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van der Pol A, Peters MC, Jorba I, Smits AM, van der Kaaij NP, Goumans MJ, Wever KE, Bouten CVC. Preclinical extracellular matrix-based treatment strategies for myocardial infarction: a systematic review and meta-analysis. COMMUNICATIONS MEDICINE 2025; 5:95. [PMID: 40159511 PMCID: PMC11955565 DOI: 10.1038/s43856-025-00812-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Accepted: 03/18/2025] [Indexed: 04/02/2025] Open
Abstract
BACKGROUND Administrating extracellular matrix (ECM) to restore cardiac function post-myocardial infarction (MI) shows promise, however study variability obscures its true impact. We therefore conducted a systematic review and meta-analysis of preclinical studies to assess the effects of ECM treatments on cardiac function and tissue homeostasis post-MI. METHODS We searched PubMed and SCOPUS from inception to June 28, 2024, for animal studies describing ECM treatment post-MI (pre-registered on PROSPERO, CRD42022368400). Random effects meta-analyses compared ECM treatment to controls regarding left ventricular ejection fraction (LVEF), fractional shortening, infarct size, stroke volume, and left ventricular wall thickness. Subgroup analyses examined the influence of sex, species, ECM source, and administration method. Funnel plots and Egger's regression assessed publication bias. RESULTS We identify 88 articles which meet our inclusion criteria. These studies describe the use of rats (51%), mice (38%), and pigs (11%). 44% of studies use males, 34% females, 5% both sexes, and 17% did not report sex. Most studies employ permanent MI models (85%) over ischemia reperfusion models (15%), and deliver ECM via intramyocardial injection (59%), cardiac patch (39%), cardiac sleeve (1%), or osmotic pump (1%). Our meta-analysis demonstrates that ECM treatment significantly improves LVEF (MD: 10.9%, 95% CI: [8.7%;13.0%]; p = 8.057e-24), fractional shortening (MD: 8.2%, 95% CI: [5.6%; 10.9%]; p = 1.751e-09), stroke volume (SMD 0.6, 95% CI: [0.2;1.0], p = 0.004), left ventricular wall thickening (SMD 1.2, 95% CI: [0.9; 1.5], p = 1.321e-17), while reducing infarct size (-11.7%, 95% CI: [-14.7%;-8.6%], p = 3.699e-14). We find no significant differences between the various subgroups and no indication of publication bias. CONCLUSIONS ECM-based treatments significantly enhance cardiac function and tissue homeostasis in preclinical post-MI models, supporting further research toward clinical translation.
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Affiliation(s)
- Atze van der Pol
- Soft Tissue Engineering and Mechanobiology, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands.
- Institute for Complex Molecular Systems, Eindhoven University of Technology, Eindhoven, The Netherlands.
| | - Marijn C Peters
- Soft Tissue Engineering and Mechanobiology, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands
- Institute for Complex Molecular Systems, Eindhoven University of Technology, Eindhoven, The Netherlands
- Department of Cardiothoracic Surgery, Regenerative Medicine Centre, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Ignasi Jorba
- Soft Tissue Engineering and Mechanobiology, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands
- Institute for Complex Molecular Systems, Eindhoven University of Technology, Eindhoven, The Netherlands
- Unitat de Biofísica i Bioenginyeria, Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona, 08036, Barcelona, Spain
| | - Anke M Smits
- Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, The Netherlands
| | - Niels P van der Kaaij
- Department of Cardiothoracic Surgery, Regenerative Medicine Centre, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Marie-Jose Goumans
- Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, The Netherlands
| | - Kimberley E Wever
- Department of Anesthesiology, Pain and Palliative Medicine, Radboud University Medical Center, Nijmegen, Gelderland, The Netherlands
| | - Carlijn V C Bouten
- Soft Tissue Engineering and Mechanobiology, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands.
- Institute for Complex Molecular Systems, Eindhoven University of Technology, Eindhoven, The Netherlands.
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Lee H, Cho HJ, Han Y, Lee SH. Mid- to long-term efficacy and safety of stem cell therapy for acute myocardial infarction: a systematic review and meta-analysis. Stem Cell Res Ther 2024; 15:290. [PMID: 39256845 PMCID: PMC11389242 DOI: 10.1186/s13287-024-03891-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Accepted: 08/21/2024] [Indexed: 09/12/2024] Open
Abstract
BACKGROUND This comprehensive systematic review and meta-analysis investigated the mid- to long-term efficacy and safety of stem cell therapy in patients with acute myocardial infarction (AMI). METHODS The study encompassed 79 randomized controlled trials with 7103 patients, rendering it the most up-to-date and extensive analysis in this field. This study specifically focused on the impact of stem cell therapy on left ventricular ejection fraction (LVEF), major adverse cardiac events (MACE), and infarct size. RESULTS Stem cell therapy significantly improved LVEF at 6, 12, 24, and 36 months post-transplantation compared to control values, indicating its potential for long-term cardiac function enhancement. A trend toward reduced MACE occurrence was observed in the intervention groups, suggesting the potential of stem cell therapy to lower the risk of cardiovascular death, reinfarction, and stroke. Significant LVEF improvements were associated with long cell culture durations exceeding 1 week, particularly when combined with high injected cell quantities (at least 108 cells). No significant reduction in infarct size was observed. CONCLUSIONS This review highlights the potential of stem cell therapy as a promising therapeutic approach for patients with AMI, offering sustained LVEF improvement and a potential reduction in MACE risk. However, further research is required to optimize cell culture techniques, determine the optimal timing and dosage, and investigate procedural variations to maximize the efficacy and safety of stem cell therapy in this context.
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Affiliation(s)
- Hyeongsuk Lee
- College of Nursing, Research Institute of AI and Nursing Science, Gachon University, 191 Hambakmoero, Yeonsu-gu, Incheon, 21936, South Korea
| | - Hyun-Jai Cho
- Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea
| | - Yeonjung Han
- College of Nursing, Research Institute of AI and Nursing Science, Gachon University, 191 Hambakmoero, Yeonsu-gu, Incheon, 21936, South Korea
| | - Seon Heui Lee
- College of Nursing, Research Institute of AI and Nursing Science, Gachon University, 191 Hambakmoero, Yeonsu-gu, Incheon, 21936, South Korea.
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Le DCP, Bui HT, Vu YTH, Vo QD. Induced pluripotent stem cell therapies in heart failure treatment: a meta-analysis and systematic review. Regen Med 2024; 19:497-509. [PMID: 39263954 PMCID: PMC11487948 DOI: 10.1080/17460751.2024.2393558] [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: 06/27/2024] [Accepted: 08/14/2024] [Indexed: 09/13/2024] Open
Abstract
Background: Heart failure (HF) causes over 266,400 deaths annually. Despite treatment advancements, HF mortality remains high. Induced pluripotent stem cells (iPSCs) offer promising new options. This review assesses iPSC-based treatments for HF.Method: the review included studies from PubMed, ScienceDirect and Web of Science.Results: Analysis of 25 studies with 553 animals showed a baseline ejection fraction (EF) of 39.2 ± 8.9%. iPSC treatment significantly improved EF (MD = 8.6, p < 0.001) and fractional shortening (MD = 6.38, p < 0.001), and reduced ventricular remodeling without increasing arrhythmia risk.Conclusion: iPSC-based therapy improves heart function and reduces ventricular volumes in HF animal models, aligning with promising early clinical trial outcomes.
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Affiliation(s)
- Duy Cao Phuong Le
- Departmentof Cardiovascular Intervention, Nguyen Tri Phuong Hospital, Ho Chi Minh city, 700000, Vietnam
- Faculty of Medicine, Nguyen Tat Thanh University, Ho Chi Minh City, 700000, Vietnam
| | - Hoa The Bui
- Departmentof Cardiovascular Intervention, Nguyen Tri Phuong Hospital, Ho Chi Minh city, 700000, Vietnam
| | - Yen Thi Hai Vu
- Faculty of Medicine, Thai Binh University of Medicine, Thai Binh, 61000, Vietnam
| | - Quan Duy Vo
- Departmentof Cardiovascular Intervention, Nguyen Tri Phuong Hospital, Ho Chi Minh city, 700000, Vietnam
- Faculty of Medicine, Nguyen Tat Thanh University, Ho Chi Minh City, 700000, Vietnam
- Cardiovascular Medicine Department, Okayama University, Okayama city, 7000000, Japan
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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: 27] [Impact Index Per Article: 27.0] [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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Attar A, Farjoud Kouhanjani M, Hessami K, Vosough M, Kojuri J, Ramzi M, Hosseini SA, Faghih M, Monabati A. Effect of once versus twice intracoronary injection of allogeneic-derived mesenchymal stromal cells after acute myocardial infarction: BOOSTER-TAHA7 randomized clinical trial. Stem Cell Res Ther 2023; 14:264. [PMID: 37740221 PMCID: PMC10517503 DOI: 10.1186/s13287-023-03495-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2023] [Accepted: 09/12/2023] [Indexed: 09/24/2023] Open
Abstract
BACKGROUND Mesenchymal stromal cell (MSC) transplantation can improve the left ventricular ejection fraction (LVEF) after an acute myocardial infarction (AMI). Transplanted MSCs exert a paracrine effect, which might be augmented if repeated doses are administered. This study aimed to compare the effects of single versus double transplantation of Wharton's jelly MSCs (WJ-MSCs) on LVEF post-AMI. METHODS We conducted a single-blind, randomized, multicenter trial. After 3-7 days of an AMI treated successfully by primary PCI, 70 patients younger than 65 with LVEF < 40% on baseline echocardiography were randomized to receive conventional care, a single intracoronary infusion of WJ-MSCs, or a repeated infusion 10 days later. The primary endpoint was the 6-month LVEF improvement as per cardiac magnetic resonance (CMR) imaging. RESULTS The mean baseline EF measured by CMR was similar (~ 40%) in all three groups. By the end of the trial, while all patients experienced a rise in EF, the most significant change was seen in the repeated intervention group. Compared to the control group (n = 25), single MSC transplantation (n = 20) improved the EF by 4.54 ± 2%, and repeated intervention (n = 20) did so by 7.45 ± 2% when measured by CMR imaging (P < 0.001); when evaluated by echocardiography, these values were 6.71 ± 2.4 and 10.71 ± 2.5%, respectively (P < 0.001). CONCLUSIONS Intracoronary transplantation of WJ-MSCs 3-7 days after AMI in selected patients significantly improves LVEF, with the infusion of a booster dose 10 days later augmenting this effect. TRIAL REGISTRATION Trial registration: Iranian Registry of Clinical Trials, IRCT20201116049408N1. Retrospectively Registered 20 Nov. 2020, https://en.irct.ir/trial/52357.
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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, 71344-1864, Iran.
| | | | - Kamran Hessami
- School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Massoud Vosough
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Javad Kojuri
- Department of Cardiovascular Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mani Ramzi
- Hematopathology and Molecular Pathology Service, Department of Pathology, Hematology Research Center, Shiraz University of Medical Sciences, Shiraz, 71344-1864, Iran
| | | | - Marjan Faghih
- Department of Biostatistics, School of Medicine, Arak University of Medical Sciences, Arak, Iran
| | - Ahmad Monabati
- Hematopathology and Molecular Pathology Service, Department of Pathology, Hematology Research Center, Shiraz University of Medical Sciences, Shiraz, 71344-1864, Iran.
- Department of Pathology, Shiraz University of Medical Sciences, Shiraz, Iran.
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Zheng Z, Wang X, Ouyang L, Chen W, Zhang L, Cao Y. Antioxidants Improve the Proliferation and Efficacy of hUC-MSCs against H 2O 2-Induced Senescence. Antioxidants (Basel) 2023; 12:1334. [PMID: 37507874 PMCID: PMC10376626 DOI: 10.3390/antiox12071334] [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: 04/15/2023] [Revised: 06/12/2023] [Accepted: 06/21/2023] [Indexed: 07/30/2023] Open
Abstract
Human umbilical cord mesenchymal stem cells (hUC-MSCs) are broadly applied in clinical treatment due to convenient accessibility, low immunogenicity, and the absence of any ethical issues involved. However, the microenvironment of inflammatory tissues may cause oxidative stress and induce senescence in transplanted hUC-MSCs, which will further reduce the proliferation, migration ability, and the final therapeutic effects of hUC-MSCs. Beta-nicotinamide mononucleotide (NMN) and coenzyme Q10 (CoQ10) are famous antioxidants and longevity medicines that could reduce intracellular reactive oxygen species levels by different mechanisms. In this study, hUC-MSCs were treated in vitro with NMN and CoQ10 to determine if they could reduce oxidative stress caused by hydrogen peroxide (H2O2) and recover cell functions. The effects of NMN and CoQ10 on the cell proliferation, the mRNA levels of the inflammatory cytokine TNFα and the anti-inflammatory cytokine IL10, and the differentiation and cell migration ability of hUC-MSCs before and after H2O2 treatment were investigated. The findings revealed that NMN and CoQ10 reduced H2O2-induced senescence and increased hUC-MSCs' proliferation in the late phase as passage 12 and later. The TNFα mRNA level of hUC-MSCs induced by H2O2 was significantly decreased after antioxidant treatment. NMN and CoQ10 all reduced the adipogenic differentiation ability of hUC-MSCs. CoQ10 improved the chondrogenic differentiation ability of hUC-MSCs. Furthermore, NMN was found to significantly enhance the migration ability of hUC-MSCs. Transcriptomic analysis revealed that NMN and CoQ10 both increased DNA repair ability and cyclin expression and downregulated TNF and IL-17 inflammatory signaling pathways, thereby contributing to the proliferative promotion of senecent stem cells and resistance to oxidative stress. These findings suggest that antioxidants can improve the survival and efficacy of hUC-MSCs in stem cell therapy for inflammation-related diseases.
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Affiliation(s)
- Zhaojuan Zheng
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, China
| | - Xia Wang
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, China
| | - Liming Ouyang
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, China
| | - Wenxia Chen
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, China
| | - Lixin Zhang
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, China
| | - Yulin Cao
- Beijing Tang Yi Hui Kang Biomedical Technology Co., Ltd., Beijing 100032, China
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Chen W, Hou CH, Chen YL, Shen HH, Lin CH, Wu CY, Lin MH, Liao CC, Huang JJ, Yang CY, Li YC, Yip HK. Safety and efficacy of intracoronary artery administration of human bone marrow-derived mesenchymal stem cells in STEMI of Lee-Sung pigs—A preclinical study for supporting the feasibility of the OmniMSC-AMI phase I clinical trial. Front Cardiovasc Med 2023; 10:1153428. [PMID: 37063964 PMCID: PMC10091140 DOI: 10.3389/fcvm.2023.1153428] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2023] [Accepted: 03/07/2023] [Indexed: 03/31/2023] Open
Abstract
BackgroundThis study tested whether early left intracoronary arterial (LAD) administration of human bone marrow-derived mesenchymal stem cells (hBMMSCs, called OmniMSCs) in acute ST-segment elevation myocardial infarction (STEMI) of Lee-Sung pigs induced by 90 min balloon-occluded LAD was safe and effective.Methods and resultsYoung male Lee-Sung pigs were categorized into SC (sham-operated control, n = 3), AMI-B (STEMI + buffer/21 cc/administered at 90 min after STEMI, n = 6), and AMI-M [acute myocardial infarction (AMI) + hBMMSCs/1.5 × 107/administered at 90 min after STEMI, n = 6] groups. By 2 and 5 months after STEMI, the cardiac magnetic resonance imaging demonstrated that the muscle scar score (MSS) and abnormal cardiac muscle exercise score in the infarct region were significantly increased in the AMI-B than in the SC group that were significantly reversed in the AMI-M group, whereas the left ventricular ejection function by each month (from 1 to 5) displayed an opposite pattern of MSS among the groups (all p < 0.001). By 5 months, histopathological findings of infarct and fibrosis areas and isolectin-B4 exhibited an identical pattern, whereas the cellular expressions of troponin-I/troponin-T/von Willebrand factor exhibited an opposite pattern of MSS among the groups (all p < 0.001). The ST-segment resolution (>80%) was significantly earlier (estimated after 6-h AMI) in the AMI-M group than in the AMI-B group (p < 0.001). The protein expressions of inflammation (IL-1β/TNF-α/NF-κB)/oxidative stress (NOX-1/NOX-2/oxidized protein)/apoptosis (cleaved caspase-3/cleaved PARP)/DNA damage (γ-H2AX) displayed an identical pattern to MSS among the groups, whereas the protein expressions of angiogenesis factors (SDF-1α/VEGF) were significantly and progressively increased from SC, AMI-B, to AMI-M groups (all p < 0.001).ConclusionEarly intra-LAD transfusion of OmniMSC treatment effectively reduced the infarct size and preserved LV function in porcine STEMI.
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Affiliation(s)
- Wannhsin Chen
- Regeneration Medicine Technology Division, Biomedical Technology and Device Research Laboratories, Industrial Technology Research Institute, Hsinchu, Taiwan
| | - Chun-Hsiang Hou
- Animal Technology Laboratories, Agricultural Technology Research Institute, Miaoli, Taiwan
| | - Yi-Ling Chen
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
- Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Hsin-Hsin Shen
- Regeneration Medicine Technology Division, Biomedical Technology and Device Research Laboratories, Industrial Technology Research Institute, Hsinchu, Taiwan
| | - Chen-Hsuan Lin
- Regeneration Medicine Technology Division, Biomedical Technology and Device Research Laboratories, Industrial Technology Research Institute, Hsinchu, Taiwan
| | - Cheng-Yi Wu
- Regeneration Medicine Technology Division, Biomedical Technology and Device Research Laboratories, Industrial Technology Research Institute, Hsinchu, Taiwan
| | - Meng-Hsueh Lin
- Regeneration Medicine Technology Division, Biomedical Technology and Device Research Laboratories, Industrial Technology Research Institute, Hsinchu, Taiwan
| | - Chih-Ching Liao
- Regeneration Medicine Technology Division, Biomedical Technology and Device Research Laboratories, Industrial Technology Research Institute, Hsinchu, Taiwan
| | - Jun-Jae Huang
- Regeneration Medicine Technology Division, Biomedical Technology and Device Research Laboratories, Industrial Technology Research Institute, Hsinchu, Taiwan
| | - Chi-Yu Yang
- Animal Technology Laboratories, Agricultural Technology Research Institute, Miaoli, Taiwan
| | - Yi-Chen Li
- Center of Cell Therapy, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Clinical Medicine Research Center, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Hon-Kan Yip
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
- Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
- Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
- School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan
- Department of Nursing, Asia University, Taichung, Taiwan
- Division of Cardiology, Department of Internal Medicine, Xiamen Chang Gung Hospital, Xiamen, China
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Hsiao LC, Lin YN, Shyu WC, Ho M, Lu CR, Chang SS, Wang YC, Chen JY, Lu SY, Wu MY, Li KY, Lin YK, Tseng WYI, Su MY, Hsu CT, Tsai CK, Chiu LT, Chen CL, Lin CL, Hu KC, Cho DY, Tsai CH, Chang KC, Jeng LB. First-in-human pilot trial of combined intracoronary and intravenous mesenchymal stem cell therapy in acute myocardial infarction. Front Cardiovasc Med 2022; 9:961920. [PMID: 36017096 PMCID: PMC9395611 DOI: 10.3389/fcvm.2022.961920] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2022] [Accepted: 07/13/2022] [Indexed: 12/17/2022] Open
Abstract
BackgroundAcute ST-elevation myocardial infarction (STEMI) elicits a robust cardiomyocyte death and inflammatory responses despite timely revascularization.ObjectivesThis phase 1, open-label, single-arm, first-in-human study aimed to assess the safety and efficacy of combined intracoronary (IC) and intravenous (IV) transplantation of umbilical cord-derived mesenchymal stem cells (UMSC01) for heart repair in STEMI patients with impaired left ventricular ejection fraction (LVEF 30-49%) following successful reperfusion by percutaneous coronary intervention.MethodsConsenting patients received the first dose of UMSC01 through IC injection 4-5 days after STEMI followed by the second dose of UMSC01 via IV infusion 2 days later. The primary endpoint was occurrence of any treatment-related adverse events and the secondary endpoint was changes of serum biomarkers and heart function by cardiac magnetic resonance imaging during a 12-month follow-up period.ResultsEight patients gave informed consents, of whom six completed the study. None of the subjects experienced treatment-related serious adverse events or major adverse cardiovascular events during IC or IV infusion of UMSC01 and during the follow-up period. The NT-proBNP level decreased (1362 ± 1801 vs. 109 ± 115 pg/mL, p = 0.0313), the LVEF increased (52.67 ± 12.75% vs. 62.47 ± 17.35%, p = 0.0246), and the wall motion score decreased (26.33 ± 5.57 vs. 22.33 ± 5.85, p = 0.0180) at the 12-month follow-up compared to the baseline values. The serial changes of LVEF were 0.67 ± 3.98, 8.09 ± 6.18, 9.04 ± 10.91, and 9.80 ± 7.56 at 1, 3, 6, and 12 months, respectively as compared to the baseline.ConclusionThis pilot study shows that combined IC and IV transplantation of UMSC01 in STEMI patients with impaired LVEF appears to be safe, feasible, and potentially beneficial in improving heart function. Further phase 2 studies are required to explore the effectiveness of dual-route transplantation of UMSC01 in STEMI patients.
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Affiliation(s)
- Lien-Cheng Hsiao
- Division of Cardiovascular Medicine, Department of Medicine, China Medical University Hospital, Taichung, Taiwan
- School of Medicine, China Medical University, Taichung, Taiwan
| | - Yen-Nien Lin
- Division of Cardiovascular Medicine, Department of Medicine, China Medical University Hospital, Taichung, Taiwan
- School of Medicine, China Medical University, Taichung, Taiwan
| | - Woei-Cherng Shyu
- Department of Neurology and Translational Medicine Research Center, China Medical University Hospital, Taichung, Taiwan
- Ever Supreme Bio Technology Co., Ltd, Taichung, Taiwan
| | - Ming Ho
- Department of Obstetrics and Gynecology, China Medical University Hospital, Taichung, Taiwan
| | - Chiung-Ray Lu
- Division of Cardiovascular Medicine, Department of Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Shih-Sheng Chang
- Division of Cardiovascular Medicine, Department of Medicine, China Medical University Hospital, Taichung, Taiwan
- School of Medicine, China Medical University, Taichung, Taiwan
| | - Yu-Chen Wang
- Division of Cardiovascular Medicine, Department of Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Jan-Yow Chen
- Division of Cardiovascular Medicine, Department of Medicine, China Medical University Hospital, Taichung, Taiwan
- School of Medicine, China Medical University, Taichung, Taiwan
| | - Shang-Yeh Lu
- Division of Cardiovascular Medicine, Department of Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Mei-Yao Wu
- School of Post-Baccalaureate Chinese Medicine, China Medical University, Taichung, Taiwan
- Department of Chinese Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Keng-Yuan Li
- Division of Cardiovascular Medicine, Department of Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Yu-Kai Lin
- Division of Cardiovascular Medicine, Department of Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Wen-Yih I. Tseng
- Molecular Imaging Center, National Taiwan University, Taipei, Taiwan
| | - Mao-Yuan Su
- Molecular Imaging Center, National Taiwan University, Taipei, Taiwan
| | - Chin-Ting Hsu
- Ever Supreme Bio Technology Co., Ltd, Taichung, Taiwan
| | | | - Lu-Ting Chiu
- Ever Supreme Bio Technology Co., Ltd, Taichung, Taiwan
| | | | - Cheng-Li Lin
- School of Medicine, China Medical University, Taichung, Taiwan
- Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan
| | - Kai-Chieh Hu
- School of Medicine, China Medical University, Taichung, Taiwan
- Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan
| | - Der-Yang Cho
- School of Medicine, China Medical University, Taichung, Taiwan
- Department of Neurosurgery, China Medical University Hospital, Taichung, Taiwan
| | - Chang-Hai Tsai
- School of Medicine, China Medical University, Taichung, Taiwan
| | - Kuan-Cheng Chang
- Division of Cardiovascular Medicine, Department of Medicine, China Medical University Hospital, Taichung, Taiwan
- School of Medicine, China Medical University, Taichung, Taiwan
- *Correspondence: Kuan-Cheng Chang,
| | - Long-Bin Jeng
- School of Medicine, China Medical University, Taichung, Taiwan
- Organ Transplantation Center, China Medical University Hospital, Taichung, Taiwan
- Long-Bin Jeng,
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9
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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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10
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Bioactive Scaffolds in Stem Cell-Based Therapies for Myocardial Infarction: a Systematic Review and Meta-Analysis of Preclinical Trials. Stem Cell Rev Rep 2021; 18:2104-2136. [PMID: 34463903 DOI: 10.1007/s12015-021-10186-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/12/2021] [Indexed: 10/20/2022]
Abstract
The use of bioactive scaffolds in conjunction with stem cell therapies for cardiac repair after a myocardial infarction shows significant promise for clinical translation. We performed a systematic review and meta-analysis of preclinical trials that investigated the use of bioactive scaffolds to support stem cell-aided cardiac regeneration, in comparison to stem cell treatment alone. Cochrane Library, Medline, Embase, PubMed, Scopus, Web of Science, and grey literature were searched through April 23, 2020 and 60 articles were included in the final analysis. The overall effect size observed in scaffold and stem cell-treated small animals compared to stem cell-treated controls for ejection fraction (EF) was 7.98 [95% confidence interval (CI): 6.36, 9.59] and for fractional shortening (FS) was 5.50 [95% CI: 4.35, 6.65] in small animal models. The largest improvements in EF and FS were observed when hydrogels were used (MD = 8.45 [95% CI: 6.46, 10.45] and MD = 5.76 [95% CI: 4.46, 7.05], respectively). Subgroup analysis revealed that cardiac progenitor cells had the largest effect size for FS, and was significant from pluripotent, mesenchymal and endothelial stem cell types. In large animal studies, the overall improvement of EF favoured the use of stem cell-embedded scaffolds compared to direct injection of cells (MD = 10.49 [95% CI: 6.30, 14.67]). Significant publication bias was present in the small animal trials for EF and FS. This study supports the use of bioactive scaffolds to aid in stem cell-based cardiac regeneration. Hydrogels should be further investigated in larger animal models for clinical translation.
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11
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Zhang R, Yu J, Zhang N, Li W, Wang J, Cai G, Chen Y, Yang Y, Liu Z. Bone marrow mesenchymal stem cells transfer in patients with ST-segment elevation myocardial infarction: single-blind, multicenter, randomized controlled trial. Stem Cell Res Ther 2021; 12:33. [PMID: 33413636 PMCID: PMC7791674 DOI: 10.1186/s13287-020-02096-6] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Accepted: 12/10/2020] [Indexed: 12/14/2022] Open
Abstract
OBJECTIVE Our aim was to evaluate the efficacy and safety of intracoronary autologous bone marrow mesenchymal stem cell (BM-MSC) transplantation in patients with ST-segment elevation myocardial infarction (STEMI). METHODS In this randomized, single-blind, controlled trial, patients with STEMI (aged 39-76 years) were enrolled at 6 centers in Beijing (The People's Liberation Army Navy General Hospital, Beijing Armed Police General Hospital, Chinese People's Liberation Army General Hospital, Beijing Huaxin Hospital, Beijing Tongren Hospital, Beijing Chaoyang Hospital West Hospital). All patients underwent optimum medical treatment and percutaneous coronary intervention and were randomly assigned in a 1:1 ratio to BM-MSC group or control group. The primary endpoint was the change of myocardial viability at the 6th month's follow-up and left ventricular (LV) function at the 12th month's follow-up. The secondary endpoints were the incidence of cardiovascular event, total mortality, and adverse event during the 12 months' follow-up. The myocardial viability assessed by single-photon emission computed tomography (SPECT). The left ventricular ejection fraction (LVEF) was used to assess LV function. All patients underwent dynamic ECG and laboratory evaluations. This trial is registered with ClinicalTrails.gov, number NCT04421274. RESULTS Between March 2008 and July 2010, 43 patients who had underwent optimum medical treatment and successful percutaneous coronary intervention were randomly assigned to BM-MSC group (n = 21) or control group (n = 22) and followed-up for 12 months. At the 6th month's follow-up, there was no significant improvement in myocardial activity in the BM-MSC group before and after transplantation. Meanwhile, there was no statistically significant difference between the two groups in the change of myocardial perfusion defect index (p = 0.37) and myocardial metabolic defect index (p = 0.90). The LVEF increased from baseline to 12 months in the BM-MSC group and control group (mean baseline-adjusted BM-MSC treatment differences in LVEF 4.8% (SD 9.0) and mean baseline-adjusted control group treatment differences in LVEF 5.8% (SD 6.04)). However, there was no statistically significant difference between the two groups in the change of the LVEF (p = 0.23). We noticed that during the 12 months' follow-up, except for one death and one coronary microvascular embolism in the BM-MSC group, no other events occurred and alanine transaminase (ALT) and C-reactive protein (CRP) in BM-MSC group were significantly lower than that in the control group. CONCLUSIONS The present study may have many methodological limitations, and within those limitations, we did not identify that intracoronary transfer of autologous BM-MSCs could largely promote the recovery of LV function and myocardial viability after acute myocardial infarction.
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Affiliation(s)
- Runfeng Zhang
- Department of Cardiology, Department of Clinical Pharmacy, The Third Hospital of Mianyang/Sichuan Mental Health Center, Mianyang, 621000, Sichuan, China
| | - Jiang Yu
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, China
| | - Ningkun Zhang
- Heart Centre, The Navy General Hospital, Beijing, 100048, China
| | - Wensong Li
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, China
| | - Jisheng Wang
- Department of Cardiology, Department of Clinical Pharmacy, The Third Hospital of Mianyang/Sichuan Mental Health Center, Mianyang, 621000, Sichuan, China
| | - Guocai Cai
- Department of Cardiology, Department of Clinical Pharmacy, The Third Hospital of Mianyang/Sichuan Mental Health Center, Mianyang, 621000, Sichuan, China
| | - Yu Chen
- Heart Centre, The Navy General Hospital, Beijing, 100048, China
| | - Yong Yang
- Department of Cardiology, The General Hospital of Chinese People's Armed Police Forces, Beijing, 100039, China
| | - Zhenhong Liu
- Department of Cardiology, Department of Clinical Pharmacy, The Third Hospital of Mianyang/Sichuan Mental Health Center, Mianyang, 621000, Sichuan, China.
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12
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Berezin AE, Berezin AA. Stem-Cell-Based Cardiac Regeneration: Is There a Place For Optimism in the Future? Stem Cells 2021. [DOI: 10.1007/978-3-030-77052-5_8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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13
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García-Sánchez D, Fernández D, Rodríguez-Rey JC, Pérez-Campo FM. Enhancing survival, engraftment, and osteogenic potential of mesenchymal stem cells. World J Stem Cells 2019; 11:748-763. [PMID: 31692976 PMCID: PMC6828596 DOI: 10.4252/wjsc.v11.i10.748] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Revised: 07/15/2019] [Accepted: 07/29/2019] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are promising candidates for bone regeneration therapies due to their plasticity and easiness of sourcing. MSC-based treatments are generally considered a safe procedure, however, the long-term results obtained up to now are far from satisfactory. The main causes of these therapeutic limitations are inefficient homing, engraftment, and osteogenic differentiation. Many studies have proposed modifications to improve MSC engraftment and osteogenic differentiation of the transplanted cells. Several strategies are aimed to improve cell resistance to the hostile microenvironment found in the recipient tissue and increase cell survival after transplantation. These strategies could range from a simple modification of the culture conditions, known as cell-preconditioning, to the genetic modification of the cells to avoid cellular senescence. Many efforts have also been done in order to enhance the osteogenic potential of the transplanted cells and induce bone formation, mainly by the use of bioactive or biomimetic scaffolds, although alternative approaches will also be discussed. This review aims to summarize several of the most recent approaches, providing an up-to-date view of the main developments in MSC-based regenerative techniques.
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Affiliation(s)
- Daniel García-Sánchez
- Department of Molecular Biology, Faculty of Medicine, University of Cantabria, Cantabria 39011, Spain
| | - Darío Fernández
- Laboratorio de Biología Celular y Molecular, Facultad de Odontología, Universidad Nacional del Nordeste, Corrientes W3400, Argentina
| | - José C Rodríguez-Rey
- Department of Molecular Biology, Faculty of Medicine, University of Cantabria, Cantabria 39011, Spain
| | - Flor M Pérez-Campo
- Department of Molecular Biology, Faculty of Medicine, University of Cantabria, Cantabria 39011, Spain.
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14
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Gyöngyösi M, Haller PM, Blake DJ, Martin Rendon E. Meta-Analysis of Cell Therapy Studies in Heart Failure and Acute Myocardial Infarction. Circ Res 2019; 123:301-308. [PMID: 29976694 DOI: 10.1161/circresaha.117.311302] [Citation(s) in RCA: 67] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Heart failure (HF) is one of the leading causes of death worldwide and has reached epidemic proportions in most industrialized nations. Despite major improvements in the treatment and management of the disease, the prognosis for patients with HF remains poor with approximately only half of patients surviving for 5 years or longer after diagnosis. The poor prognosis of HF patients is in part because of irreparable damage to cardiac tissue and concomitant maladaptive changes associated with the disease. Cell-based therapies may have the potential to transform the treatment and prognosis of HF through regeneration or repair of damaged cardiac tissue. Accordingly, numerous phase I and II randomized clinical trials have tested the clinical benefits of cell transplant, mostly autologous bone marrow-derived mononuclear cells, in patients with HF, ischemic heart disease, and acute myocardial infarction. Although many of these trials were relatively small, meta-analyses of cell-based therapies have attempted to apply rigorous statistical methodology to assess the potential clinical benefits of the intervention. As a prelude to larger phase III trials, meta-analyses, therefore, remain the obvious means of evaluating the available clinical evidence. Here, we review the different meta-analyses of randomized clinical trials that evaluate the safety and potential beneficial effect of cell therapies in HF and acute myocardial infarction spanning nearly 2 decades since the first pioneering trials were conducted.
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Affiliation(s)
- Mariann Gyöngyösi
- From the Department of Cardiology, Medical University of Vienna, Austria (M.G., P.M.H.)
| | - Paul M Haller
- From the Department of Cardiology, Medical University of Vienna, Austria (M.G., P.M.H.).,Ludwig Boltzmann Cluster for Cardiovascular Research, Vienna, Austria (P.M.H.).,3 Department of Medicine, Cardiology and Intensive Care Medicine, Chest Pain Unit, Wilhelminenhospital, Vienna, Austria (P.M.H.)
| | - Derek J Blake
- Division of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, United Kingdom (D.J.B.)
| | - Enca Martin Rendon
- Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, United Kingdom (E.M.R.)
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15
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Dhada KS, Hernandez DS, Suggs LJ. In Vivo Photoacoustic Tracking of Mesenchymal Stem Cell Viability. ACS NANO 2019; 13:7791-7799. [PMID: 31250647 PMCID: PMC7155740 DOI: 10.1021/acsnano.9b01802] [Citation(s) in RCA: 58] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/14/2023]
Abstract
Adult stem cell therapy has demonstrated improved outcomes for treating cardiovascular diseases in preclinical trials. The development of imaging tools may increase our understanding of the mechanisms of stem cell therapy, and a variety of imaging tools have been developed to image transplanted stem cells in vivo; however, they lack the ability to interrogate stem cell function longitudinally. Here, we report the use of a nanoparticle-based contrast agent that can track stem cell viability using photoacoustic imaging. The contrast agent consists of inert gold nanorods coated with IR775c, a reactive oxygen species (ROS) sensitive near-infrared dye. Upon cell death, stem cells produce ROS to degrade the cell. Using this feature of stem cells, the viability can be measured by comparing the IR775c signal to the ROS insensitive gold nanorod signal, which can also be used to track stem cell location. The nanoprobe was successfully loaded into mesenchymal stem cells (MSCs), and then, MSCs were transplanted into the lower limb of a mouse and imaged using combined ultrasound and photoacoustic imaging. MSC viability was assessed using the nanoprobe and displayed significant cell death within 24 h and an estimated 5% viability after 10 days. This nanoparticle system allows for longitudinal tracking of MSC viability in vivo with high spatial and temporal resolution which other imaging modalities currently cannot achieve.
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Affiliation(s)
- Kabir S. Dhada
- Department of Biomedical Engineering, University of Texas at Austin, Austin, Texas 78712, United States
| | - Derek S. Hernandez
- Department of Biomedical Engineering, University of Texas at Austin, Austin, Texas 78712, United States
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16
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Leavitt RJ, Limoli CL, Baulch JE. miRNA-based therapeutic potential of stem cell-derived extracellular vesicles: a safe cell-free treatment to ameliorate radiation-induced brain injury. Int J Radiat Biol 2018; 95:427-435. [PMID: 30252569 DOI: 10.1080/09553002.2018.1522012] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
PURPOSE This review compiles what is known about extracellular vesicles (EVs), their bioactive cargo, and how they might be used to treat radiation-induced brain injury. Radiotherapy (RT) is effective in cancer treatment, but can cause substantial damage to normal central nervous system tissue. Stem cell therapy has been shown to be effective in treating cognitive dysfunction arising from RT, but there remain safety concerns when grafting foreign stem cells into the brain (i.e. immunogenicity, teratoma). These limitations prompted the search for cell-free alternatives, and pointed to EVs that have been shown to have similar ameliorating effects in other tissues and injury models. CONCLUSIONS EVs are nano-scale and lipid-bound vesicles that readily pass the blood-brain barrier. Arguably the most important bioactive cargo within EVs are RNAs, in particular microRNAs (miRNA). A single miRNA can modulate entire gene networks and signalling within the recipient cell. Determining functionally relevant miRNA could lead to therapeutic treatments where synthetically-derived EVs are used as delivery vectors for miRNA. Stem cell-derived EVs can be effective in treating brain injury including radiation-induced cognitive deficits. Of particular interest are systemic modes of administration which obviate the need for invasive procedures.
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Affiliation(s)
- Ron J Leavitt
- a Department of Radiation Oncology , University of California Irvine , Irvine , CA , USA
| | - Charles L Limoli
- a Department of Radiation Oncology , University of California Irvine , Irvine , CA , USA
| | - Janet E Baulch
- a Department of Radiation Oncology , University of California Irvine , Irvine , CA , USA
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17
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Zhang J, Lin L, Zong W. Bone Marrow Mononuclear Cells Transfer for Patients after ST-Elevated Myocardial Infarction: A Meta-Analysis of Randomized Control Trials. Yonsei Med J 2018; 59:611-623. [PMID: 29869459 PMCID: PMC5990684 DOI: 10.3349/ymj.2018.59.5.611] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2017] [Revised: 02/25/2018] [Accepted: 03/14/2018] [Indexed: 01/01/2023] Open
Abstract
PURPOSE Results on the clinical utility of cell therapy for ST-elevated myocardial infarction (STEMI) are controversial. This study sought to analyze the efficacy of treatment with intracoronary bone marrow mononuclear cells (BMMC) on left ventricular (LV) function and remodeling and LV diastolic and systolic function in patients with STEMI. MATERIALS AND METHODS Literature search of PubMed and EMBASE databases between 2004 and 2017 was performed for randomized controlled trials in STEMI patients who underwent successful percutaneous coronary intervention and received intracoronary BMMC therapy. The defined end points were left ventricular ejection fraction (LVEF), left ventricular end-diastolic volume (LVEDV), and left ventricular end-systolic volume (LVESV). Also, sensitivity analysis and several subgroup analyses based on follow-up duration, timing of injection, doses of cells, and imaging modalities were conducted to strengthen the statistic power of the study. RESULTS A total of 22 trials with 1360 patients were available for the current meta-analysis. The pooled statistics showed a significant improvement in LVEF {2.58 [95% confidence interval (CI), 1.32, 3.84]; p<0.001}, LVEDV [-3.73, (95% CI, -6.94, -0.52), p=0.02], and LVESV [?4.67, (95% CI, -7.07, -2.28), p<0.001] in the BMMC group, compared with the control group. However, in sensitivity analysis, a significant reduction in LVEDV disappeared, while the outcomes of LVEF and LVESV remained unchanged. The same results were presented in the subgroup analysis adjusting for imaging modalities and timing of cells injection. CONCLUSION BMMC transplantation in patients with STEMI was found to lead to improvement in LVEF, LVEDV, and LVESV parameters, indicating that cell therapy has a potential beneficial effect on LV remodeling and function.
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Affiliation(s)
- Jingyi Zhang
- Department of Cardiovascular Medicine, The Third People's Hospital of Hubei Province, Hubei, China
| | - Li Lin
- Department of Cardiovascular Medicine, The Third People's Hospital of Hubei Province, Hubei, China
| | - Wenxia Zong
- Department of Cardiovascular Medicine, The Third People's Hospital of Hubei Province, Hubei, China.
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18
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Sun Q, Huang Z, Han F, Zhao M, Cao R, Zhao D, Hong L, Na N, Li H, Miao B, Hu J, Meng F, Peng Y, Sun Q. Allogeneic mesenchymal stem cells as induction therapy are safe and feasible in renal allografts: pilot results of a multicenter randomized controlled trial. J Transl Med 2018. [PMID: 29514693 PMCID: PMC5842532 DOI: 10.1186/s12967-018-1422-x] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Kidneys from deceased donors are being used to meet the growing need for grafts. However, delayed graft function (DGF) and acute rejection incidences are high, leading to adverse effects on graft outcomes. Optimal induction intervention should include both renal structure injury repair and immune response suppression. Mesenchymal stem cells (MSCs) with potent anti-inflammatory, regenerative, and immune-modulatory properties are considered a candidate to prevent DGF and acute rejection in renal transplantation. Thus, this prospective multicenter paired study aimed to assess the clinical value of allogeneic MSCs as induction therapy to prevent both DGF and acute rejection in deceased donor renal transplantation. METHODS Forty-two renal allograft recipients were recruited and divided into trial and control groups. The trial group (21 cases) received 2 × 106/kg human umbilical-cord-derived MSCs (UC-MSCs) via the peripheral vein before renal transplantation, and 5 × 106 cells via the renal artery during the surgical procedure. All recipients received standard induction therapy. Incidences of DGF and biopsy-proven acute rejection were recorded postoperatively and severe postoperative complications were assessed. Graft and recipient survivals were also evaluated. RESULTS Treatment with UC-MSCs achieved comparable graft and recipient survivals with non-MSC treatment (P = 0.97 and 0.15, respectively). No increase in postoperative complications, including DGF and acute rejection, were observed (incidence of DGF: 9.5% in the MSC group versus 33.3% in the non-MSC group, P = 0.13; Incidence of acute rejection: 14.3% versus 4.8%, P = 0.61). Equal postoperative estimated glomerular filtration rates were found between the two groups (P = 0.88). All patients tolerated the MSCs infusion without adverse clinical effects. Additionally, a multiprobe fluorescence in situ hybridization assay revealed that UC-MSCs administered via the renal artery were absent from the recipient's biopsy sample. CONCLUSIONS Umbilical-cord-derived MSCs can be used as clinically feasible and safe induction therapy. Adequate timing and frequency of UC-MSCs administration may have a significant effect on graft and recipient outcomes. Trial registration NCT02490020 . Registered on June 29 2015.
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Affiliation(s)
- Qipeng Sun
- Department of Renal Transplantation, The Third Affiliated Hospital, Sun Yat-sen University, Kaichuang Road 2693, Huangpu District, Guangzhou, 510530, People's Republic of China
| | - Zhengyu Huang
- Department of Renal Transplantation, The Third Affiliated Hospital, Sun Yat-sen University, Kaichuang Road 2693, Huangpu District, Guangzhou, 510530, People's Republic of China
| | - Fei Han
- Department of Renal Transplantation, The Third Affiliated Hospital, Sun Yat-sen University, Kaichuang Road 2693, Huangpu District, Guangzhou, 510530, People's Republic of China
| | - Ming Zhao
- Department of Renal Transplantation, Zhujiang Hospital, Southern Medical University, Gongye Road 253, Guangzhou, 510280, People's Republic of China
| | - Ronghua Cao
- Department of Renal Transplantation, The Second Affiliated Hospital, Guangzhou Traditional Chinese Medicine University, Inner Ring Road 55, University City, Guangzhou, 510280, People's Republic of China
| | - Daqiang Zhao
- Department of Renal Transplantation, The Third Affiliated Hospital, Sun Yat-sen University, Kaichuang Road 2693, Huangpu District, Guangzhou, 510530, People's Republic of China
| | - Liangqing Hong
- Department of Renal Transplantation, The Third Affiliated Hospital, Sun Yat-sen University, Kaichuang Road 2693, Huangpu District, Guangzhou, 510530, People's Republic of China
| | - Ning Na
- Department of Renal Transplantation, The Third Affiliated Hospital, Sun Yat-sen University, Kaichuang Road 2693, Huangpu District, Guangzhou, 510530, People's Republic of China
| | - Heng Li
- Department of Renal Transplantation, The Third Affiliated Hospital, Sun Yat-sen University, Kaichuang Road 2693, Huangpu District, Guangzhou, 510530, People's Republic of China
| | - Bin Miao
- Department of Renal Transplantation, The Third Affiliated Hospital, Sun Yat-sen University, Kaichuang Road 2693, Huangpu District, Guangzhou, 510530, People's Republic of China
| | - Jianmin Hu
- Department of Renal Transplantation, Zhujiang Hospital, Southern Medical University, Gongye Road 253, Guangzhou, 510280, People's Republic of China
| | - Fanhang Meng
- Department of Renal Transplantation, The Second Affiliated Hospital, Guangzhou Traditional Chinese Medicine University, Inner Ring Road 55, University City, Guangzhou, 510280, People's Republic of China
| | - Yanwen Peng
- Cell-gene Therapy Translational Medicine Research Center, The Third Affiliated Hospital, Sun Yat-sen University, Tianhe Road 600, Guangzhou, 510630, People's Republic of China
| | - Qiquan Sun
- Department of Renal Transplantation, The Third Affiliated Hospital, Sun Yat-sen University, Kaichuang Road 2693, Huangpu District, Guangzhou, 510530, People's Republic of China.
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Moviglia GA, Moviglia Brandolino MT, Couto D, Piccone S. Local immunomodulation and muscle progenitor cells induce recovery in atrophied muscles in spinal cord injury patients. JOURNAL OF NEURORESTORATOLOGY 2018. [DOI: 10.26599/jnr.2018.9040011] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
Objectives: Restore muscular trophism and voluntary contractile capacity through cell therapy in atrophied muscles in SCI patients. Setting: Out Patient Treatment, Universidad Maimonides, Buenos Aires, Argentina. Methods: After receiving spinal cord cell therapy and intensive rehabilitation, 7 chronic complete spinal cord injury (SCI) patients (4 people with paraplegia and 3 people with quadriplegia) regained muscular electrical activity in previously denervated territories. However, signs of severe muscular atrophy persisted. Looking to reverse chronic muscular atrophy, atrophied muscles with electrical activity were implanted with autologous type 1 macrophages (Mo1) and autologous tissue-specific T helper 1 Cells (Th1) associated with autologous muscular progenitor cells (MPC). The Mo1 and Th1 used cells were named Effector Cells (EC). Each muscle received between 6 to 8 implants, one every 6 weeks. Cellular therapy was combined with intensive rehabilitation program. Results: Sonogram and histological signs of recovery started eight weeks after the first implant. Sonograms showed progressively muscle volume increasing and gradually replacement of hyperechogenic muscle tissue by hypoechogenic muscle bands (resembling normal muscular structure). New bands were distributed parallel to the main muscle axis, along the entire muscular length. Histological samples of hypoechogenic bands showed new and normal muscular tissue. Changes were seen in 7/7 patients. Non-significant side events were detected in any patient over the 24 months of follow up. Conclusions: The results presented here suggest that the combination of immune and regenerative cell therapy may play an important therapeutic role in clinical and histological recovery of chronic muscular atrophy.
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Dorobantu M, Popa-Fotea NM, Popa M, Rusu I, Micheu MM. Pursuing meaningful end-points for stem cell therapy assessment in ischemic cardiac disease. World J Stem Cells 2017; 9:203-218. [PMID: 29321822 PMCID: PMC5746641 DOI: 10.4252/wjsc.v9.i12.203] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2017] [Revised: 11/08/2017] [Accepted: 11/27/2017] [Indexed: 02/06/2023] Open
Abstract
Despite optimal interventional and medical therapy, ischemic heart disease is still an important cause of morbidity and mortality worldwide. Although not included in standard of care rehabilitation, stem cell therapy (SCT) could be a solution for prompting cardiac regeneration. Multiple studies have been published from the beginning of SCT until now, but overall no unanimous conclusion could be drawn in part due to the lack of appropriate end-points. In order to appreciate the impact of SCT, multiple markers from different categories should be considered: Structural, biological, functional, physiological, but also major adverse cardiac events or quality of life. Imaging end-points are among the most used - especially left ventricle ejection fraction (LVEF) measured through different methods. Other imaging parameters are infarct size, myocardial viability and perfusion. The impact of SCT on all of the aforementioned end-points is controversial and debatable. 2D-echocardiography is widely exploited, but new approaches such as tissue Doppler, strain/strain rate or 3D-echocardiography are more accurate, especially since the latter one is comparable with the MRI gold standard estimation of LVEF. Apart from the objective parameters, there are also patient-centered evaluations to reveal the benefits of SCT, such as quality of life and performance status, the most valuable from the patient point of view. Emerging parameters investigating molecular pathways such as non-coding RNAs or inflammation cytokines have a high potential as prognostic factors. Due to the disadvantages of current techniques, new imaging methods with labelled cells tracked along their lifetime seem promising, but until now only pre-clinical trials have been conducted in humans. Overall, SCT is characterized by high heterogeneity not only in preparation, administration and type of cells, but also in quantification of therapy effects.
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Affiliation(s)
- Maria Dorobantu
- Department of Cardiology, Clinical Emergency Hospital of Bucharest, Bucharest 014461, Romania
| | | | - Mihaela Popa
- Carol Davila, University of Medicine, "Carol Davila" University of Medicine and Pharmacy Bucharest, Bucharest 020022, Romania
| | - Iulia Rusu
- Carol Davila, University of Medicine, "Carol Davila" University of Medicine and Pharmacy Bucharest, Bucharest 020022, Romania
| | - Miruna Mihaela Micheu
- Department of Cardiology, Clinical Emergency Hospital of Bucharest, Bucharest 014461, Romania.
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21
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Zhang S, Ma X, Guo J, Yao K, Wang C, Dong Z, Zhu H, Fan F, Huang Z, Yang X, Qian J, Zou Y, Sun A, Ge J. Bone marrow CD34 + cell subset under induction of moderate stiffness of extracellular matrix after myocardial infarction facilitated endothelial lineage commitment in vitro. Stem Cell Res Ther 2017; 8:280. [PMID: 29237495 PMCID: PMC5729449 DOI: 10.1186/s13287-017-0732-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2017] [Revised: 11/16/2017] [Accepted: 11/23/2017] [Indexed: 01/14/2023] Open
Abstract
BACKGROUND The stiffness of the myocardial extracellular matrix (ECM) and the transplanted cell type are vitally important in promoting angiogenesis. However, the combined effect of the two factors remains uncertain. The purpose of this study is to investigate in vitro the combined effect of myocardial ECM stiffness postinfarction with a bone marrow-derived cell subset expressing or not expressing CD34 on endothelial lineage commitment. METHODS Myocardial stiffness of the infarct zone was determined in mice at 1 h, 24 h, 7 days, 14 days, and 28 days after coronary artery ligation. Polyacrylamide (PA) gel substrates of different stiffnesses were prepared to mechanically mimic the myocardial ECM after infarction. Mouse bone marrow-derived CD34+ and CD34- cells were seeded on the flexible PA gels. The double-positive expression for DiI-acetylated low-density lipoprotein (acLDL) uptake and fluorescein isothiocyanate-Ulex europaeus agglutinin-1 (FITC-UEA-1) binding, the endothelial lineage antigens CD31, von Willebrand factor (vWF), Flk-1, and VE-cadherin, as well as cytoskeleton were measured by immunofluorescent staining on day 7. Cell apoptosis was evaluated by both immunofluorescent staining and flow cytometry at 24 h after culture. RESULTS We found that the numbers of the CD34+ cell subset adherent to the flexible substrates (4-72 kPa) was much larger than that of the CD34- subset. More double-positive cells for DiI-acLDL uptake/FITC-UEA-1 binding were seen on the 42-kPa (moderately stiff) substrate, corresponding to the stiffness of myocardial ECM at 7-14 days postinfarction, compared with those on substrates of other stiffnesses. Similarly, the moderately stiff substrate showed benefits in promoting the positive expressions of the endothelial lineage markers CD31, vWF, Flk-1, and VE-cadherin. In addition, the cytoskeleton F-actin network within CD34+ cells was organized more significantly at the leading edge of the adherent cells on the moderately stiff (42 kPa) or stiff (72 kPa) substrates as compared with those on the soft (4 kPa and 15 kPa) substrates. Moreover, the moderately stiff or stiff substrates showed a lower percentage of cell apoptosis than the soft substrates. CONCLUSIONS Infarcted myocardium-like ECM of moderate stiffness (42 kPa) more beneficially regulated the endothelial lineage commitment of a bone marrow-derived CD34+ subset. Thus, the combination of a CD34+ subset with a "suitable" ECM stiffness might be an optimized strategy for cell-based cardiac repair.
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Affiliation(s)
- Shuning Zhang
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China.,Institute of Cardiovascular Diseases, Fudan University, Shanghai, China.,Shanghai Cardiovascular Medical Center, Fudan University, Shanghai, China.,Institute of Pan-vascular Medicine, Fudan University, Shanghai, China
| | - Xin Ma
- Institute of Cardiovascular Diseases, Fudan University, Shanghai, China.,Shanghai Cardiovascular Medical Center, Fudan University, Shanghai, China.,Institutes of Biomedical Sciences, Fudan University, Shanghai, China.,Institute of Pan-vascular Medicine, Fudan University, Shanghai, China
| | - Junjie Guo
- Department of Cardiology, The Affiliated Hospital of Qingdao University, Qingdao University, Shandong, China
| | - Kang Yao
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China.,Institute of Cardiovascular Diseases, Fudan University, Shanghai, China.,Shanghai Cardiovascular Medical Center, Fudan University, Shanghai, China.,Institute of Pan-vascular Medicine, Fudan University, Shanghai, China
| | - Cong Wang
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China.,Institute of Cardiovascular Diseases, Fudan University, Shanghai, China.,Shanghai Cardiovascular Medical Center, Fudan University, Shanghai, China.,Institute of Pan-vascular Medicine, Fudan University, Shanghai, China
| | - Zhen Dong
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China.,Institute of Cardiovascular Diseases, Fudan University, Shanghai, China.,Shanghai Cardiovascular Medical Center, Fudan University, Shanghai, China.,Institute of Pan-vascular Medicine, Fudan University, Shanghai, China
| | - Hong Zhu
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China.,Institute of Cardiovascular Diseases, Fudan University, Shanghai, China.,Shanghai Cardiovascular Medical Center, Fudan University, Shanghai, China.,Institute of Pan-vascular Medicine, Fudan University, Shanghai, China
| | - Fan Fan
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China.,Institute of Cardiovascular Diseases, Fudan University, Shanghai, China.,Shanghai Cardiovascular Medical Center, Fudan University, Shanghai, China.,Institute of Pan-vascular Medicine, Fudan University, Shanghai, China
| | - Zheyong Huang
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China.,Institute of Cardiovascular Diseases, Fudan University, Shanghai, China.,Shanghai Cardiovascular Medical Center, Fudan University, Shanghai, China.,Institute of Pan-vascular Medicine, Fudan University, Shanghai, China
| | - Xiangdong Yang
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China.,Institute of Cardiovascular Diseases, Fudan University, Shanghai, China.,Shanghai Cardiovascular Medical Center, Fudan University, Shanghai, China.,Institutes of Biomedical Sciences, Fudan University, Shanghai, China.,Institute of Pan-vascular Medicine, Fudan University, Shanghai, China
| | - Juying Qian
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China.,Institute of Cardiovascular Diseases, Fudan University, Shanghai, China.,Shanghai Cardiovascular Medical Center, Fudan University, Shanghai, China.,Institutes of Biomedical Sciences, Fudan University, Shanghai, China.,Institute of Pan-vascular Medicine, Fudan University, Shanghai, China
| | - Yunzeng Zou
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China.,Institute of Cardiovascular Diseases, Fudan University, Shanghai, China.,Shanghai Cardiovascular Medical Center, Fudan University, Shanghai, China.,Institutes of Biomedical Sciences, Fudan University, Shanghai, China.,Institute of Pan-vascular Medicine, Fudan University, Shanghai, China
| | - Aijun Sun
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China. .,Institute of Cardiovascular Diseases, Fudan University, Shanghai, China. .,Shanghai Cardiovascular Medical Center, Fudan University, Shanghai, China. .,Institutes of Biomedical Sciences, Fudan University, Shanghai, China. .,Institute of Pan-vascular Medicine, Fudan University, Shanghai, China.
| | - Junbo Ge
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China. .,Institute of Cardiovascular Diseases, Fudan University, Shanghai, China. .,Shanghai Cardiovascular Medical Center, Fudan University, Shanghai, China. .,Institutes of Biomedical Sciences, Fudan University, Shanghai, China. .,Institute of Pan-vascular Medicine, Fudan University, Shanghai, China.
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22
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Katarzyna R. Adult Stem Cell Therapy for Cardiac Repair in Patients After Acute Myocardial Infarction Leading to Ischemic Heart Failure: An Overview of Evidence from the Recent Clinical Trials. Curr Cardiol Rev 2017; 13:223-231. [PMID: 28464769 PMCID: PMC5633717 DOI: 10.2174/1573403x13666170502103833] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2017] [Revised: 03/27/2017] [Accepted: 04/12/2017] [Indexed: 12/28/2022] Open
Abstract
Background: Cardiovascular diseases (CVD) still represent the leading cause of mortality worldwide, despite the remarkable advances in interventional cardiology, cardiac surgery, and modern pharmacotherapy, particularly in the setting of acute myocardial infarction (AMI), chronic ischemic heart failure (HF), cardiomyopathy (CM), and the associated left ventricular (LV) dysfunction. A significant loss of cardiomyocytes that underlies all of these conditions was previously considered irreversible. However, current evidence indicates that the human heart has some potential for repair, and over the past decade, many research studies have been exploring the use of stem cells (SCs) to facilitate restoration of myocardium. Consequently, the safety, feasibility, and effectiveness of SC therapy have been reported in many randomized clinical trials (RCTs), using different lineages of adult SCs. Nevertheless, the clinical benefits of SC therapy are not yet well established. In the near future, understanding of the complex interrelations between SCs, paracrine factors, genetic or epigenetic pre-dispositions, and myocardial microenvironment, in the context of an individual patient, will be crucial for translation of this knowledge into practical development of successful, long-term regenerative SC therapeutic applications, in a growing population of patients suffering from previous myocardial in-farction (MI) leading to chronic ischemic cardiomyopathy. Conclusion: This overview highlights the therapeutic potential of adult SCs in terms of their possible regenerative capacity, safety, and clinical outcomes, in patients with AMI, and/or subsequent HF (due to chronic ischemic cardiomyopathy). This review was based upon PubMed database search for trials on SC therapy, in patients with AMI and HF, and the main timeframe was set from 2006 to 2016.
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Affiliation(s)
- Rygiel Katarzyna
- Department of Family Practice, Medical University of Silesia (SUM), Katowice-Zabrze, Poland
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23
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Fan D, Wu S, Ye S, Wang W, Guo X, Liu Z. Umbilical cord mesenchyme stem cell local intramuscular injection for treatment of uterine niche: Protocol for a prospective, randomized, double-blinded, placebo-controlled clinical trial. Medicine (Baltimore) 2017; 96:e8480. [PMID: 29095305 PMCID: PMC5682824 DOI: 10.1097/md.0000000000008480] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
BACKGROUND Uterine niche is defined as a triangular anechoic structure at the site of the scar or a gap in the myometrium at the site of a previous caesarean section. The main clinical manifestations are postmenstrual spotting and intrauterine infection, which may seriously affect the daily life of nonpregnant women. Trials have shown an excellent safety and efficacy for the potential of mesenchymal stem cells (MSCs) as a therapeutic option for scar reconstruction. Therefore, this study is designed to investigate the safety and efficacy of using MSCs in the treatment for the uterine niche. METHODS/DESIGN This phase II clinical trial is a single-center, prospective, randomized, double-blind, placebo-controlled with 2 arms. One hundred twenty primiparous participants will be randomly (1:1 ratio) assigned to receive direct intramuscular injection of MSCs (a dose of 1*10 cells in 1 mL of 0.9% saline) (MSCs group) or an identical-appearing 1 mL of 0.9% saline (placebo-controlled group) near the uterine incision. The primary outcome of this trial is to evaluate the proportion of participants at 6 months who is found uterine niche in the uterus by transvaginal utrasonography. Adverse events will be documented in a case report form. The study will be conducted at the Department of Obstetric of Southern Medical University Affiliated Maternal & Child Health Hospital of Foshan. DISCUSSION This trial is the first investigation of the potential for therapeutic use of MSCs for the management of uterine niche after cesarean delivery. CONCLUSION This protocol will help to determine the efficacy and safety of MSCs treatment in uterine niche and bridge the gap with regards to the current preclinical and clinical evidence. TRIAL REGISTRATION NUMBER NCT02968459 (Clinical Trials.gov: http://clinicaltrials.gov/).
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Affiliation(s)
- Dazhi Fan
- Foshan Institute of Fetal Medicine
- Department of Obstetrics, Southern Medical University Affiliated Maternal & Child Health Hospital of Foshan, Foshan, Guangdong
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, China
| | - Shuzhen Wu
- Foshan Institute of Fetal Medicine
- Department of Obstetrics, Southern Medical University Affiliated Maternal & Child Health Hospital of Foshan, Foshan, Guangdong
| | - Shaoxin Ye
- Foshan Institute of Fetal Medicine
- Department of Obstetrics, Southern Medical University Affiliated Maternal & Child Health Hospital of Foshan, Foshan, Guangdong
| | - Wen Wang
- Foshan Institute of Fetal Medicine
- Department of Obstetrics, Southern Medical University Affiliated Maternal & Child Health Hospital of Foshan, Foshan, Guangdong
| | - Xiaoling Guo
- Foshan Institute of Fetal Medicine
- Department of Obstetrics, Southern Medical University Affiliated Maternal & Child Health Hospital of Foshan, Foshan, Guangdong
| | - Zhengping Liu
- Foshan Institute of Fetal Medicine
- Department of Obstetrics, Southern Medical University Affiliated Maternal & Child Health Hospital of Foshan, Foshan, Guangdong
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24
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Higuchi A, Ku NJ, Tseng YC, Pan CH, Li HF, Kumar SS, Ling QD, Chang Y, Alarfaj AA, Munusamy MA, Benelli G, Murugan K. Stem cell therapies for myocardial infarction in clinical trials: bioengineering and biomaterial aspects. J Transl Med 2017; 97:1167-1179. [PMID: 28869589 DOI: 10.1038/labinvest.2017.100] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2017] [Revised: 08/01/2017] [Accepted: 08/04/2017] [Indexed: 12/17/2022] Open
Abstract
Cardiovascular disease remains the leading cause of death and disability in advanced countries. Stem cell transplantation has emerged as a promising therapeutic strategy for acute and chronic ischemic cardiomyopathy. The current status of stem cell therapies for patients with myocardial infarction is discussed from a bioengineering and biomaterial perspective in this review. We describe (a) the current status of clinical trials of human pluripotent stem cells (hPSCs) compared with clinical trials of human adult or fetal stem cells, (b) the gap between fundamental research and application of human stem cells, (c) the use of biomaterials in clinical and pre-clinical studies of stem cells, and finally (d) trends in bioengineering to promote stem cell therapies for patients with myocardial infarction. We explain why the number of clinical trials using hPSCs is so limited compared with clinical trials using human adult and fetal stem cells such as bone marrow-derived stem cells.
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Affiliation(s)
- Akon Higuchi
- Department of Chemical and Materials Engineering, National Central University, Jhongli, Taoyuan, Taiwan.,Nano Medical Engineering Laboratory, RIKEN, Wako, Saitama, Japan.,Department of Botany and Microbiology, College of Science, King Saud University, Riyadh, Saudi Arabia.,Department of Chemical Engineering, R&D Center for Membrane Technology, Chung Yuan Christian University, Chungli, Taoyuan, Taiwan
| | - Nien-Ju Ku
- Department of Chemical and Materials Engineering, National Central University, Jhongli, Taoyuan, Taiwan
| | - Yeh-Chia Tseng
- Department of Chemical and Materials Engineering, National Central University, Jhongli, Taoyuan, Taiwan
| | - Chih-Hsien Pan
- Department of Chemical and Materials Engineering, National Central University, Jhongli, Taoyuan, Taiwan
| | - Hsing-Fen Li
- Department of Chemical and Materials Engineering, National Central University, Jhongli, Taoyuan, Taiwan
| | - S Suresh Kumar
- Department of Medical Microbiology and Parasitology, Universiti Putra Malaysia, Serdang, Selangor, Malaysia
| | - Qing-Dong Ling
- Cathay Medical Research Institute, Cathay General Hospital, Hsi-Chi City, Taipei, Taiwan.,Graduate Institute of Systems Biology and Bioinformatics, National Central University, Jhongli, Taoyuan, Taiwan
| | - Yung Chang
- Department of Chemical Engineering, R&D Center for Membrane Technology, Chung Yuan Christian University, Chungli, Taoyuan, Taiwan
| | - Abdullah A Alarfaj
- Department of Botany and Microbiology, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - Murugan A Munusamy
- Department of Botany and Microbiology, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - Giovanni Benelli
- Department of Agriculture, Food and Environment, University of Pisa, Via del Borghetto, Pisa, Italy.,The BioRobotics Institute, Scuola Superiore Sant'Anna, Pontedera, Pisa, Italy
| | - Kadarkarai Murugan
- Division of Entomology, Department of Zoology, School of Life Sciences, Bharathiar University, Coimbatore, Tamil Nadu, India.,Department of Zoology, Thiruvalluvar University, Vellore, Tamil Nadu, India
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25
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Xu HL, Yu WZ, Lu CT, Li XK, Zhao YZ. Delivery of growth factor-based therapeutics in vascular diseases: Challenges and strategies. Biotechnol J 2017; 12. [PMID: 28296342 DOI: 10.1002/biot.201600243] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2016] [Revised: 01/27/2017] [Accepted: 02/09/2017] [Indexed: 12/18/2022]
Abstract
Either cardiovascular or peripheral vascular diseases have become the major cause of morbidity and mortality worldwide. Recently, growth factors therapeutics, whatever administrated in form of exogenous growth factors or their relevant genes have been discovered to be an effective strategy for the prevention and therapy of vascular diseases, because of their promoting angiogenesis. Besides, as an alternative, stem cell-based therapy has been also developed in view of their paracrine-mediated effect or ability of differentiation toward angiogenesis-related cells under assistance of growth factors. Despite of being specific and potent, no matter growth factors or stem cells-based therapy, their full clinical transformation is limited from bench to bedside. In this review, the potential choices of therapeutic modes based on types of different growth factors or stem cells were firstly summarized for vascular diseases. The confronted various challenges such as lack of non-invasive delivery method, the physiochemical challenge, the short half-life time, and poor cell survival, were carefully analyzed for these therapeutic modes. Various strategies to overcome these limitations are put forward from the perspective of drug delivery. The expertised design of a suitable delivery form will undoubtedly provide valuable insight into their clinical application in the regenerative medicine.
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Affiliation(s)
- He-Lin Xu
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province, China
| | - Wen-Ze Yu
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province, China
| | - Cui-Tao Lu
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province, China
| | - Xiao-Kun Li
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province, China
- Collaborative Innovation Center of Biomedical Science by Wenzhou University & Wenzhou Medical University, Wenzhou City, Zhejiang Province, China
| | - Ying-Zheng Zhao
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province, China
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26
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Micheu MM, Dorobantu M. Fifteen years of bone marrow mononuclear cell therapy in acute myocardial infarction. World J Stem Cells 2017; 9:68-76. [PMID: 28491241 PMCID: PMC5405402 DOI: 10.4252/wjsc.v9.i4.68] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2017] [Revised: 03/16/2017] [Accepted: 04/18/2017] [Indexed: 02/07/2023] Open
Abstract
In spite of modern treatment, acute myocardial infarction (AMI) still carries significant morbidity and mortality worldwide. Even though standard of care therapy improves symptoms and also long-term prognosis of patients with AMI, it does not solve the critical issue, specifically the permanent damage of cardiomyocytes. As a result, a complex process occurs, namely cardiac remodeling, which leads to alterations in cardiac size, shape and function. This is what has driven the quest for unconventional therapeutic strategies aiming to regenerate the injured cardiac and vascular tissue. One of the latest breakthroughs in this regard is stem cell (SC) therapy. Based on favorable data obtained in experimental studies, therapeutic effectiveness of this innovative therapy has been investigated in clinical settings. Of various cell types used in the clinic, autologous bone marrow derived SCs were the first used to treat an AMI patient, 15 years ago. Since then, we have witnessed an increasing body of data as regards this cutting-edge therapy. Although feasibility and safety of SC transplant have been clearly proved, it's efficacy is still under dispute. Conducted studies and meta-analysis reported conflicting results, but there is hope for conclusive answer to be provided by the largest ongoing trial designed to demonstrate whether this treatment saves lives. In the meantime, strategies to enhance the SCs regenerative potential have been applied and/or suggested, position papers and recommendations have been published. But what have we learned so far and how can we properly use the knowledge gained? This review will analytically discuss each of the above topics, summarizing the current state of knowledge in the field.
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Affiliation(s)
- Miruna Mihaela Micheu
- Miruna Mihaela Micheu, Maria Dorobantu, Department of Cardiology, Clinical Emergency Hospital of Bucharest, 014461 Bucharest, Romania
| | - Maria Dorobantu
- Miruna Mihaela Micheu, Maria Dorobantu, Department of Cardiology, Clinical Emergency Hospital of Bucharest, 014461 Bucharest, Romania
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27
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Liu X, Cai J, Jiao X, Yu X, Ding X. Therapeutic potential of mesenchymal stem cells in acute kidney injury is affected by administration timing. Acta Biochim Biophys Sin (Shanghai) 2017; 49:338-348. [PMID: 28338909 DOI: 10.1093/abbs/gmx016] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2016] [Indexed: 12/22/2022] Open
Abstract
Mesenchymal stem cell (MSC) transplantation is a promising therapy for acute kidney injury; however, the efficacy is limited due to poor survival after transplantation. In this study, we investigated how MSC transplantation timing affected the survival and therapeutic potential of MSCs in the kidney ischemia-reperfusion (I/R) injury model. After kidney I/R injury, the inflammatory process and tissue damage were characterized over 1 week post-I/R, we found that inflammation peaked at 12-24 h post-I/R (h.p.i.), and urine neutrophil gelatinase-associated lipocalin (NGAL) measurements correlated highly with measures of inflammation. We cultured MSCs with supernatants from I/R injured kidney tissue homogenates collected at different time points and found that kidney homogenates from 12 and 24 h.p.i. were most toxic to MSCs, whereas homogenates from 1 h.p.i. were not as cytotoxic as those from 12 and 24 h.p.i. Compared with MSCs administered at 12, or 24 h.p.i., cells administered immediately after ischemia or 1 h.p.i. yielded the highest renoprotective and anti-inflammatory effects. Our findings indicate that MSC treatment for acute kidney injury is most effective when applied prior to the development of a potent inflammatory microenvironment, and urine NGAL may be helpful for detecting inflammation and selecting MSC transplantation timing in I/R kidney injury.
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Affiliation(s)
- Xiaoyan Liu
- Division of Nephrology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Department of nephrology, The Second Affiliated Hospital of Dalian Medical University, Dalian 116027, China
- Shanghai Institute of Kidney Disease and Dialysis, Shanghai 200032, China
| | - Jieru Cai
- Division of Nephrology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Institute of Kidney Disease and Dialysis, Shanghai 200032, China
| | - Xiaoyan Jiao
- Division of Nephrology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Institute of Kidney Disease and Dialysis, Shanghai 200032, China
| | - Xiaofang Yu
- Division of Nephrology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Institute of Kidney Disease and Dialysis, Shanghai 200032, China
| | - Xiaoqiang Ding
- Division of Nephrology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Institute of Kidney Disease and Dialysis, Shanghai 200032, China
- Shanghai Key Laboratory of Kidney disease and Blood Purification, Shanghai 200032, China
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28
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Liu H, Paul C, Xu M. Optimal Environmental Stiffness for Stem Cell Mediated Ischemic Myocardium Repair. Methods Mol Biol 2017; 1553:293-304. [PMID: 28229425 DOI: 10.1007/978-1-4939-6756-8_23] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Cardiovascular diseases related to myocardial infarction (MI) contribute significantly to morbidity and mortality worldwide. The loss of cardiomyocytes during MI is a key factor in the impairment of cardiac-pump functions. Employing cell transplantation has shown great potential as a therapeutic approach in regenerating ischemic myocardium. Several studies have suggested that the therapeutic effects of stem cells vary based on the timing of cell administration. It has been clearly established that the myocardium post-infarction experiences a time-dependent stiffness change, and many studies have highlighted the importance of stiffness (elasticity) of microenvironment on modulating the fate and function of stem cells. Therefore, this chapter outlines our studies and other experiments designed to establish the optimal stiffness of microenvironment that maximizes benefits for maintaining cell survival, promoting phenotypic plasticity, and improving functional specification of the engrafted stem cells.
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Affiliation(s)
- Honghai Liu
- Department of Pathology and Laboratory Medicine, University of Cincinnati Medical Center, Cincinnati, OH, 45267, USA
| | - Christian Paul
- Department of Pathology and Laboratory Medicine, University of Cincinnati Medical Center, Cincinnati, OH, 45267, USA
| | - Meifeng Xu
- Department of Pathology and Laboratory Medicine, University of Cincinnati Medical Center, Cincinnati, OH, 45267, USA.
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29
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Gyöngyösi M, Wojakowski W, Navarese EP, Moye LÀ. Meta-Analyses of Human Cell-Based Cardiac Regeneration Therapies: Controversies in Meta-Analyses Results on Cardiac Cell-Based Regenerative Studies. Circ Res 2016; 118:1254-63. [PMID: 27081108 DOI: 10.1161/circresaha.115.307347] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2015] [Accepted: 02/15/2016] [Indexed: 02/07/2023]
Abstract
In contrast to multiple publication-based meta-analyses involving clinical cardiac regeneration therapy in patients with recent myocardial infarction, a recently published meta-analysis based on individual patient data reported no effect of cell therapy on left ventricular function or clinical outcome. A comprehensive review of the data collection, statistics, and the overall principles of meta-analyses provides further clarification and explanation for this controversy. The advantages and pitfalls of different types of meta-analyses are reviewed here. Each meta-analysis approach has a place when pivotal clinical trials are lacking and sheds light on the magnitude of the treatment in a complex healthcare field.
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Affiliation(s)
- Mariann Gyöngyösi
- From the Department of Cardiology, Medical University of Vienna, Vienna, Austria (M.G.); 3rd Department of Cardiology, Medical University of Silesia, Katowice, Poland (W.W.); Division of Cardiology, Pulmonology and Vascular Medicine, Department of Internal Medicine, Heinrich-Heine-University, Düsseldorf, Germany (E.P.N.); Systematic Investigation and Research on Interventions and Outcomes (SIRIO) MEDICINE Research Network (E.P.N.); and CCTRN Data Coordinating Center, University of Texas Houston School of Public Health, Houston (L.À.M.).
| | - Wojciech Wojakowski
- From the Department of Cardiology, Medical University of Vienna, Vienna, Austria (M.G.); 3rd Department of Cardiology, Medical University of Silesia, Katowice, Poland (W.W.); Division of Cardiology, Pulmonology and Vascular Medicine, Department of Internal Medicine, Heinrich-Heine-University, Düsseldorf, Germany (E.P.N.); Systematic Investigation and Research on Interventions and Outcomes (SIRIO) MEDICINE Research Network (E.P.N.); and CCTRN Data Coordinating Center, University of Texas Houston School of Public Health, Houston (L.À.M.)
| | - Eliano P Navarese
- From the Department of Cardiology, Medical University of Vienna, Vienna, Austria (M.G.); 3rd Department of Cardiology, Medical University of Silesia, Katowice, Poland (W.W.); Division of Cardiology, Pulmonology and Vascular Medicine, Department of Internal Medicine, Heinrich-Heine-University, Düsseldorf, Germany (E.P.N.); Systematic Investigation and Research on Interventions and Outcomes (SIRIO) MEDICINE Research Network (E.P.N.); and CCTRN Data Coordinating Center, University of Texas Houston School of Public Health, Houston (L.À.M.)
| | - Lemuel À Moye
- From the Department of Cardiology, Medical University of Vienna, Vienna, Austria (M.G.); 3rd Department of Cardiology, Medical University of Silesia, Katowice, Poland (W.W.); Division of Cardiology, Pulmonology and Vascular Medicine, Department of Internal Medicine, Heinrich-Heine-University, Düsseldorf, Germany (E.P.N.); Systematic Investigation and Research on Interventions and Outcomes (SIRIO) MEDICINE Research Network (E.P.N.); and CCTRN Data Coordinating Center, University of Texas Houston School of Public Health, Houston (L.À.M.)
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Ezquer FE, Ezquer ME, Vicencio JM, Calligaris SD. Two complementary strategies to improve cell engraftment in mesenchymal stem cell-based therapy: Increasing transplanted cell resistance and increasing tissue receptivity. Cell Adh Migr 2016; 11:110-119. [PMID: 27294313 PMCID: PMC5308221 DOI: 10.1080/19336918.2016.1197480] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Over the past 2 decades, therapies based on mesenchymal stem cells (MSC) have been tested to treat several types of diseases in clinical studies, due to their potential for tissue repair and regeneration. Currently, MSC-based therapy is considered a biologically safe procedure, with the therapeutic results being very promising. However, the benefits of these therapies are not stable in the long term, and the final outcomes manifest with high inter-patient variability. The major cause of these therapeutic limitations results from the poor engraftment of the transplanted cells. Researchers have developed separate strategies to improve MSC engraftment. One strategy aims at increasing the survival of the transplanted MSCs in the recipient tissue, rendering them more resistant to the hostile microenvironment (cell-preconditioning). Another strategy aims at making the damaged tissue more receptive to the transplanted cells, favoring their interactions (tissue-preconditioning). In this review, we summarize several approaches using these strategies, providing an integral and updated view of the recent developments in MSC-based therapies. In addition, we propose that the combined use of these different conditioning strategies could accelerate the process to translate experimental evidences from pre-clinic studies to the daily clinical practice.
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Affiliation(s)
- Fernando E Ezquer
- a Centro de Medicina Regenerativa, Facultad de Medicina, Clínica Alemana-Universidad del Desarrollo , Santiago , Chile
| | - Marcelo E Ezquer
- a Centro de Medicina Regenerativa, Facultad de Medicina, Clínica Alemana-Universidad del Desarrollo , Santiago , Chile
| | | | - Sebastián D Calligaris
- a Centro de Medicina Regenerativa, Facultad de Medicina, Clínica Alemana-Universidad del Desarrollo , Santiago , Chile
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31
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Advances in the Treatment of Ischemic Diseases by Mesenchymal Stem Cells. Stem Cells Int 2016; 2016:5896061. [PMID: 27293445 PMCID: PMC4886089 DOI: 10.1155/2016/5896061] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2016] [Accepted: 04/12/2016] [Indexed: 12/13/2022] Open
Abstract
Ischemic diseases are a group of diseases, including ischemic cerebrovascular disease, ischemic cardiomyopathy (ICM), and diabetic foot as well as other diseases which are becoming a leading cause of morbidity and mortality in the whole world. Mesenchymal stem cells (MSCs) have been used to treat a variety of ischemic diseases in animal models and clinical trials. Lots of recent publications demonstrated that MSCs therapy was safe and relieved symptoms in patients of ischemic disease. However, many factors could influence therapeutic efficacy including route of delivery, MSCs' survival and residential rate in vivo, timing of transplantation, particular microenvironment, and patient's clinical condition. In this review, the current status, therapeutic potential, and the detailed factors of MSCs-based therapeutics for ischemic cerebrovascular disease, ICM, and diabetic foot are presented and discussed. We think that MSCs transplantation would constitute an ideal option for patients with ischemic diseases.
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Madonna R, Van Laake LW, Davidson SM, Engel FB, Hausenloy DJ, Lecour S, Leor J, Perrino C, Schulz R, Ytrehus K, Landmesser U, Mummery CL, Janssens S, Willerson J, Eschenhagen T, Ferdinandy P, Sluijter JPG. Position Paper of the European Society of Cardiology Working Group Cellular Biology of the Heart: cell-based therapies for myocardial repair and regeneration in ischemic heart disease and heart failure. Eur Heart J 2016; 37:1789-98. [PMID: 27055812 DOI: 10.1093/eurheartj/ehw113] [Citation(s) in RCA: 179] [Impact Index Per Article: 19.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2015] [Accepted: 02/01/2016] [Indexed: 12/27/2022] Open
Abstract
Despite improvements in modern cardiovascular therapy, the morbidity and mortality of ischaemic heart disease (IHD) and heart failure (HF) remain significant in Europe and worldwide. Patients with IHD may benefit from therapies that would accelerate natural processes of postnatal collateral vessel formation and/or muscle regeneration. Here, we discuss the use of cells in the context of heart repair, and the most relevant results and current limitations from clinical trials using cell-based therapies to treat IHD and HF. We identify and discuss promising potential new therapeutic strategies that include ex vivo cell-mediated gene therapy, the use of biomaterials and cell-free therapies aimed at increasing the success rates of therapy for IHD and HF. The overall aim of this Position Paper of the ESC Working Group Cellular Biology of the Heart is to provide recommendations on how to improve the therapeutic application of cell-based therapies for cardiac regeneration and repair.
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Affiliation(s)
- Rosalinda Madonna
- Institute of Cardiology and Center of Excellence on Aging, 'G. d'Annunzio' University - Chieti, Chieti, Italy Texas Heart Institute, Houston, USA
| | - Linda W Van Laake
- Hubrecht Institute, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Sean M Davidson
- The Hatter Cardiovascular Institute, Institute of Cardiovascular Science, University College London, London, UK
| | - Felix B Engel
- Experimental Renal and Cardiovascular Research, Department of Nephropathology, Institute of Pathology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Derek J Hausenloy
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore, National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore, Singapore The National Institute of Health Research University College London Hospitals Biomedical Research Centre, London, UK
| | - Sandrine Lecour
- MRC Cape Heart Unit, Hatter Cardiovascular Research Institute, University of Cape Town, Cape Town, South Africa
| | - Jonathan Leor
- Neufeld Cardiac Research Institute, Tel-Aviv University, Tel Aviv-Yafo, Israel Tamman Cardiovascular Research Institute, Sheba Medical Center, Tel HaShomer, Israel Sheba Center for Regenerative Medicine, Stem Cell, and Tissue Engineering, Tel Hashomer, Israel
| | - Cinzia Perrino
- Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy
| | - Rainer Schulz
- Institute of Physiology, Justus-Liebig Giessen University of Giessen, Gießen, Germany
| | - Kirsti Ytrehus
- Department of Medical Biology, Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsø, Norway
| | - Ulf Landmesser
- Department of Cardiology, Charite Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany
| | | | - Stefan Janssens
- Department of Cardiovascular Sciences, Clinical Cardiology, KU Leuven, Leuven, Belgium
| | - James Willerson
- Department of Cardiology, Texas Heart Institute, Houston, TX, USA
| | - Thomas Eschenhagen
- Department of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, Hamburg 20246, Germany
| | - Péter Ferdinandy
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary Pharmahungary Group, Szeged, Hungary
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How to Improve the Survival of Transplanted Mesenchymal Stem Cell in Ischemic Heart? Stem Cells Int 2015; 2016:9682757. [PMID: 26681958 PMCID: PMC4670674 DOI: 10.1155/2016/9682757] [Citation(s) in RCA: 152] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2015] [Accepted: 06/18/2015] [Indexed: 12/11/2022] Open
Abstract
Mesenchymal stem cell (MSC) is an intensely studied stem cell type applied for cardiac repair. For decades, the preclinical researches on animal model and clinical trials have suggested that MSC transplantation exerts therapeutic effect on ischemic heart disease. However, there remain major limitations to be overcome, one of which is the very low survival rate after transplantation in heart tissue. Various strategies have been tried to improve the MSC survival, and many of them showed promising results. In this review, we analyzed the studies in recent years to summarize the methods, effects, and mechanisms of the new strategies to address this question.
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Huang R, Yao K, Sun A, Qian J, Ge L, Zhang Y, Niu Y, Wang K, Zou Y, Ge J. Timing for intracoronary administration of bone marrow mononuclear cells after acute ST-elevation myocardial infarction: a pilot study. Stem Cell Res Ther 2015; 6:112. [PMID: 26021558 PMCID: PMC4509778 DOI: 10.1186/s13287-015-0102-5] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2014] [Revised: 07/16/2014] [Accepted: 05/20/2015] [Indexed: 12/21/2022] Open
Abstract
INTRODUCTION Most studies on intracoronary bone marrow mononuclear cell transplantation for acute myocardial infarction involve treatment 3-7 days after primary percutaneous coronary intervention (PCI); however, the optimal timing is unknown. The present study assessed the therapeutic effect at different times after ST-elevation myocardial infarction. METHODS The present trial was not blinded. A total of 104 patients with a first ST-elevation myocardial infarction and a left ventricular ejection fraction below 50 %, who had PCI of the infarct-related artery, were randomly assigned to receive intracoronary infusion of bone marrow mononuclear cells within 24 hours (group A, n = 27), 3 to 7 days after PCI (group B, n = 26), or 7 to 30 days after PCI (group C, n = 26), or to the control group (n = 25), which received saline infusion performed immediately after emergency PCI. All patients in groups A, B and C received an injection of 15 ml cell suspension containing approximately 4.9 × 10(8) bone marrow mononuclear cells into the infarct-related artery after successful PCI. RESULTS Compared to control and group C patients, group A and B patients had a significantly higher absolute increase in left ventricular ejection fraction from baseline to 12 months (change: 3.4 ± 5.7 % in control, 7.9 ± 4.9 % in group A, 6.9 ± 3.9 % in group B, 4.7 ± 3.7 % in group C), a greater decrease in left ventricular end-systolic volumes (change: -6.4 ± 15.9 ml in control, -20.5 ± 13.3 ml in group A, -19.6 ± 11.1 ml in group B, -9.4 ± 16.3 ml in group C), and significantly greater myocardial perfusion (change from baseline: -4.7 ± 5.7 % in control, -7.8 ± 4.5 % in group A, -7.5 ± 2.9 % in group B, -5.0 ± 4.0 % in group C). Group A and B patients had similar beneficial effects on cardiac function (p = 0.163) and left ventricular geometry (left ventricular end-distolic volume: p = 0.685; left ventricular end-systolic volume: p = 0.622) assessed by echocardiography, whereas group C showed similar results to those of the control group. Group B showed more expensive care (p < 0.001) and longer hospital stays during the first month after emergency PCI (p < 0.001) than group A, with a similar improvement after repeat cardiac catheterization following emergency PCI. CONCLUSION Cell therapy in acute myocardial infarction patients that is given within 24 hours is similar to 3-7 days after the primary PCI. TRIAL REGISTRATION NCT02425358 , registered 30 April 2015.
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Affiliation(s)
- Rongchong Huang
- The First Affiliated Hospital of Dalian Medical University, 222 Zhongshan Road, Dalian, 116011, China
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai, 200032, China
| | - Kang Yao
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai, 200032, China
| | - Aijun Sun
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai, 200032, China
- Institutes of Biomedical Science, Fudan University, 138 Dong'an Road, Shanghai, 200032, China
| | - Juying Qian
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai, 200032, China
| | - Lei Ge
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai, 200032, China
| | - Yiqi Zhang
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai, 200032, China
| | - Yuhong Niu
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai, 200032, China
| | - Keqiang Wang
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai, 200032, China
| | - Yunzeng Zou
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai, 200032, China
- Institutes of Biomedical Science, Fudan University, 138 Dong'an Road, Shanghai, 200032, China
| | - Junbo Ge
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai, 200032, China.
- Institutes of Biomedical Science, Fudan University, 138 Dong'an Road, Shanghai, 200032, China.
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The Clinical Status of Stem Cell Therapy for Ischemic Cardiomyopathy. Stem Cells Int 2015; 2015:135023. [PMID: 26101528 PMCID: PMC4460238 DOI: 10.1155/2015/135023] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2015] [Accepted: 05/06/2015] [Indexed: 12/14/2022] Open
Abstract
Ischemic cardiomyopathy (ICM) is becoming a leading cause of morbidity and mortality in the whole world. Stem cell-based therapy is emerging as a promising option for treatment of ICM. Several stem cell types including cardiac-derived stem cells (CSCs), bone marrow-derived stem cells, mesenchymal stem cells (MSCs), skeletal myoblasts (SMs), and CD34(+) and CD 133(+) stem cells have been applied in clinical researches. The clinical effect produced by stem cell administration in ICM mainly depends on the transdifferentiation and paracrine effect. One important issue is that low survival and residential rate of transferred stem cells in the infracted myocardium blocks the effective advances in cardiac improvement. Many other factors associated with the efficacy of cell replacement therapy for ICM mainly including the route of delivery, the type and number of stem cell infusion, the timing of injection, patient's physical condition, the particular microenvironment onto which the cells are delivered, and clinical condition remain to be addressed. Here we provide an overview of the pros and cons of these transferred cells and discuss the current state of their therapeutic potential. We believe that stem cell translation will be an ideal option for patients following ischemic heart disease in the future.
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Liebson PR. Stem-cell angiogenesis and regeneration of the heart: review of a saga of 2 decades. Clin Cardiol 2015; 38:309-16. [PMID: 25955103 DOI: 10.1002/clc.22381] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2014] [Revised: 11/26/2014] [Accepted: 12/01/2014] [Indexed: 12/20/2022] Open
Abstract
Advances in the novel approach to control ischemic heart disease and heart failure using stem cells or progenitor cells from bone marrow, mesenchyme, or myocardial tissue itself have demonstrated efficacy for increasing left ventricular function, decreasing infarct scar tissue, improving exercise tolerance and heart failure symptoms, and, in some studies, decreasing mortality and reducing rehospitalization for intractable angina or subsequent myocardial infarction. The most common techniques utilize injections of cells into the coronary vasculature or directly into specific areas of vulnerable myocardium. Although few adverse effects have been noted in clinical trials of these procedures, further clinical trials over the next decade should provide further advances in interventional techniques, ancillary supporting technologies to enhance cell regeneration, and applications in ischemic heart disease, cardiomyopathies, and cardiac genetic disorders.
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Affiliation(s)
- Philip R Liebson
- Department of Preventive Medicine, Rush University Medical Center, Chicago, Illinois
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37
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Locatelli P, Olea FD, Hnatiuk A, De Lorenzi A, Cerdá M, Giménez CS, Sepúlveda D, Laguens R, Crottogini A. Mesenchymal stromal cells overexpressing vascular endothelial growth factor in ovine myocardial infarction. Gene Ther 2015; 22:449-57. [PMID: 25789461 DOI: 10.1038/gt.2015.28] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2015] [Revised: 03/06/2015] [Accepted: 03/11/2015] [Indexed: 01/23/2023]
Abstract
Mesenchymal stromal cells (MSCs) are cardioprotective in acute myocardial infarction (AMI). Besides, we have shown that intramyocardial injection of plasmid-VEGF(165) (pVEGF) in ovine AMI reduces infarct size and improves left ventricular (LV) function. We thus hypothesized that MSCs overexpressing VEGF(165) (MSCs-pVEGF) would afford greater cardioprotection than non-modified MSCs or pVEGF alone. Sheep underwent an anteroapical AMI and, 1 week later, received intramyocardial MSCs-pVEGF in the infarct border. One month post treatment, infarct size (magnetic resonance) decreased by 31% vs pre-treatment. Of note, myocardial salvage occurred predominantly at the subendocardium, the myocardial region displaying the largest contribution to systolic performance. Consistently, LV ejection fraction recovered to almost its baseline value because of marked decrease in end-systolic volume. None of these effects were observed in sheep receiving non-transfected MSCs or pVEGF. Although myocardial retention of MSCs decreased steeply over time, the treatment induced significant capillary and arteriolar proliferation, which reduced subendocardial fibrosis. We conclude that in ovine AMI, allogeneic VEGF-overexpressing MSCs induce subendocardial myocardium salvage through microvascular proliferation, reducing infarct size and improving LV function more than non-transfected MSCs or the naked plasmid. Importantly, the use of a plasmid rather than a virus allows for repeated treatments, likely needed in ischemic heart disease.
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Affiliation(s)
- P Locatelli
- Department of Physiology, Favaloro University, Buenos Aires, Argentina
| | - F D Olea
- Department of Physiology, Favaloro University, Buenos Aires, Argentina
| | - A Hnatiuk
- Department of Physiology, Favaloro University, Buenos Aires, Argentina
| | - A De Lorenzi
- Favaloro Foundation University Hospital, Buenos Aires, Argentina
| | - M Cerdá
- Favaloro Foundation University Hospital, Buenos Aires, Argentina
| | - C S Giménez
- Favaloro Foundation University Hospital, Buenos Aires, Argentina
| | - D Sepúlveda
- Department of Pathology, Favaloro University, Buenos Aires, Argentina
| | - R Laguens
- Department of Pathology, Favaloro University, Buenos Aires, Argentina
| | - A Crottogini
- Department of Physiology, Favaloro University, Buenos Aires, Argentina
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Rosen MR, Myerburg RJ, Francis DP, Cole GD, Marbán E. Translating stem cell research to cardiac disease therapies: pitfalls and prospects for improvement. J Am Coll Cardiol 2014; 64:922-37. [PMID: 25169179 PMCID: PMC4209166 DOI: 10.1016/j.jacc.2014.06.1175] [Citation(s) in RCA: 67] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2014] [Revised: 06/02/2014] [Accepted: 06/05/2014] [Indexed: 12/23/2022]
Abstract
Over the past 2 decades, there have been numerous stem cell studies focused on cardiac diseases, ranging from proof-of-concept to phase 2 trials. This series of papers focuses on the legacy of these studies and the outlook for future treatment of cardiac diseases with stem cell therapies. The first section by Drs. Rosen and Myerburg is an independent review that analyzes the basic science and translational strategies supporting the rapid advance of stem cell technology to the clinic, the philosophies behind them, trial designs, and means for going forward that may impact favorably on progress. The second and third sections were collected as responses to the initial section of this review. The commentary by Drs. Francis and Cole discusses the review by Drs. Rosen and Myerburg and details how trial outcomes can be affected by noise, poor trial design (particularly the absence of blinding), and normal human tendencies toward optimism and denial. The final, independent paper by Dr. Marbán takes a different perspective concerning the potential for positive impact of stem cell research applied to heart disease and future prospects for its clinical application. (Compiled by the JACC editors).
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Affiliation(s)
- Michael R Rosen
- Departments of Pharmacology and Pediatrics, Columbia University Medical Center, New York, New York.
| | - Robert J Myerburg
- Division of Cardiology, University of Miami, Miller School of Medicine, Miami, Florida
| | - Darrel P Francis
- International Centre for Circulatory Health, National Heart and Lung Institute, Imperial College London, London, United Kingdom.
| | - Graham D Cole
- International Centre for Circulatory Health, National Heart and Lung Institute, Imperial College London, London, United Kingdom
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Benderitter M, Caviggioli F, Chapel A, Coppes RP, Guha C, Klinger M, Malard O, Stewart F, Tamarat R, van Luijk P, Limoli CL. Stem cell therapies for the treatment of radiation-induced normal tissue side effects. Antioxid Redox Signal 2014; 21:338-55. [PMID: 24147585 PMCID: PMC4060814 DOI: 10.1089/ars.2013.5652] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
SIGNIFICANCE Targeted irradiation is an effective cancer therapy but damage inflicted to normal tissues surrounding the tumor may cause severe complications. While certain pharmacologic strategies can temper the adverse effects of irradiation, stem cell therapies provide unique opportunities for restoring functionality to the irradiated tissue bed. RECENT ADVANCES Preclinical studies presented in this review provide encouraging proof of concept regarding the therapeutic potential of stem cells for treating the adverse side effects associated with radiotherapy in different organs. Early-stage clinical data for radiation-induced lung, bone, and skin complications are promising and highlight the importance of selecting the appropriate stem cell type to stimulate tissue regeneration. CRITICAL ISSUES While therapeutic efficacy has been demonstrated in a variety of animal models and human trials, a range of additional concerns regarding stem cell transplantation for ameliorating radiation-induced normal tissue sequelae remain. Safety issues regarding teratoma formation, disease progression, and genomic stability along with technical issues impacting disease targeting, immunorejection, and clinical scale-up are factors bearing on the eventual translation of stem cell therapies into routine clinical practice. FUTURE DIRECTIONS Follow-up studies will need to identify the best possible stem cell types for the treatment of early and late radiation-induced normal tissue injury. Additional work should seek to optimize cellular dosing regimes, identify the best routes of administration, elucidate optimal transplantation windows for introducing cells into more receptive host tissues, and improve immune tolerance for longer-term engrafted cell survival into the irradiated microenvironment.
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Affiliation(s)
- Marc Benderitter
- 1 Laboratory of Radiopathology and Experimental Therapies, IRSN , PRP-HOM, SRBE, Fontenay-aux-Roses, France
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Pavo N, Charwat S, Nyolczas N, Jakab A, Murlasits Z, Bergler-Klein J, Nikfardjam M, Benedek I, Benedek T, Pavo IJ, Gersh BJ, Huber K, Maurer G, Gyöngyösi M. Cell therapy for human ischemic heart diseases: critical review and summary of the clinical experiences. J Mol Cell Cardiol 2014; 75:12-24. [PMID: 24998410 DOI: 10.1016/j.yjmcc.2014.06.016] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2014] [Revised: 05/23/2014] [Accepted: 06/26/2014] [Indexed: 12/24/2022]
Abstract
A decade ago, stem or progenitor cells held the promise of tissue regeneration in human myocardium, with the expectation that these therapies could rescue ischemic myocyte damage, enhance vascular density and rebuild injured myocardium. The accumulated evidence in 2014 indicates, however, that the therapeutic success of these cells is modest and the tissue regeneration involves much more complex processes than cell-related biologics. As the quest for the ideal cell or combination of cells continues, alternative cell types, such as resident cardiac cells, adipose-derived or phenotypic modified stem or progenitor cells have also been applied, with the objective of increasing both the number and the retention of the reparative cells in the myocardium. Two main delivery routes (intracoronary and percutaneous intramyocardial) of stem cells are currently used preferably for patients with recent acute myocardial infarction or ischemic cardiomyopathy. Other delivery modes, such as surgical or intravenous via peripheral veins or coronary sinus have also been utilized with less success. Due to the difficult recruitment of patients within conceivable timeframe into cardiac regenerative trials, meta-analyses of human cardiac cell-based studies have tried to gather sufficient number of subjects to present a statistical compelling statement, reporting modest success with a mean increase of 0.9-6.1% in left ventricular global ejection fraction. Additionally, nearly half of the long-term studies reported the disappearance of the initial benefit of this treatment. Beside further extensive efforts to increase the efficacy of currently available methods, pre-clinical experiments using new techniques such as tissue engineering or exploiting paracrine effect hold promise to regenerate injured human cardiac tissue.
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Affiliation(s)
- Noemi Pavo
- Department of Cardiology, Medical University of Vienna, Austria
| | - Silvia Charwat
- Department of Cardiology, Medical University of Vienna, Austria
| | - Noemi Nyolczas
- Department of Cardiology, Medical University of Vienna, Austria
| | - András Jakab
- Department of Biomedical Laboratory and Imaging Science, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Zsolt Murlasits
- Exercise Biochemistry Laboratory, The University of Memphis, Department of Health and Sport Sciences, Memphis, TN, USA
| | | | | | - Imre Benedek
- Department of Cardiology, University of Medicine and Pharmacy Tirgu Mures, Romania
| | - Teodora Benedek
- Department of Cardiology, University of Medicine and Pharmacy Tirgu Mures, Romania
| | - Imre J Pavo
- Department of Cardiology, Medical University of Vienna, Austria
| | - Bernard J Gersh
- Internal Medicine, Mayo Graduate School of Medicine, Mayo Clinic, Rochester, MN, USA
| | - Kurt Huber
- 3(rd) Dept. Cardiology and Emergency Medicine, Wilhelminen hospital, Vienna, Austria
| | - Gerald Maurer
- Department of Cardiology, Medical University of Vienna, Austria
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Fan CQ, Leu S, Sheu JJ, Zhen YY, Tsai TH, Chen YL, Chung SY, Chai HT, Sun CK, Yang JL, Chang HW, Ko SF, Yip HK. Prompt bone marrow-derived mesenchymal stem cell therapy enables early porcine heart function recovery from acute myocardial infarction. Int Heart J 2014; 55:362-71. [PMID: 24965596 DOI: 10.1536/ihj.14-007] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Impact of early bone marrow-derived mesenchymal stem cell (BMDMSC) implantation on left ventricular (LV) function after AMI was studied.Twelve mini-pigs were equally divided into placebo (AMI through left coronary artery ligation) and cell-treated groups [BMDMSCs (3.0 × 10(7)) implanted into infarct area (IA)] with myocardium harvested by post-AMI day 90. Six healthy animals served as controls.On post-AMI day 90, magnetic resonance imaging showed a lower LV ejection fraction but higher LV dimensions in the placebo group (P < 0.003) that also had increased IAs but reduced wall thickness (P < 0.005). Pro-apoptotic gene expressions (Bax, caspase-3) and apoptotic nucleus number in IAs and peri-IAs were highest in the placebo group (P < 0.001). Inflammatory biomarker expressions (MMP-9, oxidized protein, CD40+ cells) were highest, whereas those of angiogenesis (VEGF, CD31+ cells, SDF-1α, CXCR4) and myocardium-preservation (connexin43, troponin-I, cytochrome-C) were lowest in the placebo group (P < 0.01).BMDMSC implantation preserved LV function and alleviated remodeling at post-AMI day 90.
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Affiliation(s)
- Chang-Qing Fan
- Division of Cardiology, Department of Internal Medicine, Xiamen Chang Gung Memorial Hospital
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Zhang S, Ma X, Yao K, Zhu H, Huang Z, Shen L, Qian J, Zou Y, Sun A, Ge J. Combination of CD34-positive cell subsets with infarcted myocardium-like matrix stiffness: a potential solution to cell-based cardiac repair. J Cell Mol Med 2014; 18:1236-8. [PMID: 24945435 PMCID: PMC4508162 DOI: 10.1111/jcmm.12301] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2014] [Accepted: 03/21/2014] [Indexed: 02/04/2023] Open
Abstract
Detection of the optimal cell transplantation strategy for myocardial infarction (MI) has attracted a great deal of attention. Commitment of engrafted cells to angiogenesis within damaged myocardium is regarded as one of the major targets in cell-based cardiac repair. Bone marrow–derived CD34-positive cells, a well-characterized population of stem cells, might represent highly functional endothelial progenitor cells and result in the formation of new blood vessels. Recently, physical microenvironment (extracellular matrix stiffness) around the engrafted cells was found to exert an essential impact on their fate. Stem cells are able to feel and respond to the tissue-like matrix stiffness to commit to a relevant lineage. Notably, the infarct area after MI experiences a time-dependent stiffness change from flexible to rigid. Our previous observations demonstrated myocardial stiffness-dependent differentiation of the unselected bone marrow–derived mononuclear cells (BMMNCs) along endothelial lineage cells. Myocardial stiffness (∽42 kPa) within the optimal time domain of cell engraftment (at week 1 to 2) after MI provided a more favourable physical microenvironment for cell specification and cell-based cardiac repair. However, the difference in tissue stiffness-dependent cell differentiation between the specific cell subsets expressing and no expressing CD34 phenotype remains uncertain. We presumed that CD34-positive cell subsets facilitated angiogenesis and subsequently resulted in cardiac repair under induction of infarcted myocardium-like matrix stiffness compared with CD34-negative cells. If the hypothesis were true, it would contribute greatly to detect the optimal cell subsets for cell therapy and to establish an optimized therapy strategy for cell-based cardiac repair.
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Affiliation(s)
- Shuning Zhang
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China
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Marbán E. Breakthroughs in cell therapy for heart disease: focus on cardiosphere-derived cells. Mayo Clin Proc 2014; 89:850-8. [PMID: 24943699 PMCID: PMC4122123 DOI: 10.1016/j.mayocp.2014.02.014] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2013] [Revised: 02/20/2014] [Accepted: 02/24/2014] [Indexed: 12/21/2022]
Abstract
The clinical reality of cell therapy for heart disease dates back to the 1990 s, when autologous skeletal myoblasts were first transplanted into failing hearts during open-chest surgery. Since then, the focus has shifted to bone marrow-derived cells and, more recently, cells extracted from the heart itself. Although progress has been nonlinear and often disheartening, the field has nevertheless made remarkable progress. Six major breakthroughs are notable: (1) the establishment of safety with intracoronary delivery; (2) the finding that therapeutic regeneration is possible; (3) the increase in allogeneic cell therapy; (4) the effect of increasing mechanistic insights; (5) glimmers of clinical efficacy; and (6) the progression to phase 2 and 3 studies. This article individually reviews these landmark developments in detail and concludes that the field has reached a new phase of maturity where the prospect of clinical impact is increasingly imminent.
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45
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Katsikis A, Koutelou M. Cardiac Stem Cell Imaging by SPECT and PET. CURRENT CARDIOVASCULAR IMAGING REPORTS 2014. [DOI: 10.1007/s12410-014-9265-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Sadat K, Ather S, Aljaroudi W, Heo J, Iskandrian AE, Hage FG. The effect of bone marrow mononuclear stem cell therapy on left ventricular function and myocardial perfusion. J Nucl Cardiol 2014; 21:351-67. [PMID: 24379128 DOI: 10.1007/s12350-013-9846-4] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2013] [Accepted: 12/08/2013] [Indexed: 12/20/2022]
Abstract
BACKGROUND Bone marrow stem cell (BMC) transfer is an emerging therapy with potential to salvage cardiomyocytes during acute myocardial infarction and promote regeneration and endogenous repair of damaged myocardium in patients with left ventricular (LV) dysfunction. We performed a meta-analysis to examine the association between administration of BMC and LV functional recovery as assessed by imaging. METHODS AND RESULTS Our meta-analysis included data from 32 trials comprising information on 1,300 patients in the treatment arm and 1,006 patients in the control arm. Overall, BMC therapy was associated with a significant increase in LV ejection fraction by 4.6% ± 0.7% (P < .001) (control-adjusted increase of 2.8% ± 0.9%, P = .001), and a significant decrease in perfusion defect size by 9.5% ± 1.4% (P < .001) (control-adjusted decrease of 3.8% ± 1.2%, P = .002). The effect of BMC therapy was similar whether the cells were administered via intra-coronary or intra-myocardial routes and was not influenced by baseline ejection fraction or perfusion defect size. CONCLUSIONS BMC transfer appears to have a positive impact on LV recovery in patients with acute coronary syndrome and those with stable coronary disease with or without heart failure. Most studies were small and a minority used a core laboratory for image analysis.
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Affiliation(s)
- Kamel Sadat
- Division of Cardiovascular Disease, University of Alabama at Birmingham, Lyons-Harrison Research Building 314, 1900 University Blvd, Birmingham, AL, 35294, USA,
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Cheng Y, Yi G, Conditt GB, Sheehy A, Kolodgie FD, Tellez A, Polyakov I, Gu A, Aboodi MS, Wallace-Bradley D, Schuster M, Martens T, Itescu S, Kaluza GL, Basu S, Virmani R, Granada JF, Sherman W. Catheter-Based Endomyocardial Delivery of Mesenchymal Precursor Cells Using 3D Echo Guidance Improves Cardiac Function in a Chronic Myocardial Injury Ovine Model. Cell Transplant 2013; 22:2299-309. [DOI: 10.3727/096368912x658016] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
The administration of bone marrow-derived stem cells may provide a new treatment option for patients with heart failure. Transcatheter cell injection may require multi-imaging modalities to optimize delivery. This study sought to evaluate whether endomyocardial injection of mesenchymal precursor cells (MPCs) could be guided by real-time 3D echocardiography (RT3DE) in treating chronic, postinfarction (MI) left ventricular (LV) dysfunction in sheep. Four weeks after induction of an anterior wall myocardial infarction in 39 sheep, allogeneic MPCs in doses of either 25 × 106 ( n = 10), 75 × 106 ( n = 9), or 225 × 106 ( n = 10) cells or nonconditioned control media ( n = 10) were administered intramyocardially into infarct and border zone areas using a catheter designed for combined fluoroscopic and RT3DE-guided injections. LV function was assessed before and after injection. Infarct dimension and vascular density were evaluated histologically. RT3DE-guided injection procedures were safe. Compared to controls, the highest dose MPC treatment led to increments in ejection fraction (3±3% in 225M MPCs vs. −5±4% in the control group, p < 0.01) and wall thickening in both infarct (4±4% in 225M MPCs vs. −3±6% in the control group, p = 0.02) and border zones (4±6% in 225M MPCs vs. −8±9% in the control group, p = 0.01). Histology analysis demonstrated significantly higher arteriole density in the infarct and border zones in the highest dose MPC-treated animals compared to the lower dose or control groups. Endomyocardial implantation of MPCs under RT3DE guidance was safe and without observed logistical obstacles. Significant increases in LV performance (ejection fraction and wall thickening) and neovascularization resulted from this technique, and so this technique has important implications for treating patients with postischemic LV dysfunction.
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Affiliation(s)
- Yanping Cheng
- The Jack Skirball Center for Cardiovascular Research, Cardiovascular Research Foundation, Orangeburg, NY, USA
| | - Genghua Yi
- The Jack Skirball Center for Cardiovascular Research, Cardiovascular Research Foundation, Orangeburg, NY, USA
| | - Gerard B. Conditt
- The Jack Skirball Center for Cardiovascular Research, Cardiovascular Research Foundation, Orangeburg, NY, USA
| | | | | | - Armando Tellez
- The Jack Skirball Center for Cardiovascular Research, Cardiovascular Research Foundation, Orangeburg, NY, USA
| | | | - Anguo Gu
- The Jack Skirball Center for Cardiovascular Research, Cardiovascular Research Foundation, Orangeburg, NY, USA
| | - Michael S. Aboodi
- The Jack Skirball Center for Cardiovascular Research, Cardiovascular Research Foundation, Orangeburg, NY, USA
| | - David Wallace-Bradley
- The Jack Skirball Center for Cardiovascular Research, Cardiovascular Research Foundation, Orangeburg, NY, USA
| | | | | | | | - Greg L. Kaluza
- The Jack Skirball Center for Cardiovascular Research, Cardiovascular Research Foundation, Orangeburg, NY, USA
| | | | | | - Juan F. Granada
- The Jack Skirball Center for Cardiovascular Research, Cardiovascular Research Foundation, Orangeburg, NY, USA
| | - Warren Sherman
- The Jack Skirball Center for Cardiovascular Research, Cardiovascular Research Foundation, Orangeburg, NY, USA
- Abbott Vascular, Santa Clara, CA, USA
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Zhang Y, Liang X, Lian Q, Tse HF. Perspective and challenges of mesenchymal stem cells for cardiovascular regeneration. Expert Rev Cardiovasc Ther 2013; 11:505-17. [PMID: 23570363 DOI: 10.1586/erc.13.5] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Mesenchymal stem cells (MSCs) exhibit multipotent differentiation potential and can be derived from embryonic, neonatal and adult differentiation stage III tissue sources. While increasing preclinical studies and clinical trials have indicated that MSC-based therapy is a promising strategy for cardiovascular regeneration, there are major challenges to overcome before this stem-cell technology can be widely applied in clinical settings. In this review, the following important issues will be addressed. First, optimal sources of MSC derivation suitable for myocardial repair are not determined. Second, assessments for preclinical and clinical studies of MSCs require more scientific data analysis. Third, mechanisms of MSC-based therapy for cardiovascular regeneration have not been fully understood yet. Finally, the potential benefit-risk ratio of MSC therapy needs to be evaluated systematically. Additionally, future development of MSC therapy will be discussed.
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Affiliation(s)
- Yuelin Zhang
- Cardiology Division, Department of Medicine, University of Hong Kong, Hong Kong
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Chen IY, Wu JC. Molecular imaging: the key to advancing cardiac stem cell therapy. Trends Cardiovasc Med 2013; 23:201-10. [PMID: 23561794 DOI: 10.1016/j.tcm.2012.12.003] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2012] [Revised: 12/10/2012] [Accepted: 12/11/2012] [Indexed: 12/30/2022]
Abstract
Cardiac stem cell therapy continues to hold promise for the treatment of ischemic heart disease despite the fact that early promising pre-clinical findings have yet to be translated into consistent clinical success. The latest human studies have collectively identified a pressing need to better understand stem cell behavior in humans and called for more incorporation of noninvasive imaging techniques into the design and evaluation of human stem cell therapy trials. This review discusses the various molecular imaging techniques validated to date for studying stem cells in living subjects, with a particular emphasis on their utilities in assessing the acute retention and the long-term survival of transplanted stem cells. These imaging techniques will be essential for advancing cardiac stem cell therapy by providing the means to both guide ongoing optimization and predict treatment response in humans.
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Affiliation(s)
- Ian Y Chen
- Department of Medicine, Division of Cardiovascular Medicine, Stanford, CA, USA; Department of Radiology, Molecular Imaging Program at Stanford, Stanford, CA 94305-5454, USA
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Abstract
The past decade has witnessed a marked increase in the number of clinical trials of cardiac repair with adult bone marrow cells (BMCs). These trials included patients with acute myocardial infarction (MI) as well as chronic ischemic heart disease (IHD) and utilized different types of BMCs with variable numbers, routes of administration, and timings after MI. Given these differences in methods, the outcomes from these trials have been often disparate and controversial. However, analysis of pooled data suggests that BMC injection enhances left ventricular function, reduces infarct scar size, and improves remodeling in patients with acute MI as well as chronic IHD. BMC therapy also improves clinical outcomes during follow-up without any increase in adverse effects. Although the underlying mechanisms of heart repair are difficult to elucidate in human studies, valuable insights may be gleaned from subgroup analysis of key variables. This information may be utilized to design future randomized controlled trials to carefully determine the long-term safety and benefits of BMC therapy.
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