNFα. Whilst the lungs are the primary site of infection for SARS-CoV-2, in more severe cases its effects can be detected in multiple organ systems. Indeed, many COVID-19 positive patients develop cardiovascular complications, such as myocardial injury, myocarditis, cardiac arrhythmia, and thromboembolism, which are associated with higher mortality. Drug and cell therapies targeting immunosuppression have been suggested to help combat the cytokine storm. In particular, mesenchymal stromal cells (MSCs), owing to their powerful immunomodulatory ability, have shown promise in early clinical studies to avoid, prevent or attenuate the cytokine storm. In this review, we will discuss the mechanistic underpinnings of the cytokine storm on the cardiovascular system, and how MSCs potentially attenuate the damage caused by the cytokine storm induced by COVID-19. We will also address how MSC transplantation could alleviate the long-term complications seen in some COVID-19 patients, such as improving tissue repair and regeneration.
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Affiliation(s)
- Georgina M. Ellison-Hughes
- Faculty of Life Sciences & Medicine, Centre for Human and Applied Physiological Sciences, School of Basic and Medical Biosciences, King's College London Guy's Campus, London, United Kingdom
| | - Liam Colley
- School of Sport, Health, and Exercise Sciences, Bangor University, Bangor, United Kingdom
| | - Katie A. O'Brien
- Department of Physiology, Development, and Neuroscience, University of Cambridge, Cambridge, United Kingdom
| | - Kirsty A. Roberts
- Research Institute for Sport and Exercise Sciences, Liverpool John Moores University, Liverpool, United Kingdom
| | - Thomas A. Agbaedeng
- Faculty of Health & Medical Sciences, Centre for Heart Rhythm Disorders, School of Medicine, The University of Adelaide, Adelaide, SA, Australia
| | - Mark D. Ross
- School of Applied Sciences, Edinburgh Napier University, Edinburgh, United Kingdom
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The role of mesenchymal stem/stromal cells in the acute clinical setting. Am J Emerg Med 2020; 46:572-578. [PMID: 33279332 DOI: 10.1016/j.ajem.2020.11.035] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Revised: 11/09/2020] [Accepted: 11/15/2020] [Indexed: 12/14/2022] Open
Abstract
INTRODUCTION Accumulating evidence supports the use of mesenchymal stem/stromal cells (MSCs), particularly bone marrow derived, as a safe and promising biologic therapy for promoting tissue repair and regeneration in various chronic diseases and disorders. Despite growing evidence that MSCs are potent anti-inflammatory mediators that can provide substantial benefits in acute organ injury, there are limited clinical trials utilizing MSCs in acute care settings, such as in the emergency department (ED) or intensive care unit (ICU). OBJECTIVE This article reviews the current state of MSC-based therapeutics and further explores the untapped potential role to treat various acute, life-threating injuries in the ED and ICU. DISCUSSION All clinical trials using MSCs in acute myocardial infarction (AMI), acute respiratory distress syndrome (ARDS), sepsis and acute kidney injury (AKI) demonstrated safety. While some also demonstrate clinical efficacy, efficacy data is inconsistent, with some studies limited by sample size, cell integrity and different dosages, necessitating further studies. CONCLUSION MSCs are potentially promising novel biologic therapeutics for clinical application in AMI, ARDS, sepsis, AKI and COVID-19 that have demonstrated safety in all clinical trials. More rigorous clinical trials are necessary and warranted to determine the efficacy of MSCs as a novel therapeutic in an acute setting, such as the ED.
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Hotham WE, Henson FMD. The use of large animals to facilitate the process of MSC going from laboratory to patient-'bench to bedside'. Cell Biol Toxicol 2020; 36:103-114. [PMID: 32206986 PMCID: PMC7196082 DOI: 10.1007/s10565-020-09521-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2019] [Accepted: 03/03/2020] [Indexed: 12/20/2022]
Abstract
Large animal models have been widely used to facilitate the translation of mesenchymal stem cells (MSC) from the laboratory to patient. MSC, with their multi-potent capacity, have been proposed to have therapeutic benefits in a number of pathological conditions. Laboratory studies allow the investigation of cellular and molecular interactions, while small animal models allow initial 'proof of concept' experiments. Large animals (dogs, pigs, sheep, goats and horses) are more similar physiologically and structurally to man. These models have allowed clinically relevant assessments of safety, efficacy and dosing of different MSC sources prior to clinical trials. In this review, we recapitulate the use of large animal models to facilitate the use of MSC to treat myocardial infarction-an example of one large animal model being considered the 'gold standard' for research and osteoarthritis-an example of the complexities of using different large animal models in a multifactorial disease. These examples show how large animals can provide a research platform that can be used to evaluate the value of cell-based therapies and facilitate the process of 'bench to bedside'.
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Affiliation(s)
- W E Hotham
- Division of Trauma and Orthopaedic Surgery, Cambridge University, Cambridge, UK.
| | - F M D Henson
- Division of Trauma and Orthopaedic Surgery, Cambridge University, Cambridge, UK
- Animal Health Trust, Newmarket, UK
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Schaeffer B, Tanigawa S, Nakamura T, Muthalaly RG, Sapp J, John R, Ghidoli D, Pellegrini C, Tedrow U, Stevenson WG. Characteristics of myocardial tissue staining and lesion creation with an infusion-needle ablation catheter for the treatment of ventricular tachycardia in humans. Heart Rhythm 2020; 17:398-405. [DOI: 10.1016/j.hrthm.2019.10.007] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Indexed: 01/09/2023]
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Adipose tissue derived mesenchymal stem cells are better respondents to TGFβ1 for in vitro generation of cardiomyocyte-like cells. Mol Cell Biochem 2019; 460:53-66. [DOI: 10.1007/s11010-019-03570-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Accepted: 06/04/2019] [Indexed: 12/14/2022]
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Lu D, Liao Y, Zhu SH, Chen QC, Xie DM, Liao JJ, Feng X, Jiang MH, He W. Bone-derived Nestin-positive mesenchymal stem cells improve cardiac function via recruiting cardiac endothelial cells after myocardial infarction. Stem Cell Res Ther 2019; 10:127. [PMID: 31029167 PMCID: PMC6487029 DOI: 10.1186/s13287-019-1217-x] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2018] [Revised: 03/17/2019] [Accepted: 03/19/2019] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Bone-derived mesenchymal stem cell (BMSC) transplantation has been reported to be effective for the treatment of ischemic heart disease, but whether BMSCs are the optimal cell type remains under debate. Increasing numbers of studies have shown that Nestin, an intermediate filament protein, is a potential marker for MSCs, which raises the question of whether Nestin+ cells in BMSCs may play a more crucial role in myocardial repair. METHODS Nestin+ cells were isolated using flow cytometry by gating for CD45- Ter119- CD31- cells from the compact bone of Nestin-GFP transgenic mice, expressing GFP driven by the Nestin promoter. Colony-forming and proliferative curve assays were conducted to determine the proliferative capacity of these cells, while qRT-PCR was used to analyze the mRNA levels of relative chemokines and growth factors. Cardiac endothelial cell (CEC) recruitment was assessed via a transwell assay. Moreover, permanent ligation of the left anterior descending (LAD) coronary artery was performed to establish an acute myocardial infarction (AMI) mouse model. After cell transplantation, conventional echocardiography was conducted 1 and 4 weeks post-MI, and hearts were harvested for hematoxylin-and-eosin (HE) staining and immunofluorescence staining 1 week post-MI. Further evaluation of paracrine factor levels and administration of a neutralizing antibody (TIMP-1, TIMP-2, and CXCL12) or a CXCR4 antagonist (AMD3100) in MI hearts were performed to elucidate the mechanism involved in the chemotactic effect of Nestin+ BMSCs in vivo. RESULTS Compared with Nestin- BMSCs, a greater proliferative capacity of Nestin+ BMSCs was observed, which further exhibited moderately high expression of chemokines instead of growth factors. More CEC recruitment in the Nestin+ BMSC-cocultured group was observed in vitro, while this effect was obviously abolished after treatment with neutralizing antibodies against TIMP-1, TIMP-2, or CXCL12, and more importantly, blocking the CXCL12/CXCR4 axis with a AMD3100 significantly reduced the chemotactic effect of Nestin+ BMSCs. After transplantation into mice exposed to myocardial infarction (MI), Nestin+ BMSC-treated mice showed significantly improved survival and left ventricular function compared with Nestin- BMSC-treated mice. Moreover, endogenous CECs were markedly increased, and chemokine levels were significantly higher, in the infarcted border zone with Nestin+ BMSC treatment. Meanwhile, neutralization of each TIMP-1, TIMP-2, or CXCL12 in vivo could reduce the left ventricular function at 1 and 4 weeks post-MI; importantly, the combined use of these three neutralizing antibodies could make a higher significance on cardiac function. Finally, blocking the CXCL12/CXCR4 axis with AMD3100 significantly reduced the left ventricular function and greatly inhibited Nestin+ BMSC-induced CEC chemotaxis in vivo. CONCLUSIONS These results suggest that Nestin+ BMSC transplantation can improve cardiac function in an AMI model by recruiting resident CECs to the infarcted border region via the CXCL12/CXCR4 chemokine pathway. And we demonstrated that Nestin+BMSC-secreted TIMP-1/2 enhances CXCL12(SDF1α)/CXCR4 axis-driven migration of endogenous Sca-1+ endothelial cells in ischemic heart post-AMI. Taken together, our results show that Nestin is a useful marker for the identification of functional BMSCs and indicate that Nestin+ BMSCs could be a better therapeutic candidate for cardiac repair.
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Affiliation(s)
- Dihan Lu
- Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, 510080, People's Republic of China
| | - Yan Liao
- Key Laboratory for Stem Cells and Tissue Engineering, Center for Stem Cell Biology and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou, Guangdong, 510080, People's Republic of China
| | - Shuang-Hua Zhu
- Department of Cardiology, the Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, 510080, People's Republic of China
| | - Qiao-Chao Chen
- Department of Geriatrics, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, 510080, People's Republic of China
| | - Dong-Mei Xie
- Department of Cardiology, the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, 510080, People's Republic of China
| | - Jian-Jun Liao
- Department of Geriatrics, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, 510080, People's Republic of China
| | - Xia Feng
- Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, 510080, People's Republic of China
| | - Mei Hua Jiang
- Key Laboratory for Stem Cells and Tissue Engineering, Center for Stem Cell Biology and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou, Guangdong, 510080, People's Republic of China. .,Department of Anatomy, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong, 510080, People's Republic of China.
| | - Wen He
- Department of Geriatrics, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, 510080, People's Republic of China.
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Fang Y, Zhang Y, Zhou J, Cao K. Adipose-derived mesenchymal stem cell exosomes: a novel pathway for tissues repair. Cell Tissue Bank 2019; 20:153-161. [PMID: 30852701 DOI: 10.1007/s10561-019-09761-y] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2018] [Accepted: 03/04/2019] [Indexed: 12/11/2022]
Abstract
The well-characterized curative effect of transplanted mesenchymal stem cells has been mainly attributed to their homing and subsequent differentiation for the repair and regeneration of damaged tissue. Adipose-derived mesenchymal stem cells (ADMSCs) are not only multipotent and plastic, but also abundant as they can be easily harvested with minimally invasive surgical techniques. This makes ADMSCs conducive for clinical applications. Recently, the secretory function of ADMSCs has been regarded as the primary mediator of MSC-based therapy. Exosomes are one kind of small cell extracellular membrane vesicles, which are primarily used to deliver cell-specific proteins, as well as nucleic acids secreted by various cell types. This review will introduce and characterize exosomes-derived ADMSCs (ADMSCs-Exo) and look at new therapies and prospective, including the limitations and outlook for therapeutic strategy. We will describe the latest research progress on myocardial repair, neuroprotection and neurotrophic effects, hepatic repair, renal repair, cutaneous repair, regeneration and other aspects using these cells.
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Affiliation(s)
- Yuan Fang
- The Third Xiangya Hospital of Central South University, No.138.Tongzipo Road, 410013, Changsha, Hunan, People's Republic of China
| | - Yufang Zhang
- Anyang Tumor Hospital, No. 1 Huanbin North Road, 455000, Anyang, Henan, People's Republic of China
| | - Jianda Zhou
- The Third Xiangya Hospital of Central South University, No.138.Tongzipo Road, 410013, Changsha, Hunan, People's Republic of China.
| | - Ke Cao
- The Third Xiangya Hospital of Central South University, No.138.Tongzipo Road, 410013, Changsha, Hunan, People's Republic of China.
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Liang X, Ding Y, Lin F, Zhang Y, Zhou X, Meng Q, Lu X, Jiang G, Zhu H, Chen Y, Lian Q, Fan H, Liu Z. Overexpression of ERBB4 rejuvenates aged mesenchymal stem cells and enhances angiogenesis via PI3K/AKT and MAPK/ERK pathways. FASEB J 2019; 33:4559-4570. [PMID: 30566395 DOI: 10.1096/fj.201801690r] [Citation(s) in RCA: 92] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The age-related functional exhaustion limits potential efficacy of mesenchymal stem cells (MSC) in treating cardiovascular disease. Therefore, rejuvenation of aged MSC in the elderly population is of great interest. We have previously reported that Erb-B2 receptor tyrosine kinase 4 ( ERBB4) plays a critical role in regulating MSC survival under hypoxia. The aim of this study was to investigate whether ERBB4 rejuvenates aged MSC and how ERBB4 enhances therapeutic efficacy of aged MSC in treating myocardial infarction (MI). Compared with vector aged MSC (aged-MSC), ERBB4-engineered aged MSC (ER4-aged-MSC) conferred resistance to oxidative stress-induced cell death and ameliorated the senescent phenotype in vitro. Four weeks after MI, the ER4-aged-MSC group exhibited enhanced blood vessel density, reduced cardiac remodeling and apoptosis with improved heart function compared with the aged-MSC group. Overexpression of ERBB4 caused an increase in phosphorylated v-akt murine thymoma viral oncogene homolog 1 (AKT), and phosphorylated ERK expression under hypoxia. ER4-aged-MSC secreted higher levels of angiopoietin, epithelial neutrophil activating peptide 78, VEGF, and fibroblast growth factor 2, and enhanced tube formation in HUVEC. The impact of ERBB4 on protein expression, proangiogenesis, cell behavior, and cytokine secretion was abolished by inhibiting PI3K/AKT and MAPK/ERK signaling pathway.-Liang, X., Ding, Y., Lin, F., Zhang, Y., Zhou, X., Meng, Q., Lu, X., Jiang, G., Zhu, H., Chen, Y., Lian, Q., Fan, H., Liu, Z. Overexpression of ERBB4 rejuvenates aged mesenchymal stem cells and enhances angiogenesis via PI3K/AKT and MAPK/ERK pathways.
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Affiliation(s)
- Xiaoting Liang
- Clinical Translational Medical Research Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
- Translational Medical Center for Stem Cell Therapy, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yue Ding
- Department of Organ Transplantation, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Fang Lin
- Clinical Translational Medical Research Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yuelin Zhang
- Department of Emergency, Guangdong General Hospital, Guangdong Academy of Medical Science, China
- Faculty of Pharmacy, Bengbu Medical College, China
- Department of Medicine, The University of Hong Kong, Hong Kong, China; and
| | - Xiaohui Zhou
- Clinical Translational Medical Research Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Qingshu Meng
- Clinical Translational Medical Research Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Xingyue Lu
- Faculty of Pharmacy, Bengbu Medical College, China
| | - Guojun Jiang
- Faculty of Pharmacy, Bengbu Medical College, China
| | - Hongming Zhu
- Clinical Translational Medical Research Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
- Translational Medical Center for Stem Cell Therapy, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yu Chen
- Department of Organ Transplantation, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Qizhou Lian
- Department of Medicine, The University of Hong Kong, Hong Kong, China; and
| | - Huimin Fan
- Department of Cardiovascular and Thoracic Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Zhongmin Liu
- Translational Medical Center for Stem Cell Therapy, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
- Department of Cardiovascular and Thoracic Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
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Cellular Therapy for Ischemic Heart Disease: An Update. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1201:195-213. [PMID: 31898788 DOI: 10.1007/978-3-030-31206-0_10] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Ischemic heart disease (IHD), which includes heart failure (HF) induced by heart attack (myocardial infarction, MI), is a significant cause of morbidity and mortality worldwide (Benjamin, et al. Circulation 139:e56-e66, 2019). MI occurs at an alarmingly high rate in the United States (approx. One case every 40 seconds), and the failure to repair damaged myocardium is the leading cause of recurrent heart attacks, heart failure (HF), and death within 5 years of MI (Benjamin, et al. Circulation 139:e56-e66, 2019). At present, HF represents an unmet need with no approved clinical therapies to replace the damaged myocardium. As the population ages, the number of heart failure patients is projected to increase, doubling the annual cost by 2030 (Benjamin, et al. Circulation 139:e56-e66, 2019). In the past decades, stem cell therapy has become a promising strategy for cardiac regeneration. However, stem cell-based therapy yielded modest success in human clinical trials. This chapter examines the types of cells examined in cardiac therapy in the setting of IHD, with a brief introduction to ongoing research aiming at enhancing the therapeutic potential of transplanted cells.
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Yao Y, Liao W, Yu R, Du Y, Zhang T, Peng Q. Potentials of combining nanomaterials and stem cell therapy in myocardial repair. Nanomedicine (Lond) 2018; 13:1623-1638. [PMID: 30028249 DOI: 10.2217/nnm-2018-0013] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Cardiac diseases have become the leading cause of death worldwide. Developing efficient strategies to treat such diseases is of great urgency. Stem cell-based regeneration medicine offers a novel approach for heart repair. However, low retention and poor survival rate of engrafted cells limit its applications. Nanomaterials have shown great potentials in addressing above issues due to nanoparticles-bio interactions. Therefore, combining nanomaterials and stem cell therapy is of great interest and significance for heart repair. Herein, we provide a comprehensive understanding of the applications of four types of nanomaterials (nanogels, polymeric nanomaterials, inorganic nanomaterials and exosomes) in stem cell therapy for myocardial repair. In addition, we launch an initial discussion on current problems and more importantly, possible solutions for myocardial repair.
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Affiliation(s)
- Yang Yao
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China.,Department of Oral Implant Center, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Wen Liao
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China.,Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Ruichao Yu
- Department of Pathophysiology & Molecular Pharmacology, Joslin Diabetes Center, Harvard Medical School, 1 Joslin Place, Boston, MA 02215, USA
| | - Yu Du
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Ting Zhang
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Qiang Peng
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
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Wang BH, Liew D, Huang KW, Huang L, Tang W, Kelly DJ, Reid C, Liu Z. The Challenges of Stem Cell Therapy in Myocardial Infarction and Heart Failure and the Potential Strategies to Improve the Outcomes. ACTA ACUST UNITED AC 2018. [DOI: 10.1142/s1793984418410088] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Cardiovascular disease remains the single highest global cause of death and a significant financial burden on the healthcare system. Despite the advances in medical treatments, the prevalence and mortality for heart failure remain unacceptably high. New approaches are urgently needed to reduce this burden and improve patient outcomes and quality of life. One such promising approach is stem cell therapy, including embryonic stem cells, bone marrow derived stem cells, induced pluripotent stem cells and mesenchymal stem cells. However, the cardiac microenvironment following myocardial infarction poses huge challenges with inflammation, adequate retention, engraftment and functional incorporation all crucial concerns. The lack of cardiac regeneration, cell viability and functional improvement has hindered the success of stem cell therapy in clinical settings. The use of biomaterial scaffolds in conjunction with stem cells has recently been shown to enhance the outcome of stem cell therapy for heart failure and myocardial infarction. This review outlines some of the current challenges in the treatment of heart failure and acute myocardial infarction through improving stem cell therapeutic strategies, as well as the prospect of suitable biomaterial scaffolds to enhance their efficacy and improve patient clinical outcomes.
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Affiliation(s)
- Bing Hui Wang
- Monash Centre of Cardiovascular Research and Education in Therapeutics, School of Public Health and Preventive Medicine, Monash University, Melbourne 3004, Australia
| | - Danny Liew
- Monash Centre of Cardiovascular Research and Education in Therapeutics, School of Public Health and Preventive Medicine, Monash University, Melbourne 3004, Australia
| | - Kevin W. Huang
- Monash Centre of Cardiovascular Research and Education in Therapeutics, School of Public Health and Preventive Medicine, Monash University, Melbourne 3004, Australia
| | - Li Huang
- Monash Centre of Cardiovascular Research and Education in Therapeutics, School of Public Health and Preventive Medicine, Monash University, Melbourne 3004, Australia
| | - Wenjie Tang
- Department of Cardiovascular and Thoracic Surgery, Research Center for Translational Medicine and Biomedical Multidisciplinary Innovation Research Institute, Shanghai East Hospital, Tongji University, Shanghai 200120, P. R. China
| | - Darren J. Kelly
- Department of Medicine, St Vincent’s Hospital, University of Melbourne, Fitzroy Victoria, Australia
| | - Christopher Reid
- Monash Centre of Cardiovascular Research and Education in Therapeutics, School of Public Health and Preventive Medicine, Monash University, Melbourne 3004, Australia
| | - Zhongmin Liu
- Department of Cardiovascular and Thoracic Surgery, Research Center for Translational Medicine and Biomedical Multidisciplinary Innovation Research Institute, Shanghai East Hospital, Tongji University, Shanghai 200120, P. R. China
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Functionally Improved Mesenchymal Stem Cells to Better Treat Myocardial Infarction. Stem Cells Int 2018; 2018:7045245. [PMID: 30622568 PMCID: PMC6286742 DOI: 10.1155/2018/7045245] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2018] [Revised: 09/10/2018] [Accepted: 09/30/2018] [Indexed: 12/14/2022] Open
Abstract
Myocardial infarction (MI) is one of the leading causes of death worldwide. Mesenchymal stem cell (MSC) transplantation is considered a promising approach and has made significant progress in preclinical studies and clinical trials for treating MI. However, hurdles including poor survival, retention, homing, and differentiation capacity largely limit the therapeutic effect of transplanted MSCs. Many strategies such as preconditioning, genetic modification, cotransplantation with bioactive factors, and tissue engineering were developed to improve the survival and function of MSCs. On the other hand, optimizing the hostile transplantation microenvironment of the host myocardium is also of importance. Here, we review the modifications of MSCs as well as the host myocardium to improve the efficacy of MSC-based therapy against MI.
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Cell-Based Therapies for Cardiac Regeneration: A Comprehensive Review of Past and Ongoing Strategies. Int J Mol Sci 2018; 19:ijms19103194. [PMID: 30332812 PMCID: PMC6214096 DOI: 10.3390/ijms19103194] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2018] [Revised: 10/11/2018] [Accepted: 10/12/2018] [Indexed: 12/20/2022] Open
Abstract
Despite considerable improvements in the treatment of cardiovascular diseases, heart failure (HF) still represents one of the leading causes of death worldwide. Poor prognosis is mostly due to the limited regenerative capacity of the adult human heart, which ultimately leads to left ventricular dysfunction. As a consequence, heart transplantation is virtually the only alternative for many patients. Therefore, novel regenerative approaches are extremely needed, and several attempts have been performed to improve HF patients’ clinical conditions by promoting the replacement of the lost cardiomyocytes and by activating cardiac repair. In particular, cell-based therapies have been shown to possess a great potential for cardiac regeneration. Different cell types have been extensively tested in clinical trials, demonstrating consistent safety results. However, heterogeneous efficacy data have been reported, probably because precise end-points still need to be clearly defined. Moreover, the principal mechanism responsible for these beneficial effects seems to be the paracrine release of antiapoptotic and immunomodulatory molecules from the injected cells. This review covers past and state-of-the-art strategies in cell-based heart regeneration, highlighting the advantages, challenges, and limitations of each approach.
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Lalu MM, Mazzarello S, Zlepnig J, Dong YYR, Montroy J, McIntyre L, Devereaux PJ, Stewart DJ, David Mazer C, Barron CC, McIsaac DI, Fergusson DA. Safety and Efficacy of Adult Stem Cell Therapy for Acute Myocardial Infarction and Ischemic Heart Failure (SafeCell Heart): A Systematic Review and Meta-Analysis. Stem Cells Transl Med 2018; 7:857-866. [PMID: 30255989 PMCID: PMC6265630 DOI: 10.1002/sctm.18-0120] [Citation(s) in RCA: 95] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2018] [Accepted: 07/02/2018] [Indexed: 12/25/2022] Open
Abstract
Preclinical and clinical evidence suggests that mesenchymal stem cells (MSCs) may be beneficial in treating both acute myocardial infarction (AMI) and ischemic heart failure (IHF). However, the safety profile and efficacy of MSC therapy is not well‐known. We conducted a systematic review of clinical trials that evaluated the safety or efficacy of MSCs for AMI or IHF. Embase, PubMed/Medline, and Cochrane Central Register of Controlled Trials were searched from inception to September 27, 2017. Studies that examined the use of MSCs administered to adults with AMI or IHF were eligible. The Cochrane risk of bias tool was used to assess bias of included studies. The primary outcome was safety assessed by adverse events and the secondary outcome was efficacy which was assessed by mortality and left ventricular ejection fraction (LVEF). A total of 668 citations were reviewed and 23 studies met eligibility criteria. Of these, 11 studies evaluated AMI and 12 studies evaluated IHF. There was no association between MSCs and acute adverse events. There was a significant improvement in overall LVEF in patients who received MSCs (SMD 0.73, 95% CI 0.24–1.21). No significant difference in mortality was noted (Peto OR 0.68, 95% CI 0.38–1.22). Results from our systematic review suggest that MSC therapy for ischemic heart disease appears to be safe. There is a need for a well‐designed adequately powered randomized control trial (with rigorous adverse event reporting and evaluations of cardiac function) to further establish a clear risk‐benefit profile of MSCs. Stem Cells Translational Medicine2018;7:857–866
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Affiliation(s)
- Manoj M Lalu
- Department of Anesthesiology and Pain Medicine, The Ottawa Hospital, Ottawa, Ontario, Canada.,Blueprint Translational Research Group, Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.,Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.,Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Sasha Mazzarello
- Blueprint Translational Research Group, Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | - Jennifer Zlepnig
- Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | | | - Joshua Montroy
- Blueprint Translational Research Group, Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | - Lauralyn McIntyre
- Blueprint Translational Research Group, Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.,Division of Critical Care, The Ottawa Hospital, Ottawa, Ontario, Canada
| | - P J Devereaux
- Population Health Research Institute, David Braley Cardiac, Vascular, and Stroke Research Institute, Departments of Medicine and Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada
| | - Duncan J Stewart
- Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.,Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - C David Mazer
- Department of Anesthesia, Li Ka Shing Knowledge Institute of St. Michael's Hospital, University of Toronto, Department of Physiology, Toronto, Ontario, Canada
| | - Carly C Barron
- Department of Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Daniel I McIsaac
- Department of Anesthesiology and Pain Medicine, The Ottawa Hospital, Ottawa, Ontario, Canada.,Blueprint Translational Research Group, Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | - Dean A Fergusson
- Blueprint Translational Research Group, Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.,Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
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The use of stem cells in ischemic heart disease treatment. POLISH JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY 2018; 15:196-199. [PMID: 30310400 PMCID: PMC6180025 DOI: 10.5114/kitp.2018.78446] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/10/2018] [Accepted: 06/12/2018] [Indexed: 11/22/2022]
Abstract
Ischemic heart disease is a major cause of death and disabilities worldwide. Unfortunately, not all patients are suitable for direct revascularization. Cell-based therapies may be alternative options because of their potential to promote neovascularisation and endothelial repair, improving myocardial perfusion. The success of cell-based therapies depends on the type of implanted stem cells, delivery method and underlying disease. Several different cell populations including bone marrow-derived mononuclear cells (MNCs), mesenchymal stromal cells (MSCs), CD34+, CD133+, endothelial progenitor cells, adipose-derived mesenchymal stromal cells (ASCs) and stem cells from placenta and umbilical cord have been investigated. Presently, no consensus exists about the best cell type for clinical regenerative therapy. Because the system of coronary arteries in the ischemic area is poor and most of the coronary artery is significantly narrowed or closed, direct implantation of stem cells in the ischemic area of the heart muscle appears an attractive method.
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Kobayashi K, Suzuki K. Mesenchymal Stem/Stromal Cell-Based Therapy for Heart Failure ― What Is the Best Source? ―. Circ J 2018; 82:2222-2232. [DOI: 10.1253/circj.cj-18-0786] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Affiliation(s)
- Kazuya Kobayashi
- William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London
| | - Ken Suzuki
- William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London
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Abstract
After a myocardial infarction, heart tissue becomes irreversibly damaged, leading to scar formation and inevitably ischemic heart failure. Of the many available interventions after a myocardial infarction, such as percutaneous intervention or pharmacological optimization, none can reverse the ischemic insult on the heart and restore cardiac function. Thus, the only available cure for patients with scarred myocardium is allogeneic heart transplantation, which comes with extensive costs, risks, and complications. However, multiple studies have shown that the heart is, in fact, not an end-stage organ and that there are endogenous mechanisms in place that have the potential to spark regeneration. Stem cell therapy has emerged as a potential tool to tap into and activate this endogenous framework. Particularly promising are stem cells derived from cardiac tissue itself, referred to as cardiosphere-derived cells (CDCs). CDCs can be extracted and isolated from the patient's myocardium and then administered by intramyocardial injection or intracoronary infusion. After early success in the animal model, multiple clinical trials have demonstrated the safety and efficacy of autologous CDC therapy in humans. Clinical trials with allogeneic CDCs showed early promising results and pose a potential "off-the-shelf" therapy for patients in the acute setting after a myocardial infarction. The mechanism responsible for CDC-induced cardiac regeneration seems to be a combination of triggering native cardiomyocyte proliferation and recruitment of endogenous progenitor cells, which most prominently occurs via paracrine effects. A further understanding of the mediators involved in paracrine signaling can help with the development of a stem cell-free therapy, with all the benefits and none of the associated complications.
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Detela G, Bain OW, Kim HW, Williams DJ, Mason C, Mathur A, Wall IB. Donor Variability in Growth Kinetics of Healthy hMSCs Using Manual Processing: Considerations for Manufacture of Cell Therapies. Biotechnol J 2018; 13. [PMID: 29334181 DOI: 10.1002/biot.201700085] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2017] [Revised: 12/04/2017] [Indexed: 12/28/2022]
Abstract
Human mesenchymal stromal cells (hMSCs) are excellent candidates for cell therapy but their expansion to desired clinical quantities can be compromised by ex vivo processing, due to differences between donor material and process variation. The aim of this article is to characterize growth kinetics of healthy baseline "reference" hMSCs using typical manual processing. Bone-marrow derived hMSCs from ten donors are isolated based on plastic adherence, expanded, and analyzed for their growth kinetics until passage 4. Results indicate that hMSC density decreases with overall time in culture (p < 0.001) but no significant differences are observed between successive passages after passage 1. In addition, fold increase in cell number dropped between passage 1 and 2 for three batches, which correlated to lower performance in total fold increase and expansion potential of these batches, suggesting that proliferative ability of hMSCs can be predicted at an early stage. An indicative bounded operating window is determined between passage 1 and 3 (PDL < 10), despite the high inter-donor variability present under standardized hMSC expansion conditions used. hMSC growth profile analysis will be of benefit to cell therapy manufacturing as a tool to predict culture performance and attainment of clinically-relevant yields, therefore stratifying the patient population based on early observation.
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Affiliation(s)
- Giulia Detela
- Department of Biochemical Engineering, University College London, Gordon Street, WC1H 0AH, London, United Kingdom
| | - Owen W Bain
- Department of Biochemical Engineering, University College London, Gordon Street, WC1H 0AH, London, United Kingdom
| | - Hae-Won Kim
- Department of Nanobiomedical Science and BK21 Plus NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan 31116, Republic of Korea.,College of Dentistry and Institute of Tissue Regeneration Engineering (ITREN),, Dankook University, Cheonan 31116, Republic of Korea
| | - David J Williams
- Centre for Biological Engineering, Wolfson School of Mechanical and Manufacturing Engineering, Loughborough University, Loughborough LE11 3TU, United Kingdom
| | - Chris Mason
- Department of Biochemical Engineering, University College London, Gordon Street, WC1H 0AH, London, United Kingdom
| | - Anthony Mathur
- Barts Health NIHR Biomedical Research Unit, Department of Cardiology, London Chest Hospital, London E2 9JX, United Kingdom
| | - Ivan B Wall
- Department of Biochemical Engineering, University College London, Gordon Street, WC1H 0AH, London, United Kingdom.,Department of Nanobiomedical Science and BK21 Plus NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan 31116, Republic of Korea.,School of Life and Health Sciences, Aston University, Aston Triangle, B4 7ET, Birmingham, United Kingdom
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