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Ding JY, Meng TT, Du RL, Song XB, Li YX, Gao J, Ji R, He QY. Bibliometrics of trends in global research on the roles of stem cells in myocardial fibrosis therapy. World J Stem Cells 2024; 16:1086-1105. [PMID: 39734477 PMCID: PMC11669986 DOI: 10.4252/wjsc.v16.i12.1086] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2024] [Revised: 10/05/2024] [Accepted: 11/11/2024] [Indexed: 12/13/2024] Open
Abstract
BACKGROUND Myocardial fibrosis, a condition linked to several cardiovascular diseases, is associated with a poor prognosis. Stem cell therapy has emerged as a potential treatment option and the application of stem cell therapy has been studied extensively. However, a comprehensive bibliometric analysis of these studies has yet to be conducted. AIM To map thematic trends, analyze research hotspots, and project future directions of stem cell-based myocardial fibrosis therapy. METHODS We conducted a bibliometric and visual analysis of studies in the Web of Science Core Collection using VOSviewer and Microsoft Excel. The dataset included 1510 articles published between 2001 and 2024. Countries, organizations, authors, references, keywords, and co-citation networks were examined to identify evolving research trends. RESULTS Our findings revealed a steady increase in the number of publications, with a projected increase to over 200 publications annually by 2030. Initial research focused on stem cell-based therapy, particularly for myocardial infarction and heart failure. More recently, there has been a shift toward cell-free therapy, involving extracellular vesicles, exosomes, and microRNAs. Key research topics include angiogenesis, inflammation, apoptosis, autophagy, and oxidative stress. CONCLUSION This analysis highlights the evolution of stem cell therapies for myocardial fibrosis, with emerging interest in cell-free approaches. These results are expected to guide future scientific exploration and decision-making.
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Affiliation(s)
- Jing-Yi Ding
- Department of Cardiology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Tian-Tian Meng
- Department of Rehabilitation, Dongfang Hospital, Beijing University of Chinese Medicine, Beijing 100071, China
| | - Ruo-Lin Du
- Department of Emergency Medicine, South Branch of Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Xin-Bin Song
- Department of Intensive Care Unit, Zhumadian Hospital of Traditional Chinese Medicine, Zhumadian 463000, Henan Province, China
| | - Yi-Xiang Li
- Department of Chinese Medicine, The Third People's Hospital of Henan Province, Zhengzhou 450000 Henan Province, China
| | - Jing Gao
- Department of Cardiology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Ran Ji
- Department of Intensive Care Unit, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Qing-Yong He
- Department of Cardiology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China.
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Park KH, He X, Jiang L, Zhu H, Liang J, Wang Y, Ma J. Activation of MG53 Enhances Cell Survival and Engraftment of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes in Injured Hearts. Stem Cell Rev Rep 2023; 19:2420-2428. [PMID: 37477774 PMCID: PMC10579131 DOI: 10.1007/s12015-023-10596-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/13/2023] [Indexed: 07/22/2023]
Abstract
BACKGROUND AND OBJECTIVE Our previous studies demonstrated that MG53 protein can protect the myocardium, but its use as a therapeutic is challenging due to its short half-life in blood circulation. This study aimed to investigate the cardioprotective role of MG53 on human induced pluripotent stem cell-derived cardiomyocytes (HiPSC-CMs) in the context of myocardial ischemia/reperfusion (I/R). METHODS In vitro: HiPSC-CMs were transfected with adenoviral MG53 (HiPSC-CMsMG53), in which the expression of MG53 can be controlled by doxycycline (Dox), and the cells were then exposed to H2O2 to mimic ischemia/reperfusion injury. In vivo: HiPSC-CMsMG53 were transplanted into the peri-infarct region in NSG™ mice after I/R. After surgery, mice were treated with Dox (+ Dox) to activate MG53 expression (sucrose as a control of -Dox) and then assessed by echocardiography and immunohistochemistry. RESULTS MG53 can be expressed in HiPSC-CMMG53 and released into the culture medium after adding Dox. The cell survival rate of HiPSC-CMMG53 was improved by Dox under the H2O2 condition. After 14 and 28 days of ischemia/reperfusion (I/R), transplanted HiPSC-CMsMG53 + Dox significantly improved heart function, including ejection fraction (EF) and fractional shortening (FS) in mice, compared to HiPSC-CMsMG53-Dox, and reduced the size of the infarction. Additionally, HiPSC-CMMG53 + Dox mice demonstrated significant engraftment in the myocardium as shown by staining human nuclei-positive cells. In addition, the cell survival-related AKT signaling was found to be more active in HiPSC-CMMG53 + Dox transplanted mice's myocardium compared to the HiPSC-CMMG53-Dox group. Notably, the Dox treatment did not cause harm to other organs. CONCLUSION Inducible MG53 expression is a promising approach to enhance cell survival and engraftment of HiPSC-CMs for cardiac repair.
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Affiliation(s)
- Ki Ho Park
- Division of Surgical Sciences, Department of Surgery, University of Virginia School of Medicine, Charlottesville, VA, USA.
| | - Xingyu He
- Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH, USA
| | - Lin Jiang
- Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH, USA
| | - Hua Zhu
- Department of Surgery, College of Medicine, The Ohio State University, Columbus, OH, USA
| | - Jialiang Liang
- Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH, USA
| | - Yigang Wang
- Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH, USA.
| | - Jianjie Ma
- Division of Surgical Sciences, Department of Surgery, University of Virginia School of Medicine, Charlottesville, VA, USA.
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Can a Large Number of Transplanted Mesenchymal Stem Cells Have an Optimal Therapeutic Effect on Improving Ovarian Function? Int J Mol Sci 2022; 23:ijms232416009. [PMID: 36555651 PMCID: PMC9788312 DOI: 10.3390/ijms232416009] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Revised: 12/10/2022] [Accepted: 12/14/2022] [Indexed: 12/23/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are next-generation treatment in degenerative diseases. For the application of mesenchymal stem cell therapy to degenerative disease, transplantation conditions (e.g., optimized dose, delivery route and regenerating efficacy) should be considered. Recently, researchers have studied the mode of action of MSC in the treatment of ovarian degenerative disease. However, the evidence for the optimal number of cells for the developing stem cell therapeutics is insufficient. The objective of this study was to evaluate the efficacy in ovarian dysfunction, depends on cell dose. By intraovarian transplantation of low (1 × 105) and high (5 × 105) doses of placenta-derived mesenchymal stem cells (PD-MSCs) into thioacetamide (TAA)-injured rats, we compared the levels of apoptosis and oxidative stress that depend on different cell doses. Apoptosis and oxidative stress were significantly decreased in the transplanted (Tx) group compared to the non-transplanted (NTx) group in ovarian tissues from TAA-injured rats (* p < 0.05). In addition, we confirmed that follicular development was significantly increased in the Tx groups compared to the NTx group (* p < 0.05). However, there were no significant differences in the apoptosis, antioxidant or follicular development of injured ovarian tissues between the low and high doses PD-MSCs group. These findings provide new insights into the understanding and evidence obtained from clinical trials for stem cell therapy in reproductive systems.
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Nummi A, Pätilä T, Mulari S, Lampinen M, Nieminen T, Mäyränpää MI, Vento A, Harjula A, Kankuri E. Epicardial transplantation of autologous atrial appendage micrografts: evaluation of safety and feasibility in pigs after coronary artery occlusion. SCAND CARDIOVASC J 2022; 56:352-360. [PMID: 36002941 DOI: 10.1080/14017431.2022.2111462] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Revised: 07/04/2022] [Accepted: 08/05/2022] [Indexed: 06/15/2023]
Abstract
Objectives. Several approaches devised for clinical utilization of cell-based therapies for heart failure often suffer from complex and lengthy preparation stages. Epicardial delivery of autologous atrial appendage micrografts (AAMs) with a clinically used extracellular matrix (ECM) patch provides a straightforward therapy alternative. We evaluated the operative feasibility and the effect of micrografts on the patch-induced epicardial foreign body inflammatory response in a porcine model of myocardial infarction. Design. Right atrial appendages were harvested and mechanically processed into AAMs. The left anterior descending coronary artery was ligated to generate acute infarction. Patches of ECM matrix with or without AAMs were transplanted epicardially onto the infarcted area. Four pigs received the ECM and four received the AAMs patch. Cardiac function was studied by echocardiography both preoperatively and at 3-week follow-up. The primary outcome measures were safety and feasibility of the therapy administration, and the secondary outcome was the inflammatory response to ECM. Results. Neither AAMs nor ECM patch-related complications were detected during the follow-up time. AAMs patch preparation was feasible according to time and safety. Inflammation was greatly reduced in AAMs when compared with ECM patches as measured by the amount of infiltrated inflammatory cells and area of inflammation. Immunohistochemistry demonstrated an increased CD3+ cell density in the AAMs patch infiltrate. Conclusions. Epicardial AAMs transplantation demonstrated safety and clinical feasibility. The use of micrografts significantly inhibited ECM-induced foreign body inflammatory reactivity. Transplantation of AAMs shows good clinical applicability as adjuvant therapy to cardiac surgery and can suppress acute inflammatory reactivity.
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Affiliation(s)
- Annu Nummi
- Heart and Lung Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Tommi Pätilä
- Pediatric Cardiac Surgery, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Severi Mulari
- Heart and Lung Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Milla Lampinen
- Department of Pharmacology, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Tuomo Nieminen
- Heart and Lung Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Päijät-Häme Joint Authority for Health and Wellbeing, Lahti, Finland
| | - Mikko I Mäyränpää
- Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Antti Vento
- Heart and Lung Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Ari Harjula
- Heart and Lung Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Esko Kankuri
- Department of Pharmacology, Faculty of Medicine, University of Helsinki, Helsinki, Finland
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SDF-1/CXCR4-Mediated Stem Cell Mobilization Involved in Cardioprotective Effects of Electroacupuncture on Mouse with Myocardial Infarction. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:4455183. [PMID: 35982734 PMCID: PMC9381195 DOI: 10.1155/2022/4455183] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/12/2021] [Revised: 06/19/2022] [Accepted: 06/28/2022] [Indexed: 02/07/2023]
Abstract
Stem cell-based therapeutic strategies have obtained a significant breakthrough in the treatment of cardiovascular diseases, particularly in myocardial infarction (MI). Nevertheless, limited retention and poor migration of stem cells are still problems for stem cell therapeutic development. Hence, there is an urgent need to develop new strategies that can mobilize stem cells to infarcted myocardial tissues effectively. Electroacupuncture (EA) intervention can improve cardiac function and alleviate myocardial injury after MI, but its molecular mechanism is still unclear. This study is aimed at observing the effects of EA treatment on the stem cell mobilization and revealing possible mechanisms in the MI model of mice. EA treatment at Neiguan (PC6) and Xinshu (BL15) acupoints was conducted on the second day after the ligation surgery. Then, the number of stem cells in peripheral blood after EA in MI mice and their cardiac function, infarct size, and collagen deposition was observed. We found that the number of CD34-, CD117-, Sca-1-, and CD90-positive cells increased at 6 h and declined at 24 h after EA intervention in the blood of MI mice. The expression of CXC chemokine receptor-4 (CXCR4) protein was upregulated at 6 h after EA treatment, while the ratio of LC3B II/I or p-ERK/ERK showed a reverse trend. In addition, there was obvious difference in EF and FS between wild-type mice and CXCR4+/− mice. The infarct size, collagen deposition, and apoptosis of the injured myocardium in CXCR4+/− mice increased but could be ameliorated by EA. In a word, our study demonstrates that EA alleviates myocardial injury via stem cell mobilization which may be regulated by the SDF-1/CXCR4 axis.
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Fields L, Ito T, Kobayashi K, Ichihara Y, Podaru MN, Hussain M, Yamashita K, Machado V, Lewis-McDougall F, Suzuki K. Epicardial placement of human MSC-loaded fibrin sealant films for heart failure: Preclinical efficacy and mechanistic data. Mol Ther 2021; 29:2554-2570. [PMID: 33887461 PMCID: PMC8353205 DOI: 10.1016/j.ymthe.2021.04.018] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 02/28/2021] [Accepted: 04/15/2021] [Indexed: 12/31/2022] Open
Abstract
Mesenchymal stromal cell (MSC) transplantation has been investigated as an advanced treatment of heart failure; however, further improvement of the therapeutic efficacy and mechanistic understanding are needed. Our previous study has reported that epicardial placement of fibrin sealant films incorporating rat amniotic membrane-derived (AM)-MSCs (MSC-dressings) could address limitations of traditional transplantation methods. To progress this finding toward clinical translation, this current study aimed to examine the efficacy of MSC-dressings using human AM-MSCs (hAM-MSCs) and the underpinning mechanism for myocardial repair. Echocardiography demonstrated that cardiac function and structure were improved in a rat ischemic cardiomyopathy model after hAM-MSC-dressing therapy. hAM-MSCs survived well in the rat heart, enhanced myocardial expression of reparative genes, and attenuated adverse remodeling. Copy number analysis by qPCR revealed that upregulated reparative genes originated from endogenous rat cells rather than hAM-MSCs. These results suggest hAM-MSC-dressing therapy stimulates a secondary release of paracrine factors from endogenous cells improving myocardial repair ("secondary paracrine effect"), and cardiac M2-like macrophages were identified as a potential cell source of repair. We demonstrated hAM-MSCs increased M2-like macrophages through not only enhancing M2 polarization but also augmenting their proliferation and migration capabilities via PGE2, CCL2, and TGF-β1, resulting in enhanced cardiac function after injury.
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Affiliation(s)
- Laura Fields
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Tomoya Ito
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Kazuya Kobayashi
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Yuki Ichihara
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Mihai-Nicolae Podaru
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Mohsin Hussain
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Kizuku Yamashita
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Vanessa Machado
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Fiona Lewis-McDougall
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Ken Suzuki
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
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Li J, Hu S, Zhu D, Huang K, Mei X, López de Juan Abad B, Cheng K. All Roads Lead to Rome (the Heart): Cell Retention and Outcomes From Various Delivery Routes of Cell Therapy Products to the Heart. J Am Heart Assoc 2021; 10:e020402. [PMID: 33821664 PMCID: PMC8174178 DOI: 10.1161/jaha.120.020402] [Citation(s) in RCA: 58] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
In the past decades, numerous preclinical studies and several clinical trials have evidenced the feasibility of cell transplantation in treating heart diseases. Over the years, different delivery routes of cell therapy have emerged and broadened the width of the field. However, a common hurdle is shared by all current delivery routes: low cell retention. A myriad of studies confirm that cell retention plays a crucial role in the success of cell-mediated cardiac repair. It is important for any delivery route to maintain donor cells in the recipient heart for enough time to not only proliferate by themselves, but also to send paracrine signals to surrounding damaged heart cells and repair them. In this review, we first undertake an in-depth study of primary theories of cell loss, including low efficiency in cell injection, "washout" effects, and cell death, and then organize the literature from the past decade that focuses on cell transplantation to the heart using various cell delivery routes, including intracoronary injection, systemic intravenous injection, retrograde coronary venous injection, and intramyocardial injection. In addition to a recapitulation of these approaches, we also clearly evaluate their strengths and weaknesses. Furthermore, we conduct comparative research on the cell retention rate and functional outcomes of these delivery routes. Finally, we extend our discussion to state-of-the-art bioengineering techniques that enhance cell retention, as well as alternative delivery routes, such as intrapericardial delivery. A combination of these novel strategies and more accurate assessment methods will help to address the hurdle of low cell retention and boost the efficacy of cell transplantation to the heart.
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Affiliation(s)
- Junlang Li
- Department of Molecular Biomedical SciencesNorth Carolina State UniversityRaleighNC
- Joint Department of Biomedical EngineeringNorth Carolina State University and University of North Carolina at Chapel HillRaleighNC
| | - Shiqi Hu
- Department of Molecular Biomedical SciencesNorth Carolina State UniversityRaleighNC
- Joint Department of Biomedical EngineeringNorth Carolina State University and University of North Carolina at Chapel HillRaleighNC
| | - Dashuai Zhu
- Department of Molecular Biomedical SciencesNorth Carolina State UniversityRaleighNC
- Joint Department of Biomedical EngineeringNorth Carolina State University and University of North Carolina at Chapel HillRaleighNC
| | - Ke Huang
- Department of Molecular Biomedical SciencesNorth Carolina State UniversityRaleighNC
- Joint Department of Biomedical EngineeringNorth Carolina State University and University of North Carolina at Chapel HillRaleighNC
| | - Xuan Mei
- Department of Molecular Biomedical SciencesNorth Carolina State UniversityRaleighNC
- Joint Department of Biomedical EngineeringNorth Carolina State University and University of North Carolina at Chapel HillRaleighNC
| | - Blanca López de Juan Abad
- Department of Molecular Biomedical SciencesNorth Carolina State UniversityRaleighNC
- Joint Department of Biomedical EngineeringNorth Carolina State University and University of North Carolina at Chapel HillRaleighNC
| | - Ke Cheng
- Department of Molecular Biomedical SciencesNorth Carolina State UniversityRaleighNC
- Joint Department of Biomedical EngineeringNorth Carolina State University and University of North Carolina at Chapel HillRaleighNC
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Characterization of encapsulated porcine cardiosphere-derived cells embedded in 3D alginate matrices. Int J Pharm 2021; 599:120454. [PMID: 33676988 DOI: 10.1016/j.ijpharm.2021.120454] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 02/23/2021] [Accepted: 03/01/2021] [Indexed: 12/22/2022]
Abstract
Myocardial infarction is caused by an interruption of coronary blood flow, leading to one of the main death causes worldwide. Current therapeutic approaches are palliative and not able to solve the loss of cardiac tissue. Cardiosphere derived cells (CDCs) reduce scarring, and increase viable myocardium, with safety and adequate biodistribution, but show a low rate engraftment and survival after implantation. In order to solve the low retention, we propose the encapsulation of CDCs within three-dimensional alginate-poly-L-lysine-alginate matrix as therapy for cardiac regeneration. In this work, we demonstrate the encapsulation of CDCs in alginate matrix, with no decrease in viability over a month, and showing the preservation of CDCs phenotype, differentiation potential, gene expression profile and growth factor release after encapsulation, moving a step forward to clinical translation of CDCs therapy in regeneration in heart failure.
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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: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 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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Jiang L, Liang J, Huang W, Wu Z, Paul C, Wang Y. Strategies and Challenges to Improve Cellular Programming-Based Approaches for Heart Regeneration Therapy. Int J Mol Sci 2020; 21:E7662. [PMID: 33081233 PMCID: PMC7589611 DOI: 10.3390/ijms21207662] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 10/13/2020] [Accepted: 10/15/2020] [Indexed: 12/29/2022] Open
Abstract
Limited adult cardiac cell proliferation after cardiovascular disease, such as heart failure, hampers regeneration, resulting in a major loss of cardiomyocytes (CMs) at the site of injury. Recent studies in cellular reprogramming approaches have provided the opportunity to improve upon previous techniques used to regenerate damaged heart. Using these approaches, new CMs can be regenerated from differentiation of iPSCs (similar to embryonic stem cells), the direct reprogramming of fibroblasts [induced cardiomyocytes (iCMs)], or induced cardiac progenitors. Although these CMs have been shown to functionally repair infarcted heart, advancements in technology are still in the early stages of development in research laboratories. In this review, reprogramming-based approaches for generating CMs are briefly introduced and reviewed, and the challenges (including low efficiency, functional maturity, and safety issues) that hinder further translation of these approaches into a clinical setting are discussed. The creative and combined optimal methods to address these challenges are also summarized, with optimism that further investigation into tissue engineering, cardiac development signaling, and epigenetic mechanisms will help to establish methods that improve cell-reprogramming approaches for heart regeneration.
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Affiliation(s)
- Lin Jiang
- Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati Medical Center, Cincinnati, OH 45267-0529, USA
| | - Jialiang Liang
- Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati Medical Center, Cincinnati, OH 45267-0529, USA
| | - Wei Huang
- Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati Medical Center, Cincinnati, OH 45267-0529, USA
| | - Zhichao Wu
- Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati Medical Center, Cincinnati, OH 45267-0529, USA
| | - Christian Paul
- Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati Medical Center, Cincinnati, OH 45267-0529, USA
| | - Yigang Wang
- Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati Medical Center, Cincinnati, OH 45267-0529, USA
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Wang Q, He X, Wang B, Pan J, Shi C, Li J, Wang L, Zhao Y, Dai J, Wang D. Injectable collagen scaffold promotes swine myocardial infarction recovery by long-term local retention of transplanted human umbilical cord mesenchymal stem cells. SCIENCE CHINA-LIFE SCIENCES 2020; 64:269-281. [PMID: 32712833 DOI: 10.1007/s11427-019-1575-x] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/23/2019] [Accepted: 10/25/2019] [Indexed: 12/12/2022]
Abstract
Stem cell therapy is an attractive approach for recovery from myocardial infarction (MI) but faces the challenges of rapid diffusion and poor survival after transplantation. Here we developed an injectable collagen scaffold to promote the long-term retention of transplanted cells in chronic MI. Forty-five minipigs underwent left anterior descending artery (LAD) ligation and were equally divided into three groups 2 months later (collagen scaffold loading with human umbilical mesenchymal stem cell (hUMSC) group, hUMSC group, and placebo group (only phosphate-buffered saline (PBS) injection)). Immunofluorescence staining indicated that the retention of transplanted cells was promoted by the collagen scaffold. Echocardiography and cardiac magnetic resonance imaging (CMR) showed much higher left ventricular ejection fraction (LVEF) and lower infarct size percentage in the collagen/hUMSC group than in the hUMSC and placebo groups at 12 months after treatment. There were also higher densities of vWf-, α-sma-, and cTnT-positive cells in the infarct border zone in the collagen/cell group, as revealed by immunohistochemical analysis, suggesting better angiogenesis and more cardiomyocyte survival after MI. Thus, the injectable collagen scaffold was safe and effective on a large animal myocardial model, which is beneficial for constructing a favorable microenvironment for applying stem cells in clinical MI.
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Affiliation(s)
- Qiang Wang
- Department of Thoracic and Cardiovascular Surgery, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, China
| | - Xiaojun He
- Department of Thoracic and Cardiovascular Surgery, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, China
| | - Bin Wang
- Center for Clinical Stem Cell Research, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, China
| | - Jun Pan
- Department of Thoracic and Cardiovascular Surgery, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, China
| | - Chunying Shi
- Department of Human Anatomy, Histology and Embryology, School of Basic Medicine, Qingdao University, Qingdao, 266021, China
| | - Jie Li
- Department of Cardiology, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, China
| | - Liudi Wang
- Center for Clinical Stem Cell Research, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, China
| | - Yannan Zhao
- Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, 100190, China.
| | - Jianwu Dai
- Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, 100190, China.
| | - Dongjin Wang
- Department of Thoracic and Cardiovascular Surgery, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, China.
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Lundberg J, Grankvist R, Holmin S. The creation of an endovascular exit through the vessel wall using a minimally invasive working channel in order to reach all human organs. J Intern Med 2019; 286:309-316. [PMID: 31108016 DOI: 10.1111/joim.12939] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Since the establishment of the Seldinger technique for secure entry to the vascular system, there has been a rapid evolution in imaging and catheters that has made the arteries and veins internal routes to any place in the body for interventions. It is curious that a general exit from the vasculature in a similar manner has not been proposed earlier. Possibly, the simplest reason is that accidental perforation of the vasculature by guide wire or catheter is a feared adverse event in endovascular intervention. Most places in the body can be reached by ultrasonography or computed tomography-guided intervention. Some organs such as the central nervous system, the heart and pancreas are harder to access and, in some organs, like the kidney, repeated percutaneous punctions to cover large areas is not suitable. We present a new general purpose micro-endovascular device creating a working channel to these 'hard to reach' organs by an inverted Seldinger technique. This review details this trans-vessel wall technique, which has been studied in pancreas for transplantation of insulin-producing cells, for injection of contrast agent to the heart and to the brain, bowels and kidney in rat, rabbit, swine and macaque monkeys with up to one year of follow-up without adverse events. Furthermore, the payloads that can be given through such a system are briefly discussed. Drugs, cells, gene vectors and other therapeutic substances may be injected directly to the tissue to increase efficacy and decrease risk of off-site adverse effects.
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Affiliation(s)
- J Lundberg
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.,Department of Neuroradiology, Karolinska University Hospital, Stockholm, Sweden
| | - R Grankvist
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.,Department of Neuroradiology, Karolinska University Hospital, Stockholm, Sweden
| | - S Holmin
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.,Department of Neuroradiology, Karolinska University Hospital, Stockholm, Sweden
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Kobayashi K, Ichihara Y, Sato N, Umeda N, Fields L, Fukumitsu M, Tago Y, Ito T, Kainuma S, Podaru M, Lewis-McDougall F, Yamahara K, Uppal R, Suzuki K. On-site fabrication of Bi-layered adhesive mesenchymal stromal cell-dressings for the treatment of heart failure. Biomaterials 2019; 209:41-53. [PMID: 31026610 PMCID: PMC6527869 DOI: 10.1016/j.biomaterials.2019.04.014] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2019] [Revised: 04/09/2019] [Accepted: 04/09/2019] [Indexed: 12/12/2022]
Abstract
Mesenchymal stromal/stem cell (MSC)-based therapy is a promising approach for the treatment of heart failure. However, current MSC-delivery methods result in poor donor cell engraftment, limiting the therapeutic efficacy. To address this issue, we introduce here a novel technique, epicardial placement of bi-layered, adhesive dressings incorporating MSCs (MSC-dressing), which can be easily fabricated from a fibrin sealant film and MSC suspension at the site of treatment. The inner layer of the MSC dressing, an MSC-fibrin complex, promptly and firmly adheres to the heart surface without sutures or extra glues. We revealed that fibrin improves the potential of integrated MSCs through amplifying their tissue-repair abilities and activating the Akt/PI3K self-protection pathway. Outer collagen-sheets protect the MSC-fibrin complex from abrasion by surrounding tissues and also facilitates easy handling. As such, the MSC-dressing technique not only improves initial retention and subsequent maintenance of donor MSCs but also augment MSC's reparative functions. As a result, this technique results in enhanced cardiac function recovery with improved myocardial tissue repair in a rat ischemic cardiomyopathy model, compared to the current method. Dose-dependent therapeutic effects by this therapy is also exhibited. This user-friendly, highly-effective bioengineering technique will contribute to future success of MSC-based therapy.
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Affiliation(s)
- Kazuya Kobayashi
- William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, United Kingdom
| | - Yuki Ichihara
- William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, United Kingdom
| | - Nobuhiko Sato
- William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, United Kingdom; Kaneka Corporation, Osaka, Japan
| | | | - Laura Fields
- William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, United Kingdom
| | - Masafumi Fukumitsu
- William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, United Kingdom
| | | | - Tomoya Ito
- William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, United Kingdom
| | - Satoshi Kainuma
- William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, United Kingdom
| | - Mihai Podaru
- William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, United Kingdom
| | - Fiona Lewis-McDougall
- William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, United Kingdom
| | - Kenichi Yamahara
- Transfusion Medicine and Cellular Therapy, Hyogo College of Medicine, Japan
| | - Rakesh Uppal
- William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, United Kingdom
| | - Ken Suzuki
- William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, United Kingdom.
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Kobayashi K, Suzuki K. Mesenchymal Stem/Stromal Cell-Based Therapy for Heart Failure ― What Is the Best Source? ―. Circ J 2018; 82:2222-2232. [DOI: 10.1253/circj.cj-18-0786] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Affiliation(s)
- Kazuya Kobayashi
- William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London
| | - Ken Suzuki
- William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London
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Kobayashi K, Ichihara Y, Tano N, Fields L, Murugesu N, Ito T, Ikebe C, Lewis F, Yashiro K, Shintani Y, Uppal R, Suzuki K. Fibrin Glue-aided, Instant Epicardial Placement Enhances the Efficacy of Mesenchymal Stromal Cell-Based Therapy for Heart Failure. Sci Rep 2018; 8:9448. [PMID: 29930312 PMCID: PMC6013428 DOI: 10.1038/s41598-018-27881-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2018] [Accepted: 06/11/2018] [Indexed: 02/07/2023] Open
Abstract
Transplantation of mesenchymal stromal cells (MSCs) is a promising new therapy for heart failure. However, the current cell delivery routes result in poor donor cell engraftment. We therefore explored the role of fibrin glue (FG)-aided, instant epicardial placement to enhance the efficacy of MSC-based therapy in a rat ischemic cardiomyopathy model. We identified a feasible and reproducible method to instantly produce a FG-MSC complex directly on the heart surface. This complex exhibited prompt, firm adhesion to the heart, markedly improving initial retention of donor MSCs compared to intramyocardial injection. In addition, maintenance of retained MSCs was enhanced using this method, together contributing the increased donor cell presence. Such increased donor cell quantity using the FG-aided technique led to further improved cardiac function in association with augmented histological myocardial repair, which correlated with upregulation of tissue repair-related genes. We identified that the epicardial layer was eliminated shortly after FG-aided epicardial placement of MSCs, facilitating permeation of the donor MSC's secretome into the myocardium enabling myocardial repair. These data indicate that FG-aided, on-site, instant epicardial placement enhances MSC engraftment, promoting the efficacy of MSC-based therapy for heart failure. Further development of this accessible, advanced MSC-therapy is justified.
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Affiliation(s)
- Kazuya Kobayashi
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Yuki Ichihara
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Nobuko Tano
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Laura Fields
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Nilaani Murugesu
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Tomoya Ito
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Chiho Ikebe
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Fiona Lewis
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Kenta Yashiro
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Yasunori Shintani
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Rakesh Uppal
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Ken Suzuki
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
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Ichihara Y, Kaneko M, Yamahara K, Koulouroudias M, Sato N, Uppal R, Yamazaki K, Saito S, Suzuki K. Self-assembling peptide hydrogel enables instant epicardial coating of the heart with mesenchymal stromal cells for the treatment of heart failure. Biomaterials 2018; 154:12-23. [PMID: 29117575 PMCID: PMC5768325 DOI: 10.1016/j.biomaterials.2017.10.050] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2017] [Revised: 09/19/2017] [Accepted: 10/30/2017] [Indexed: 12/11/2022]
Abstract
Transplantation of mesenchymal stromal cells (MSCs) is an emerging therapy for the treatment of heart failure. However, the delivery method of MSC is currently suboptimal. The use of self-assembling peptide hydrogels, including PuraMatrix® (PM; 3-D Matrix, Ltd), has been reported for clinical hemostasis and in research models. This study demonstrates the feasibility and efficacy of an advanced approach for MSC-therapy, that is coating of the epicardium with the instantly-produced PM hydrogel incorporating MSCs (epicardial PM-MSC therapy). We optimized the conditions/procedure to produce "instant" 2PM-MSC complexes. After spreading on the epicardium by easy pipetting, the PM-MSC complex promptly and stably adhere to the beating heart. Of note, this treatment achieved more extensive improvement of cardiac function, with greater initial retention and survival of donor MSCs, compared to intramyocardial MSC injection in rat heart failure models. This enhanced efficacy was underpinned by amplified myocardial upregulation of a group of tissue repair-related genes, which led to enhanced repair of the damaged myocardium, i.e. augmented microvascular formation and reduced interstitial fibrosis. These data suggest a potential for epicardial PM-MSC therapy to be a widely-adopted treatment of heart failure. This approach may also be useful for treating diseases in other organs than the heart.
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Affiliation(s)
- Yuki Ichihara
- William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom; Cardiovascular Surgery, Tokyo Women's Medical University, Japan
| | - Masahiro Kaneko
- William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom
| | - Kenichi Yamahara
- Transfusion Medicine and Cellular Therapy, Hyogo College of Medicine, Japan
| | - Marinos Koulouroudias
- William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom
| | - Nobuhiko Sato
- William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom; Kaneka Corporation, Osaka, Japan
| | - Rakesh Uppal
- William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom
| | - Kenji Yamazaki
- Cardiovascular Surgery, Tokyo Women's Medical University, Japan
| | - Satoshi Saito
- Cardiovascular Surgery, Tokyo Women's Medical University, Japan
| | - Ken Suzuki
- William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom.
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Abstract
INTRODUCTION In specific forms of congenital heart defects and pulmonary hypertension, the right ventricle (RV) is exposed to systemic levels of pressure overload. The RV is prone to failure in these patients because of its vulnerability to chronic pressure overload. As patients with a systemic RV reach adulthood, an emerging epidemic of RV failure has become evident. Medical therapies proven for LV failure are ineffective in treating RV failure. Areas covered: In this review, the pathophysiology of the failing RV under pressure overload is discussed, with specific emphasis on the pivotal roles of angiogenesis and oxidative stress. Studies investigating the ability of stem cell therapy to improve angiogenesis and mitigate oxidative stress in the setting of pressure overload are then reviewed. Finally, clinical trials utilizing stem cell therapy to prevent RV failure under pressure overload in congenital heart disease will be discussed. Expert commentary: Although considerable hurdles remain before their mainstream clinical implementation, stem cell therapy possesses revolutionary potential in the treatment of patients with failing systemic RVs who currently have very limited long-term treatment options. Rigorous clinical trials of stem cell therapy for RV failure that target well-defined mechanisms will ensure success adoption of this therapeutic strategy.
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Affiliation(s)
- Ming-Sing Si
- a Department of Cardiac Surgery, Section of Pediatric Cardiovascular Surgery , University of Michigan Medical School , Ann Arbor , MI , USA
| | - Richard G Ohye
- a Department of Cardiac Surgery, Section of Pediatric Cardiovascular Surgery , University of Michigan Medical School , Ann Arbor , MI , USA
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18
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Miyagawa S, Fukushima S, Imanishi Y, Kawamura T, Mochizuki-Oda N, Masuda S, Sawa Y. Building A New Treatment For Heart Failure-Transplantation of Induced Pluripotent Stem Cell-derived Cells into the Heart. Curr Gene Ther 2016; 16:5-13. [PMID: 26785736 PMCID: PMC4997929 DOI: 10.2174/1566523216666160119094143] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2015] [Revised: 01/07/2016] [Accepted: 01/08/2016] [Indexed: 02/08/2023]
Abstract
Advanced cardiac failure is a progressive intractable disease and is the main cause of mortality and morbidity worldwide. Since this pathology is represented by a definite decrease in cardiomyocyte number, supplementation of functional cardiomyocytes into the heart would hypothetically be an ideal therapeutic option. Recently, unlimited in vitro production of human functional cardiomyocytes was established by using induced pluripotent stem cell (iPSC) technology, which avoids the use of human embryos. A number of basic studies including ours have shown that transplantation of iPSC-derived cardiomyocytes (iPSC-CMs) into the damaged heart leads to recovery of cardiac function, thereby establishing “proof-of-concept” of this iPSC-transplantation therapy. However, considering clinical application of this therapy, its feasibility, safety, and therapeutic efficacy need to be further investigated in the pre-clinical stage. This review summarizes up-to-date important topics related to safety and efficacy of iPSC-CMs transplantation therapy for cardiac disease and discusses the prospects for this treatment in clinical studies.
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Affiliation(s)
| | | | | | | | | | | | - Yoshiki Sawa
- Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
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Fukushima S, Miyagawa S, Sakai Y, Sawa Y. A sustained-release drug-delivery system of synthetic prostacyclin agonist, ONO-1301SR: a new reagent to enhance cardiac tissue salvage and/or regeneration in the damaged heart. Heart Fail Rev 2016; 20:401-13. [PMID: 25708182 PMCID: PMC4464640 DOI: 10.1007/s10741-015-9477-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Cardiac failure is a major cause of mortality and morbidity worldwide, since the standard treatment for cardiac failure in the clinical practice is chiefly to focus on removal of insults against the heart or minimisation of additional factors to exacerbate cardiac failure, but not on regeneration of the damaged cardiac tissue. A synthetic prostacyclin agonist, ONO-1301, has been developed as a long-acting drug for acute and chronic pathologies related to regional ischaemia, inflammation and/or interstitial fibrosis by pre-clinical studies. In addition, poly-lactic co-glycolic acid-polymerised form of ONO-1301, ONO-1301SR, was generated to achieve a further sustained release of this drug into the targeted region. This unique reagent has been shown to act on fibroblasts, vascular smooth muscle cells and endothelial cells in the tissue via the prostaglandin IP receptor to exert paracrinal release of multiple protective factors, such as hepatocyte growth factor, vascular endothelial growth factor or stromal cell-derived factor-1, into the adjacent damaged tissue, which is salvaged and/or regenerated as a result. Our laboratory developed a new surgical approach to treat acute and chronic cardiac failure using a variety of animal models, in which ONO-1301SR is directly placed over the cardiac surface to maximise the therapeutic effects and minimise the systemic complications. This review summarises basic and pre-clinical information of ONO-1301 and ONO-1301SR as a new reagent to enhance tissue salvage and/or regeneration, with a particular focus on the therapeutic effects on acute and chronic cardiac failure and underlying mechanisms, to explore a potential in launching the clinical study.
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Affiliation(s)
- Satsuki Fukushima
- Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan,
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20
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Abdelwahid E, Kalvelyte A, Stulpinas A, de Carvalho KAT, Guarita-Souza LC, Foldes G. Stem cell death and survival in heart regeneration and repair. Apoptosis 2016; 21:252-68. [PMID: 26687129 PMCID: PMC5200890 DOI: 10.1007/s10495-015-1203-4] [Citation(s) in RCA: 89] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Cardiovascular diseases are major causes of mortality and morbidity. Cardiomyocyte apoptosis disrupts cardiac function and leads to cardiac decompensation and terminal heart failure. Delineating the regulatory signaling pathways that orchestrate cell survival in the heart has significant therapeutic implications. Cardiac tissue has limited capacity to regenerate and repair. Stem cell therapy is a successful approach for repairing and regenerating ischemic cardiac tissue; however, transplanted cells display very high death percentage, a problem that affects success of tissue regeneration. Stem cells display multipotency or pluripotency and undergo self-renewal, however these events are negatively influenced by upregulation of cell death machinery that induces the significant decrease in survival and differentiation signals upon cardiovascular injury. While efforts to identify cell types and molecular pathways that promote cardiac tissue regeneration have been productive, studies that focus on blocking the extensive cell death after transplantation are limited. The control of cell death includes multiple networks rather than one crucial pathway, which underlies the challenge of identifying the interaction between various cellular and biochemical components. This review is aimed at exploiting the molecular mechanisms by which stem cells resist death signals to develop into mature and healthy cardiac cells. Specifically, we focus on a number of factors that control death and survival of stem cells upon transplantation and ultimately affect cardiac regeneration. We also discuss potential survival enhancing strategies and how they could be meaningful in the design of targeted therapies that improve cardiac function.
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Affiliation(s)
- Eltyeb Abdelwahid
- Feinberg School of Medicine, Feinberg Cardiovascular Research Institute, Northwestern University, 303 E. Chicago Ave., Tarry 14-725, Chicago, IL, 60611, USA.
| | - Audrone Kalvelyte
- Department of Molecular Cell Biology, Vilnius University Institute of Biochemistry, Vilnius, Lithuania
| | - Aurimas Stulpinas
- Department of Molecular Cell Biology, Vilnius University Institute of Biochemistry, Vilnius, Lithuania
| | - Katherine Athayde Teixeira de Carvalho
- Cell Therapy and Biotechnology in Regenerative Medicine Research Group, Pequeno Príncipe Faculty, Pelé Pequeno Príncipe Institute, Curitiba, Paraná, 80250-200, Brazil
| | - Luiz Cesar Guarita-Souza
- Experimental Laboratory of Institute of Biological and Health Sciences of Pontifical Catholic University of Parana, Curitiba, Paraná, 80215-901, Brazil
| | - Gabor Foldes
- National Heart and Lung Institute, Imperial College London, Imperial Centre for Experimental and Translational Medicine, Du Cane Road, London, W12 0NN, UK
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Blázquez R, Sánchez-Margallo FM, Crisóstomo V, Báez C, Maestre J, Álvarez V, Casado JG. Intrapericardial Delivery of Cardiosphere-Derived Cells: An Immunological Study in a Clinically Relevant Large Animal Model. PLoS One 2016; 11:e0149001. [PMID: 26866919 PMCID: PMC4750976 DOI: 10.1371/journal.pone.0149001] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2015] [Accepted: 01/25/2016] [Indexed: 01/22/2023] Open
Abstract
Introduction The intrapericardial delivery has been defined as an efficient method for pharmacological agent delivery. Here we hypothesize that intrapericardial administration of cardiosphere-derived cells (CDCs) may have an immunomodulatory effect providing an optimal microenvironment for promoting cardiac repair. To our knowledge, this is the first report studying the effects of CDCs for myocardial repair using the intrapericardial delivery route. Material and Methods CDCs lines were isolated, expanded and characterized by flow cytometry and PCR. Their differentiation ability was determined using specific culture media and differential staining. 300,000 CDCs/kg were injected into the pericardial space of a swine myocardial infarcted model. Magnetic resonance imaging, biochemical analysis of pericardial fluid and plasma, cytokine measurements and flow cytometry analysis were performed. Results Our results showed that, phenotype and differentiation behavior of porcine CDCs were equivalent to previously described CDCs. Moreover, the intrapericardial administration of CDCs fulfilled the safety aspects as non-adverse effects were reported. Finally, the phenotypes of resident lymphocytes and TH1 cytokines in the pericardial fluid were significantly altered after CDCs administration. Conclusions The pericardial fluid could be considered as a safe and optimal vehicle for CDCs administration. The observed changes in the studied immunological parameters could exert a modulation in the inflammatory environment of infarcted hearts, indirectly benefiting the endogenous cardiac repair.
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Affiliation(s)
- Rebeca Blázquez
- Stem Cell Therapy Unit, 'Jesús Usón' Minimally Invasive Surgery Centre, Cáceres, Spain
| | | | - Verónica Crisóstomo
- Endoluminal Therapy and Diagnosis, 'Jesús Usón' Minimally Invasive Surgery Centre, Cáceres, Spain
| | - Claudia Báez
- Endoluminal Therapy and Diagnosis, 'Jesús Usón' Minimally Invasive Surgery Centre, Cáceres, Spain
| | - Juan Maestre
- Endoluminal Therapy and Diagnosis, 'Jesús Usón' Minimally Invasive Surgery Centre, Cáceres, Spain
| | - Verónica Álvarez
- Stem Cell Therapy Unit, 'Jesús Usón' Minimally Invasive Surgery Centre, Cáceres, Spain
| | - Javier G Casado
- Stem Cell Therapy Unit, 'Jesús Usón' Minimally Invasive Surgery Centre, Cáceres, Spain
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Blázquez R, Sánchez-Margallo FM, Crisóstomo V, Báez C, Maestre J, García-Lindo M, Usón A, Álvarez V, Casado JG. Intrapericardial administration of mesenchymal stem cells in a large animal model: a bio-distribution analysis. PLoS One 2015; 10:e0122377. [PMID: 25816232 PMCID: PMC4376786 DOI: 10.1371/journal.pone.0122377] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2014] [Accepted: 02/15/2015] [Indexed: 12/18/2022] Open
Abstract
The appropriate administration route for cardiovascular cell therapy is essential to ensure the viability, proliferative potential, homing capacity and implantation of transferred cells. At the present, the intrapericardial administration of pharmacological agents is considered an efficient method for the treatment of cardiovascular diseases. However, only a few reports have addressed the question whether the intrapericardial delivery of Mesenchymal Stem Cells (MSCs) could be an optimal administration route. This work firstly aimed to analyze the pericardial fluid as a cell-delivery vehicle. Moreover, the in vivo biodistribution pattern of intrapericardially administered MSCs was evaluated in a clinically relevant large animal model. Our in vitro results firstly showed that, MSCs viability, proliferative behavior and phenotypic profile were unaffected by exposure to pericardial fluid. Secondly, in vivo cell tracking by magnetic resonance imaging, histological examination and Y-chromosome amplification clearly demonstrated the presence of MSCs in pericardium, ventricles (left and right) and atrium (left and right) when MSCs were administered into the pericardial space. In conclusion, here we demonstrate that pericardial fluid is a suitable vehicle for MSCs and intrapericardial route provides an optimal retention and implantation of MSCs.
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Affiliation(s)
- Rebeca Blázquez
- Stem Cell Therapy Unit, Minimally Invasive Surgery Centre, Caceres, Spain
| | | | - Verónica Crisóstomo
- Endoluminal Therapy and Diagnosis, Minimally Invasive Surgery Centre, Caceres, Spain
| | - Claudia Báez
- Endoluminal Therapy and Diagnosis, Minimally Invasive Surgery Centre, Caceres, Spain
| | - Juan Maestre
- Endoluminal Therapy and Diagnosis, Minimally Invasive Surgery Centre, Caceres, Spain
| | | | - Alejandra Usón
- Stem Cell Therapy Unit, Minimally Invasive Surgery Centre, Caceres, Spain
| | - Verónica Álvarez
- Stem Cell Therapy Unit, Minimally Invasive Surgery Centre, Caceres, Spain
| | - Javier G. Casado
- Stem Cell Therapy Unit, Minimally Invasive Surgery Centre, Caceres, Spain
- * E-mail:
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Higuchi T, Miyagawa S, Pearson JT, Fukushima S, Saito A, Tsuchimochi H, Sonobe T, Fujii Y, Yagi N, Astolfo A, Shirai M, Sawa Y. Functional and Electrical Integration of Induced Pluripotent Stem Cell-Derived Cardiomyocytes in a Myocardial Infarction Rat Heart. Cell Transplant 2015; 24:2479-89. [PMID: 25606821 DOI: 10.3727/096368914x685799] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
In vitro expanded beating cardiac myocytes derived from induced pluripotent stem cells (iPSC-CMs) are a promising source of therapy for cardiac regeneration. Meanwhile, the cell sheet method has been shown to potentially maximize survival, functionality, and integration of the transplanted cells into the heart. It is thus hypothesized that transplanted iPSC-CMs in a cell sheet manner may contribute to functional recovery via direct mechanical effects on the myocardial infarction (MI) heart. F344/NJcl-rnu/rnu rats were left coronary artery ligated (n = 30), followed by transplantation of Dsred-labeled iPSC-CM cell sheets of murine origin over the infarct heart surface. Effects of the treatment were assessed, including in vivo molecular/cellular evaluations using a synchrotron radiation scattering technique. Ejection fraction and activation recovery interval were significantly greater from day 3 onward after iPSC-CM transplantation compared to those after sham operation. A number of transplanted iPSC-CMs were present on the heart surface expressing cardiac myosin or connexin 43 over 2 weeks, assessed by immunoconfocal microscopy, while mitochondria in the transplanted iPSC-CMs gradually showed mature structure as assessed by electron microscopy. Of note, X-ray diffraction identified 1,0 and 1,1 equatorial reflections attributable to myosin and actin-myosin lattice planes typical of organized cardiac muscle fibers within the transplanted cell sheets at 4 weeks, suggesting cyclic systolic myosin mass transfer to actin filaments in the transplanted iPSC-CMs. Transplantation of iPSC-CM cell sheets into the heart yielded functional and electrical recovery with cyclic contraction of transplanted cells in the rat MI heart, indicating that this strategy may be a promising cardiac muscle replacement therapy.
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Affiliation(s)
- Takahiro Higuchi
- Department of Cardiac Surgery, Osaka University Graduate School of Medicine, Osaka, Japan
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24
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Epicardial placement of mesenchymal stromal cell-sheets for the treatment of ischemic cardiomyopathy; in vivo proof-of-concept study. Mol Ther 2014; 22:1864-71. [PMID: 24930600 DOI: 10.1038/mt.2014.110] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2014] [Accepted: 06/06/2014] [Indexed: 12/13/2022] Open
Abstract
Transplantation of bone marrow mesenchymal stromal cells (MSCs) is an emerging treatment for heart failure. We have reported that epicardial placement of MSC-sheets generated using temperature-responsive dishes markedly increases donor MSC survival and augments therapeutic effects in an acute myocardial infarction (MI) model, compared to intramyocardial (IM) injection. This study aims to expand this knowledge for the treatment of ischemic cardiomyopathy, which is likely to be more difficult to treat due to mature fibrosis and chronically stressed myocardium. Four weeks after MI, rats underwent either epicardial MSC-sheet placement, IM MSC injection, or sham treatment. At day 28 after treatment, the cell-sheet group showed augmented cardiac function improvement, which was associated with over 11-fold increased donor cell survival at both days 3 and 28 compared to IM injection. Moreover, the cell-sheet group showed improved myocardial repair, in conjunction with amplified upregulation of a group of reparative factors. Furthermore, by comparing with our own previous data, this study highlighted similar dynamics and behavior of epicardially placed MSCs in acute and chronic stages after MI, while the acute-phase myocardium may be more responsive to the stimuli from donor MSCs. These proof-of-concept data encourage further development of the MSC-sheet therapy for ischemic cardiomyopathy toward clinical application.
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Liang CJ, Shen WC, Chang FB, Wu VC, Wang SH, Young GH, Tsai JS, Tseng YC, Peng YS, Chen YL. Endothelial Progenitor Cells Derived From Wharton's Jelly of Human Umbilical Cord Attenuate Ischemic Acute Kidney Injury by Increasing Vascularization and Decreasing Apoptosis, Inflammation, and Fibrosis. Cell Transplant 2014; 24:1363-77. [PMID: 24819279 DOI: 10.3727/096368914x681720] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Ischemia-reperfusion (I/R) injury to the kidney, a major cause of acute renal failure in humans, is associated with a high mortality, and the development of a new therapeutic strategy is therefore highly desirable. In this study, we examined the therapeutic potential of implantation of endothelial progenitor cells (EPCs) isolated from Wharton's jelly of human umbilical cords in the treatment of renal I/R injury in mice. To visualize the localization of the transplanted EPCs, the cells were labeled with Q-tracker before injection into the renal capsule. Mice with renal I/R injury showed a significant increase in blood urea nitrogen and creatinine levels, and these effects were decreased by EPC transplantation. The kidney injury score in the mice with I/R injury was also significantly decreased by EPC transplantation. EPC transplantation increased the microvascular density, and some of the EPCs surrounded and were incorporated into microvessels. In addition, EPC transplantation inhibited the I/R-induced cell apoptosis of endothelial, glomerular, and renal tubular cells, as demonstrated by TUNEL staining, and significantly reduced reactive oxygen species production and the expression of the inflammatory chemokines macrophage inflammatory protein-2 and keratinocyte-derived cytokine, as shown by immunostaining and ELISA. Moreover, EPC transplantation reduced I/R-induced fibrosis, as demonstrated by immunostaining for S100A4, a fibroblast marker, and by Jones silver staining. To our knowledge, this is the first report that transplantation of EPCs from Wharton's jelly of human umbilical cords might provide a novel therapy for ischemic acute kidney injury by promoting angiogenesis and inhibiting apoptosis, inflammation, and fibrosis.
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Affiliation(s)
- Chan-Jung Liang
- Institute of Anatomy and Cell Biology, College of Medicine, National Taiwan University, Taipei, Taiwan
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26
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Georgiadis V, Knight RA, Jayasinghe SN, Stephanou A. Cardiac tissue engineering: renewing the arsenal for the battle against heart disease. Integr Biol (Camb) 2014; 6:111-26. [DOI: 10.1039/c3ib40097b] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
The development of therapies that lead to the regeneration or functional repair of compromised cardiac tissue is the most important challenge facing translational cardiovascular research today.
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Affiliation(s)
| | - Richard A. Knight
- Medical Molecular Biology Unit
- University College London
- London WC1E 6JF, UK
| | - Suwan N. Jayasinghe
- BioPhysics Group
- UCL Institute of Biomedical Engineering
- UCL Centre for Stem Cells and Regenerative Medicine and Department of Mechanical Engineering
- University College London
- London WC1E 7JE, UK
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