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1
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Sarathkumar E, Victor M, Menon JA, Jibin K, Padmini S, Jayasree RS. Nanotechnology in cardiac stem cell therapy: cell modulation, imaging and gene delivery. RSC Adv 2021; 11:34572-34588. [PMID: 35494731 PMCID: PMC9043027 DOI: 10.1039/d1ra06404e] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Accepted: 10/04/2021] [Indexed: 12/11/2022] Open
Abstract
The wide arena of applications opened by nanotechnology is multidimensional. It is already been proven that its prominence can continuously influence human life. The role of stem cells in curing degenerative diseases is another major area of research. Cardiovascular diseases are one of the major causes of death globally. Nanotechnology-assisted stem cell therapy could be used to tackle the challenges faced in the management of cardiovascular diseases. In spite of the positive indications and proven potential of stem cells to differentiate into cardiomyocytes for cardiac repair and regeneration during myocardial infarction, this therapeutic approach still remains in its infancy due to several factors such as non-specificity of injected cells, insignificant survival rate, and low cell retention. Attempts to improve stem cell therapy using nanoparticles have shown some interest among researchers. This review focuses on the major hurdles associated with cardiac stem cell therapy and the role of nanoparticles to overcome the major challenges in this field, including cell modulation, imaging, tracking and gene delivery. This review summarizes the potential challenges present in cardiac stem cell therapy and the major role of nanotechnology to overcome these challenges including cell modulation, tracking and imaging of stem cells.![]()
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Affiliation(s)
- Elangovan Sarathkumar
- Division of Biophotonics and Imaging, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Biomedical Technology Wing Trivandrum India
| | - Marina Victor
- Division of Biophotonics and Imaging, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Biomedical Technology Wing Trivandrum India
| | | | - Kunnumpurathu Jibin
- Division of Biophotonics and Imaging, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Biomedical Technology Wing Trivandrum India
| | - Suresh Padmini
- Sree Narayana Institute of Medical Sciences Kochi Kerala India
| | - Ramapurath S Jayasree
- Division of Biophotonics and Imaging, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Biomedical Technology Wing Trivandrum India
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2
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Roushandeh AM, Tomita K, Kuwahara Y, Jahanian-Najafabadi A, Igarashi K, Roudkenar MH, Sato T. Transfer of healthy fibroblast-derived mitochondria to HeLa ρ 0 and SAS ρ 0 cells recovers the proliferation capabilities of these cancer cells under conventional culture medium, but increase their sensitivity to cisplatin-induced apoptotic death. Mol Biol Rep 2020; 47:4401-4411. [PMID: 32394308 DOI: 10.1007/s11033-020-05493-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Accepted: 04/30/2020] [Indexed: 01/02/2023]
Abstract
Mitochondrial dysfunction is known to contribute to cancer initiation, progression, and chemo-and radio-resistance. However, the precise role of mitochondria in cancer is controversial. Hence, here we tried to further clarify the role of mitochondria in cancer by transferring healthy mitochondria to cancer cells, and also to cells with depleted mitochondrial DNA (ρ0). Healthy mitochondria were isolated from WI-38 cells and were transferred to HeLa, SAS, HeLa ρ0, and SAS ρ0 cells. Then, cell proliferation was verified. In addition, the cells were treated by different concentrations of cisplatin and assessed for apoptosis induction and quantifying the mRNA expression of apoptosis-related genes. Results revealed that incubation of the HeLa, SAS and HeLa ρ0 cells with 5 µg/ml of the isolated mitochondria for 24 h significantly (p < 0.001) increased cell proliferation compared to non-treated controls. Interestingly, the mitochondria transfer rescued the ρ0 cells and made them capable of growing under conventional culture medium. However, the number of apoptotic cells was significantly higher in the HeLa ρ0 cells that received the mitochondria (HeLa-Fibro-Mit) compared to the HeLa ρ0. Furthermore, the expression level of BCL-2 anti-apoptotic gene was down-regulated in both HeLa-Fibro-Mit and SAS-Fibro-Mit cell lines while the expression levels of the BAX, caspase8, caspase9, and AIF pro-apoptotic genes were upregulated. Our findings indicated that although the response of cancer cells to the mitochondria transfer is cancer-type dependent, but the introduction of normal exogenous mitochondria to some cancer cells might be considered as a potential novel therapeutic strategy.
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Affiliation(s)
- Amaneh Mohammadi Roushandeh
- Medical Biotechnology Department, Paramedicine faculty, Guilan University of Medical Sciences, Rasht, Iran.,Department of Applied Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Kazuo Tomita
- Department of Applied Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Yoshikazu Kuwahara
- Division of Radiation Biology and Medicine, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, Sendai, Japan
| | - Ali Jahanian-Najafabadi
- Department of Pharmaceutical Biotechnology, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Kento Igarashi
- Department of Applied Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Mehryar Habibi Roudkenar
- Medical Biotechnology Department, Paramedicine faculty, Guilan University of Medical Sciences, Rasht, Iran. .,Department of Applied Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan. .,Cardiovascular Diseases Research Center, Department of Cardiology, Heshmat Hospital, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran.
| | - Tomoaki Sato
- Department of Applied Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
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Seetharaman R, Mahmood A, Kshatriya P, Patel D, Srivastava A. An Overview on Stem Cells in Tissue Regeneration. Curr Pharm Des 2020; 25:2086-2098. [PMID: 31298159 DOI: 10.2174/1381612825666190705211705] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Accepted: 06/19/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND Deteriorations in tissues and decline in organ functions, due to chronic diseases or with advancing age or sometimes due to infections or injuries, can severely compromise the quality of life of an individual. Regenerative medicine, a field of medical research focuses on replacing non-functional or dead cells or repairing or regenerating tissues and organs to restore normal functions of an impaired organ. Approaches used in regenerative therapy for achieving the objective employ a number of means which include soluble biomolecules, stem cell transplants, tissue engineering, gene therapy and reprogramming of cells according to target tissue types. Stem cells transplant and tissue regeneration methods for treating various diseases have rapidly grown in usage over the past decades or so. There are different types of stem cells such as mesenchymal, hematopoietic, embryonic, mammary, intestinal, endothelial, neural, olfactory, neural crest, testicular and induced pluripotent stem cells. METHODS This review covers the recent advances in tissue regeneration and highlights the application of stem cell transplants in treating many life-threatening diseases or in improving quality of life. RESULTS Remarkable progress in stem cell research has established that the cell-based therapy could be an option for treating diseases which could not be cured by conventional medical means till recent. Stem cells play major roles in regenerative medicine with its exceptional characteristics of self-renewal capacity and potential to differentiate into almost all types of cells of a body. CONCLUSION Vast number of reports on preclinical and clinical application of stem cells revealed its vital role in disease management and many pharmacological industries around the globe working to achieve effective stem cell based products.
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Affiliation(s)
| | | | | | | | - Anand Srivastava
- Global Institute of Stem Cell Therapy and Research, 4660 La Jolla Village Drive, San Diego, CA 92122, United States
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4
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Gollmann-Tepeköylü C, Lobenwein D, Theurl M, Primessnig U, Lener D, Kirchmair E, Mathes W, Graber M, Pölzl L, An A, Koziel K, Pechriggl E, Voelkl J, Paulus P, Schaden W, Grimm M, Kirchmair R, Holfeld J. Shock Wave Therapy Improves Cardiac Function in a Model of Chronic Ischemic Heart Failure: Evidence for a Mechanism Involving VEGF Signaling and the Extracellular Matrix. J Am Heart Assoc 2019; 7:e010025. [PMID: 30371289 PMCID: PMC6474945 DOI: 10.1161/jaha.118.010025] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Background Mechanical stimulation of acute ischemic myocardium by shock wave therapy (SWT) is known to improve cardiac function by induction of angiogenesis. However, SWT in chronic heart failure is poorly understood. We aimed to study whether mechanical stimulation upon SWT improves heart function in chronic ischemic heart failure by induction of angiogenesis and postnatal vasculogenesis and to dissect underlying mechanisms. Methods and Results SWT was applied in a mouse model of chronic myocardial ischemia. To study effects of SWT on postnatal vasculogenesis, wild‐type mice received bone marrow transplantation from green fluorescence protein donor mice. Underlying mechanisms were elucidated in vitro in endothelial cells and murine aortic rings. Echocardiography and pressure/volume measurements revealed improved left ventricular ejection fraction, myocardial contractility, and diastolic function and decreased myocardial fibrosis after treatment. Concomitantly, numbers of capillaries and arterioles were increased. SWT resulted in enhanced expression of the chemoattractant stromal cell–derived factor 1 in ischemic myocardium and serum. Treatment induced recruitment of bone marrow–derived endothelial cells to the site of injury. In vitro, SWT resulted in endothelial cell proliferation, enhanced survival, and capillary sprouting. The effects were vascular endothelial growth factor receptor 2 and heparan sulfate proteoglycan dependent. Conclusions SWT positively affects heart function in chronic ischemic heart failure by induction of angiogenesis and postnatal vasculogenesis. SWT upregulated pivotal angiogenic and vasculogenic factors in the myocardium in vivo and induced proliferative and anti‐apoptotic effects on endothelial cells in vitro. Mechanistically, these effects depend on vascular endothelial growth factor signaling and heparan sulfate proteoglycans. SWT is a promising treatment option for regeneration of ischemic myocardium.
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Affiliation(s)
| | | | - Markus Theurl
- 3 Internal Medicine III Medical University of Innsbruck Austria
| | - Uwe Primessnig
- 4 Department of Internal Medicine and Cardiology Charité - Universitätsmedizin Berlin Germany
| | - Daniela Lener
- 2 Cardiac Surgery Medical University of Innsbruck Austria
| | - Elke Kirchmair
- 2 Cardiac Surgery Medical University of Innsbruck Austria
| | | | - Michael Graber
- 2 Cardiac Surgery Medical University of Innsbruck Austria
| | - Leo Pölzl
- 2 Cardiac Surgery Medical University of Innsbruck Austria
| | - Angela An
- 2 Cardiac Surgery Medical University of Innsbruck Austria
| | | | - Elisabeth Pechriggl
- 1 Division of Clinical and Functional Anatomy Department of Anatomy, Histology and Embryology Medical University of Innsbruck Austria
| | - Jakob Voelkl
- 4 Department of Internal Medicine and Cardiology Charité - Universitätsmedizin Berlin Germany
| | - Patrick Paulus
- 5 Department of Anaesthesiology and Operative Intensive Care Medicine Kepler University Hospital Linz Austria
| | - Wolfgang Schaden
- 6 Ludwig Boltzmann Institute for Experimental and Clinical Traumatology AUVA Research Centre Vienna Austria.,7 Austrian Cluster for Tissue Regeneration Vienna Austria
| | - Michael Grimm
- 2 Cardiac Surgery Medical University of Innsbruck Austria
| | | | - Johannes Holfeld
- 2 Cardiac Surgery Medical University of Innsbruck Austria.,7 Austrian Cluster for Tissue Regeneration Vienna Austria
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Wong TW, Kan CD, Chiu WT, Fok KL, Ruan YC, Jiang X, Chen J, Kao CC, Chen IY, Lin HC, Chou CH, Lin CW, Yu CK, Tsao S, Lee YP, Chan HC, Wang JN. Progenitor Cells Derived from Drain Waste Product of Open-Heart Surgery in Children. J Clin Med 2019; 8:jcm8071028. [PMID: 31336927 PMCID: PMC6678880 DOI: 10.3390/jcm8071028] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2019] [Revised: 06/25/2019] [Accepted: 07/10/2019] [Indexed: 11/23/2022] Open
Abstract
Human cardiac progenitor cells isolated from the same host may have advantages over other sources of stem cells. The aim of this study is to establish a new source of human progenitor cells collected from a waste product, pericardiac effusion fluid, after open-heart surgery in children with congenital heart diseases. The fluid was collected every 24 h for 2 days after surgery in 37 children. Mononuclear cells were isolated and expanded in vitro. These pericardial effusion-derived progenitor cells (PEPCs) exhibiting cardiogenic lineage markers, were highly proliferative and enhanced angiogenesis in vitro. Three weeks after stem cell transplantation into the ischemic heart in mice, cardiac ejection fraction was improved significantly without detectable progenitor cells. Gene expression profiles of the repaired hearts revealed activation of several known repair mechanisms including paracrine effects, cell migration, and angiogenesis. These progenitor cells may have the potential for heart regeneration.
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Affiliation(s)
- Tak-Wah Wong
- Department of Dermatology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan
- Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan
- Center of Applied Nanomedicine, National Cheng Kung University, Tainan 701, Taiwan
| | - Chung-Dann Kan
- Department of Surgery, Institute of Cardiovascular Research Center, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan
| | - Wen-Tai Chiu
- Department of Biomedical Engineering, National Cheng Kung University, Tainan 701, Taiwan
| | - Kin Lam Fok
- Epithelial Cell Biology Research Center, School of Biomedical Sciences, Faculty of Medicine, the Chinese University of Hong Kong, Shatin, Hong Kong
| | - Ye Chun Ruan
- Epithelial Cell Biology Research Center, School of Biomedical Sciences, Faculty of Medicine, the Chinese University of Hong Kong, Shatin, Hong Kong
| | - Xiaohua Jiang
- Epithelial Cell Biology Research Center, School of Biomedical Sciences, Faculty of Medicine, the Chinese University of Hong Kong, Shatin, Hong Kong
- Key Laboratory for Regenerative Medicine, Ministry of Education of the People's Republic of China, Shatin, HongKong
| | - Junjiang Chen
- Epithelial Cell Biology Research Center, School of Biomedical Sciences, Faculty of Medicine, the Chinese University of Hong Kong, Shatin, Hong Kong
| | - Chiu-Ching Kao
- Department of Dermatology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan
| | - I-Yu Chen
- Department of Dermatology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan
| | - Hui-Chun Lin
- Department of Dermatology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan
| | - Chia-Hsuan Chou
- Department of Dermatology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan
| | - Chou-Wen Lin
- Biomedical Technology and Device Research Laboratories, Industrial Technology Research Institute, Liuo-Jia, Tainan 734, Taiwan
| | - Chun-Keung Yu
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan
- Department of Microbiology and Immunology, Center of Infectious Disease and Signaling Research, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan
- National Laboratory Animal Center, National Applied Research Laboratories, Taipei 11529, Taiwan
| | - Stephanie Tsao
- Department of Dermatology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan
| | - Yi-Ping Lee
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan
| | - Hsiao Chang Chan
- Epithelial Cell Biology Research Center, School of Biomedical Sciences, Faculty of Medicine, the Chinese University of Hong Kong, Shatin, Hong Kong
- Key Laboratory for Regenerative Medicine, Ministry of Education of the People's Republic of China, Shatin, HongKong
| | - Jieh-Neng Wang
- Department of Pediatrics, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan.
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6
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Wang BH, Liew D, Huang KW, Huang L, Tang W, Kelly DJ, Reid C, Liu Z. The Challenges of Stem Cell Therapy in Myocardial Infarction and Heart Failure and the Potential Strategies to Improve the Outcomes. ACTA ACUST UNITED AC 2018. [DOI: 10.1142/s1793984418410088] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Cardiovascular disease remains the single highest global cause of death and a significant financial burden on the healthcare system. Despite the advances in medical treatments, the prevalence and mortality for heart failure remain unacceptably high. New approaches are urgently needed to reduce this burden and improve patient outcomes and quality of life. One such promising approach is stem cell therapy, including embryonic stem cells, bone marrow derived stem cells, induced pluripotent stem cells and mesenchymal stem cells. However, the cardiac microenvironment following myocardial infarction poses huge challenges with inflammation, adequate retention, engraftment and functional incorporation all crucial concerns. The lack of cardiac regeneration, cell viability and functional improvement has hindered the success of stem cell therapy in clinical settings. The use of biomaterial scaffolds in conjunction with stem cells has recently been shown to enhance the outcome of stem cell therapy for heart failure and myocardial infarction. This review outlines some of the current challenges in the treatment of heart failure and acute myocardial infarction through improving stem cell therapeutic strategies, as well as the prospect of suitable biomaterial scaffolds to enhance their efficacy and improve patient clinical outcomes.
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Affiliation(s)
- Bing Hui Wang
- Monash Centre of Cardiovascular Research and Education in Therapeutics, School of Public Health and Preventive Medicine, Monash University, Melbourne 3004, Australia
| | - Danny Liew
- Monash Centre of Cardiovascular Research and Education in Therapeutics, School of Public Health and Preventive Medicine, Monash University, Melbourne 3004, Australia
| | - Kevin W. Huang
- Monash Centre of Cardiovascular Research and Education in Therapeutics, School of Public Health and Preventive Medicine, Monash University, Melbourne 3004, Australia
| | - Li Huang
- Monash Centre of Cardiovascular Research and Education in Therapeutics, School of Public Health and Preventive Medicine, Monash University, Melbourne 3004, Australia
| | - Wenjie Tang
- Department of Cardiovascular and Thoracic Surgery, Research Center for Translational Medicine and Biomedical Multidisciplinary Innovation Research Institute, Shanghai East Hospital, Tongji University, Shanghai 200120, P. R. China
| | - Darren J. Kelly
- Department of Medicine, St Vincent’s Hospital, University of Melbourne, Fitzroy Victoria, Australia
| | - Christopher Reid
- Monash Centre of Cardiovascular Research and Education in Therapeutics, School of Public Health and Preventive Medicine, Monash University, Melbourne 3004, Australia
| | - Zhongmin Liu
- Department of Cardiovascular and Thoracic Surgery, Research Center for Translational Medicine and Biomedical Multidisciplinary Innovation Research Institute, Shanghai East Hospital, Tongji University, Shanghai 200120, P. R. China
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7
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Wang H, Kuang W. Optimization of MSC therapeutic strategies for improved GVHD treatment. INFECTION INTERNATIONAL 2017. [DOI: 10.1515/ii-2017-0151] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Abstract
Mesenchymal stem cells (MSCs) have a powerful immunosuppressive capacity, and they have been used to treat numerous immune diseases, such as refractory graft-versus-host disease. Nevertheless, there are conflicting clinical data. To our knowledge, MSCs from different donors do not share the same qualities and have different immunosuppressive capacities. Infused MSCs are cleared by the recipient’s immune cells or macrophages. Therefore, the MSC therapeutic strategy might be the most important factor that determines treatment success. Repeated infusions would lead to a relatively stable MSC concentration, which would benefit a sustained therapeutic effect. In this review, we focus on the quality of MSCs and the associated therapeutic strategy, as well as other potential variables affecting their utility as a cellular pharmaceutical.
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Bhartiya D. National multicentric M13 Stem Cell Trial reports negative outcome - Need to look at VSELs as an alternative to bone marrow MNCs for cardiac regeneration. Indian J Med Res 2016; 143:830-832. [PMID: 27748311 PMCID: PMC5094126 DOI: 10.4103/0971-5916.192080] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Affiliation(s)
- Deepa Bhartiya
- Stem Cell Biology Department, National Institute for Research in Reproductive Health (ICMR), Jehangir Merwanji Street, Parel, Mumbai 400 012, Maharashtra, India
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9
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Silva AC, Rodrigues SC, Caldeira J, Nunes AM, Sampaio-Pinto V, Resende TP, Oliveira MJ, Barbosa MA, Thorsteinsdóttir S, Nascimento DS, Pinto-do-Ó P. Three-dimensional scaffolds of fetal decellularized hearts exhibit enhanced potential to support cardiac cells in comparison to the adult. Biomaterials 2016; 104:52-64. [PMID: 27424216 DOI: 10.1016/j.biomaterials.2016.06.062] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2016] [Revised: 06/25/2016] [Accepted: 06/28/2016] [Indexed: 12/11/2022]
Abstract
A main challenge in cardiac tissue engineering is the limited data on microenvironmental cues that sustain survival, proliferation and functional proficiency of cardiac cells. The aim of our study was to evaluate the potential of fetal (E18) and adult myocardial extracellular matrix (ECM) to support cardiac cells. Acellular three-dimensional (3D) bioscaffolds were obtained by parallel decellularization of fetal- and adult-heart explants thereby ensuring reliable comparison. Acellular scaffolds retained main constituents of the cardiac ECM including distinctive biochemical and structural meshwork features of the native equivalents. In vitro, fetal and adult ECM-matrices supported 3D culture of heart-derived Sca-1(+) progenitors and of neonatal cardiomyocytes, which migrated toward the center of the scaffold and displayed elongated morphology and excellent viability. At the culture end-point, more Sca-1(+) cells and cardiomyocytes were found adhered and inside fetal bioscaffolds, compared to the adult. Higher repopulation yields of Sca-1(+) cells on fetal ECM relied on β1-integrin independent mitogenic signals. Sca-1(+) cells on fetal bioscaffolds showed a gene expression profile that anticipates the synthesis of a permissive microenvironment for cardiomyogenesis. Our findings demonstrate the superior potential of the 3D fetal microenvironment to support and instruct cardiac cells. This knowledge should be integrated in the design of next-generation biomimetic materials for heart repair.
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Affiliation(s)
- A C Silva
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto 4200-135, Portugal; INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Porto 4200-135, Portugal; Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto 4050-313, Portugal; Gladstone Institutes, University of California San Francisco, San Francisco 94158, USA
| | - S C Rodrigues
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto 4200-135, Portugal; INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Porto 4200-135, Portugal
| | - J Caldeira
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto 4200-135, Portugal; INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Porto 4200-135, Portugal
| | - A M Nunes
- Centre for Ecology, Evolution and Environmental Change, Departamento de Biologia Animal, Faculdade de Ciências, Universidade de Lisboa, Lisboa 1749-016, Portugal
| | - V Sampaio-Pinto
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto 4200-135, Portugal; INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Porto 4200-135, Portugal; Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto 4050-313, Portugal
| | - T P Resende
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto 4200-135, Portugal; INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Porto 4200-135, Portugal
| | - M J Oliveira
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto 4200-135, Portugal; INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Porto 4200-135, Portugal; Faculty of Medicine, University of Porto, Porto 4200-319, Portugal
| | - M A Barbosa
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto 4200-135, Portugal; INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Porto 4200-135, Portugal; Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto 4050-313, Portugal
| | - S Thorsteinsdóttir
- Centre for Ecology, Evolution and Environmental Change, Departamento de Biologia Animal, Faculdade de Ciências, Universidade de Lisboa, Lisboa 1749-016, Portugal
| | - D S Nascimento
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto 4200-135, Portugal; INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Porto 4200-135, Portugal.
| | - P Pinto-do-Ó
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto 4200-135, Portugal; INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Porto 4200-135, Portugal; Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto 4050-313, Portugal; Unit for Lymphopoiesis, Immunology Department, INSERM U668, University Paris Diderot, Sorbonne Paris Cité, Cellule Pasteur. Institut Pasteur, Paris, France.
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10
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Novel therapeutic strategies targeting fibroblasts and fibrosis in heart disease. Nat Rev Drug Discov 2016; 15:620-638. [PMID: 27339799 DOI: 10.1038/nrd.2016.89] [Citation(s) in RCA: 236] [Impact Index Per Article: 26.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Our understanding of the functions of cardiac fibroblasts has moved beyond their roles in heart structure and extracellular matrix generation and now includes their contributions to paracrine, mechanical and electrical signalling during ontogenesis and normal cardiac activity. Fibroblasts also have central roles in pathogenic remodelling during myocardial ischaemia, hypertension and heart failure. As key contributors to scar formation, they are crucial for tissue repair after interventions including surgery and ablation. Novel experimental approaches targeting cardiac fibroblasts are promising potential therapies for heart disease. Indeed, several existing drugs act, at least partially, through effects on cardiac connective tissue. This Review outlines the origins and roles of fibroblasts in cardiac development, homeostasis and disease; illustrates the involvement of fibroblasts in current and emerging clinical interventions; and identifies future targets for research and development.
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11
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Huang Y, Mai L, Cai X, Hu Y, Mai W. Stem cell therapy for heart disease-Meta-analysis may be misleading. Int J Cardiol 2016; 203:351-352. [PMID: 26529085 DOI: 10.1016/j.ijcard.2015.10.193] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2015] [Accepted: 10/24/2015] [Indexed: 12/26/2022]
Affiliation(s)
- Yuli Huang
- Department of Cardiology, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China; Department of Cardiology, the First People's Hospital of Shunde, Foshan, 528300, China
| | - Linlin Mai
- Department of Cardiology, the First People's Hospital of Shunde, Foshan, 528300, China
| | - Xiaoyan Cai
- Clinical Medicine Research Center, the First People's Hospital of Shunde Foshan, 528300, China
| | - Yunzhao Hu
- Department of Cardiology, the First People's Hospital of Shunde, Foshan, 528300, China
| | - Weiyi Mai
- Department of Cardiology, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China.
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12
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Bilgimol JC, Ragupathi S, Vengadassalapathy L, Senthil NS, Selvakumar K, Ganesan M, Manjunath SR. Stem cells: An eventual treatment option for heart diseases. World J Stem Cells 2015; 7:1118-1126. [PMID: 26435771 PMCID: PMC4591785 DOI: 10.4252/wjsc.v7.i8.1118] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2015] [Revised: 07/04/2015] [Accepted: 08/03/2015] [Indexed: 02/06/2023] Open
Abstract
Stem cells are of global excitement for various diseases including heart diseases. It is worth to understand the mechanism or role of stem cells in the treatment of heart failure. Bone marrow derived stem cells are commonly practiced with an aim to improve the function of the heart. The majority of studies have been conducted with acute myocardial infarction and a few has been investigated with the use of stem cells for treating chronic or dilated cardiomyopathy. Heterogeneity in the treated group using stem cells has greatly emerged. Ever increasing demand for any alternative made is of at most priority for cardiomyopathy. Stem cells are of top priority with the current impact that has generated among physicians. However, meticulous selection of proper source is required since redundancy is clearly evident with the present survey. This review focuses on the methods adopted using stem cells for heart diseases and outcomes that are generated so far with an idea to determine the best therapeutic possibility in order to fulfill the present demand.
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Hinkel R, Ball HL, DiMaio JM, Shrivastava S, Thatcher JE, Singh AN, Sun X, Faskerti G, Olson EN, Kupatt C, Bock-Marquette I. C-terminal variable AGES domain of Thymosin β4: the molecule's primary contribution in support of post-ischemic cardiac function and repair. J Mol Cell Cardiol 2015; 87:113-25. [PMID: 26255251 DOI: 10.1016/j.yjmcc.2015.07.004] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2015] [Revised: 06/12/2015] [Accepted: 07/08/2015] [Indexed: 12/19/2022]
Abstract
Repairing defective cardiac cells is important towards improving heart function. Due to the frequency and severity of ischemic heart disease, management of patients featuring this type of cardiac failure receives significant interest. Previously we discovered that Thymosin β4 (TB4), a 43 amino-acid secreted actin sequestering peptide, is beneficial for myocardial cell survival and coronary re-growth after infarction in adult mammals. Considering the regenerative potential of full-length TB4 in the heart, and that minimal structural variations alter TB4's influence on actin assembly and cell movement, we investigated how various TB4 domains affect cardiac cell behavior and post-ischemic mammalian heart function. We synthesized 17 domain combinations of full-length TB4 and analyzed their impact on embryonic cardiac cells in vitro, and after cardiac infarction in vivo. We discovered the domains of TB4 affect cardiac cell behavior distinctly. We revealed TB4 specific C-terminal tetrapeptide, AGES, increases embryonic cardiac cell migration and myocyte beating in culture, and improves adult mammalian heart function following ischemia. Investigating the molecular background and mechanism we discovered systemic injection of AGES enhances early myocyte survival by activating Akt-mediated signaling mechanisms, increases coronary vessel growth and inhibits inflammation in mice and pigs. Biodistribution analyses revealed cardiomyocytes uptake AGES efficiently in vitro and in vivo projecting a potential independent clinical utilization for the tetrapeptide. Our comprehensive domain investigations also suggest, preservation and/or restoration of cardiomyocyte communication is a target of TB4 and AGES, and critical to improve post-ischemic heart function in pigs. In summary, we identified the C-terminal four amino-acid variable end of TB4 as the essential and responsible domain for the molecule's full benefits in the hypoxic heart. Additionally, we introduced AGES as a novel, systemically applicable drug candidate to aid cardiac infarction in adult mammals.
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Affiliation(s)
- Rabea Hinkel
- Internal Medicine I, University Clinic Grosshadern, Munich 81377, Germany
| | - Haydn L Ball
- Protein Chemistry Technology Center University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - J Michael DiMaio
- Department of Cardiovascular and Thoracic Surgery University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Santwana Shrivastava
- Department of Cardiovascular and Thoracic Surgery University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Jeffrey E Thatcher
- Department of Cardiovascular and Thoracic Surgery University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Ajay N Singh
- Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Xiankai Sun
- Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Gabor Faskerti
- University of Pecs, Faculty of Medicine, Szentagothai Research Centre, Pecs 7624, Hungary
| | - Eric N Olson
- Department of Molecular Biology University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Christian Kupatt
- Internal Medicine I, University Clinic Grosshadern, Munich 81377, Germany
| | - Ildiko Bock-Marquette
- Department of Cardiovascular and Thoracic Surgery University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; University of Pecs, Faculty of Medicine, Szentagothai Research Centre, Pecs 7624, Hungary.
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Blocki A, Beyer S, Dewavrin JY, Goralczyk A, Wang Y, Peh P, Ng M, Moonshi SS, Vuddagiri S, Raghunath M, Martinez EC, Bhakoo KK. Microcapsules engineered to support mesenchymal stem cell (MSC) survival and proliferation enable long-term retention of MSCs in infarcted myocardium. Biomaterials 2015; 53:12-24. [DOI: 10.1016/j.biomaterials.2015.02.075] [Citation(s) in RCA: 79] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2014] [Revised: 02/10/2015] [Accepted: 02/15/2015] [Indexed: 12/16/2022]
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15
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Dixit P, Katare R. Challenges in identifying the best source of stem cells for cardiac regeneration therapy. Stem Cell Res Ther 2015; 6:26. [PMID: 25886612 PMCID: PMC4357059 DOI: 10.1186/s13287-015-0010-8] [Citation(s) in RCA: 80] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2014] [Accepted: 02/17/2015] [Indexed: 12/14/2022] Open
Abstract
The overall clinical cardiac regeneration experience suggests that stem cell therapy can be safely performed, but it also underlines the need for reproducible results for their effective use in a real-world scenario. One of the significant challenges is the identification and selection of the best suited stem cell type for regeneration therapy. Bone marrow mononuclear cells, bone marrow-derived mesenchymal stem cells, resident or endogenous cardiac stem cells, endothelial progenitor cells and induced pluripotent stem cells are some of the stem cell types which have been extensively tested for their ability to regenerate the lost myocardium. While most of these cell types are being evaluated in clinical trials for their safety and efficacy, results show significant heterogeneity in terms of efficacy. The enthusiasm surrounding regenerative medicine in the heart has been dampened by the reports of poor survival, proliferation, engraftment, and differentiation of the transplanted cells. Therefore, the primary challenge is to create clearcut evidence on what actually drives the improvement of cardiac function after the administration of stem cells. In this review, we provide an overview of different types of stem cells currently being considered for cardiac regeneration and discuss why associated factors such as practicality and difficulty in cell collection should also be considered when selecting the stem cells for transplantation. Next, we discuss how the experimental variables (type of disease, marker-based selection and use of different isolation techniques) can influence the study outcome. Finally, we provide an outline of the molecular and genetic approaches to increase the functional ability of stem cells before and after transplantation.
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Affiliation(s)
- Parul Dixit
- Department of Physiology, HeartOtago, Otago School of Medical Sciences, University of Otago, Dunedin, 9010, New Zealand.
| | - Rajesh Katare
- Department of Physiology, HeartOtago, Otago School of Medical Sciences, University of Otago, Dunedin, 9010, New Zealand.
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16
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Huang YL, Tang HF, Hu YZ. Stem cells for cardiac repair--should we be cautious? Nat Rev Cardiol 2014; 11:615. [PMID: 25178502 DOI: 10.1038/nrcardio.2014.9-c3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Affiliation(s)
- Yu-Li Huang
- Clinical Medicine Research Institute, The First People's Hospital of Shunde, Penglai Road 1, Daliang Town, Shunde District, Foshan 528300, PR China
| | - Hong-Feng Tang
- Clinical Medicine Research Institute, The First People's Hospital of Shunde, Penglai Road 1, Daliang Town, Shunde District, Foshan 528300, PR China
| | - Yun-Zhao Hu
- Clinical Medicine Research Institute, The First People's Hospital of Shunde, Penglai Road 1, Daliang Town, Shunde District, Foshan 528300, PR China
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17
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Zhou N, Fu Y, Wang Y, Chen P, Meng H, Guo S, Zhang M, Yang Z, Ge Y. p27 kip1 haplo-insufficiency improves cardiac function in early-stages of myocardial infarction by protecting myocardium and increasing angiogenesis by promoting IKK activation. Sci Rep 2014; 4:5978. [PMID: 25099287 PMCID: PMC4124466 DOI: 10.1038/srep05978] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2014] [Accepted: 07/11/2014] [Indexed: 11/09/2022] Open
Abstract
p27kip1 (p27) is widely known as a potent cell cycle inhibitor in several organs, especially in the heart. However, its role has not been fully defined during the early phase of myocardial infarction (MI). In this study, we investigated the relationships between p27, vascular endothelial growth factor/hepatocyte growth factor (VEGF/HGF) and NF-κB in post-MI cardiac function repair both in vivo and in the hypoxia/ischemia-induced rat myocardiocyte model. In vivo, haplo-insufficiency of p27 improved cardiac function, diminished the infarct zone, protected myocardiocytes and increased angiogenesis by enhancing the production of VEGF/HGF. In vitro, the presence of conditioned medium from hypoxia/ischemia-induced p27 knockdown myocardiocytes reduced the injury caused by hypoxia/ischemia in myocardiocytes, and this effect was reversed by VEGF/HGF neutralizing antibodies, consistent with the cardioprotection being due to VEGF/HGF secretion. We also observed that p27 bound to IKK and that p27 haplo-insufficiency promoted IKK/p65 activation both in vivo and in vitro, thereby inducing the NF-κB downstream regulator, VEGF/HGF. Furthermore, IKKi and IKK inhibitor negated the effect of VEGF/HGF. Therefore, we conclude that p27 haplo-insufficiency protects against heart injury by VEGF/HGF mediated cardioprotection and increased angiogenesis through promoting IKK activation.
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Affiliation(s)
- Ningtian Zhou
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People's Republic of China
| | - Yuxuan Fu
- Department of Physiology, Nanjing Medical University, Nanjing, People's Republic of China
| | - Yunle Wang
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People's Republic of China
| | - Pengsheng Chen
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People's Republic of China
| | - Haoyu Meng
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People's Republic of China
| | - Shouyu Guo
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People's Republic of China
| | - Min Zhang
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People's Republic of China
| | - Zhijian Yang
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People's Republic of China
| | - Yingbin Ge
- Department of Physiology, Nanjing Medical University, Nanjing, People's Republic of China
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Rossier BC, Kraehenbuhl JP, Rossier M. [Role of distance learning in the education and the training of the investigator]. Med Sci (Paris) 2014; 30:603-4. [PMID: 25014442 DOI: 10.1051/medsci/20143006001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Affiliation(s)
- Bernard C Rossier
- Département de pharmacologie et de toxicologie, faculté de biologie et de médecine, université de Lausanne, rue du Bugnon 27, CH 1005 Lausanne, Suisse - Fondation HseT (Health Science e-Training), CH 1066 Epalinges, Suisse
| | - Jean-Pierre Kraehenbuhl
- Fondation HseT (Health Science e-Training), CH 1066 Epalinges, Suisse - Département de biochimie, faculté de biologie et de médecine, université de Lausanne, Suisse
| | - Michelle Rossier
- Fondation HseT (Health Science e-Training), CH 1066 Epalinges, Suisse
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