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1
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Carvalho AB, Kasai-Brunswick TH, Campos de Carvalho AC. Advanced cell and gene therapies in cardiology. EBioMedicine 2024; 103:105125. [PMID: 38640834 PMCID: PMC11052923 DOI: 10.1016/j.ebiom.2024.105125] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 04/01/2024] [Accepted: 04/04/2024] [Indexed: 04/21/2024] Open
Abstract
We review the evidence for the presence of stem/progenitor cells in the heart and the preclinical and clinical data using diverse cell types for the therapy of cardiac diseases. We highlight the failure of adult stem/progenitor cells to ameliorate heart function in most cardiac diseases, with the possible exception of refractory angina. The use of pluripotent stem cell-derived cardiomyocytes is analysed as a viable alternative therapeutic option but still needs further research at preclinical and clinical stages. We also discuss the use of direct reprogramming of cardiac fibroblasts into cardiomyocytes and the use of extracellular vesicles as therapeutic agents in ischemic and non-ischemic cardiac diseases. Finally, gene therapies and genome editing for the treatment of hereditary cardiac diseases, ablation of genes responsible for atherosclerotic disease, or modulation of gene expression in the heart are discussed.
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Affiliation(s)
- Adriana Bastos Carvalho
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil; Instituto Nacional de Ciência e Tecnologia em Medicina Regenerativa, Universidade Federal do RIo de Janeiro, Rio de Janeiro, RJ, Brazil
| | - Tais Hanae Kasai-Brunswick
- Centro Nacional de Biologia Estrutural e Bioimagem (CENABIO), Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil; Instituto Nacional de Ciência e Tecnologia em Medicina Regenerativa, Universidade Federal do RIo de Janeiro, Rio de Janeiro, RJ, Brazil
| | - Antonio Carlos Campos de Carvalho
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil; Centro Nacional de Biologia Estrutural e Bioimagem (CENABIO), Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil; Instituto Nacional de Ciência e Tecnologia em Medicina Regenerativa, Universidade Federal do RIo de Janeiro, Rio de Janeiro, RJ, Brazil.
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2
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Pezhouman A, Nguyen NB, Kay M, Kanjilal B, Noshadi I, Ardehali R. Cardiac regeneration - Past advancements, current challenges, and future directions. J Mol Cell Cardiol 2023; 182:75-85. [PMID: 37482238 DOI: 10.1016/j.yjmcc.2023.07.009] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Revised: 07/13/2023] [Accepted: 07/18/2023] [Indexed: 07/25/2023]
Abstract
Cardiovascular disease is the leading cause of mortality and morbidity worldwide. Despite improvements in the standard of care for patients with heart diseases, including innovation in pharmacotherapy and surgical interventions, none have yet been proven effective to prevent the progression to heart failure. Cardiac transplantation is the last resort for patients with severe heart failure, but donor shortages remain a roadblock. Cardiac regenerative strategies include cell-based therapeutics, gene therapy, direct reprogramming of non-cardiac cells, acellular biologics, and tissue engineering methods to restore damaged hearts. Significant advancements have been made over the past several decades within each of these fields. This review focuses on the advancements of: 1) cell-based cardiac regenerative therapies, 2) the use of noncoding RNA to induce endogenous cell proliferation, and 3) application of bioengineering methods to promote retention and integration of engrafted cells. Different cell sources have been investigated, including adult stem cells derived from bone marrow and adipose cells, cardiosphere-derived cells, skeletal myoblasts, and pluripotent stem cells. In addition to cell-based transplantation approaches, there have been accumulating interest over the past decade in inducing endogenous CM proliferation for heart regeneration, particularly with the use of noncoding RNAs such as miRNAs and lncRNAs. Bioengineering applications have focused on combining cell-transplantation approaches with fabrication of a porous, vascularized scaffold using biomaterials and advanced bio-fabrication techniques that may offer enhanced retention of transplanted cells, with the hope that these cells would better engraft with host tissue to improve cardiac function. This review summarizes the present status and future challenges of cardiac regenerative therapies.
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Affiliation(s)
- Arash Pezhouman
- Baylor College of Medicine, Department of Medicine, Division of Cardiology, Houston, Texas 77030, United States; Texas Heart Institute, Houston, Texas 77030, United States
| | - Ngoc B Nguyen
- Baylor College of Medicine, Department of Internal Medicine, Houston, Texas 77030, United States
| | - Maryam Kay
- Department of Medicine, Division of Cardiology, University of California, Los Angeles, CA 90095, United States
| | - Baishali Kanjilal
- Department of Bioengineering, University of California, Riverside, Riverside, CA 92521, United States
| | - Iman Noshadi
- Department of Bioengineering, University of California, Riverside, Riverside, CA 92521, United States
| | - Reza Ardehali
- Baylor College of Medicine, Department of Medicine, Division of Cardiology, Houston, Texas 77030, United States; Texas Heart Institute, Houston, Texas 77030, United States.
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3
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Tonkin D, Yee-Goh A, Katare R. Healing the Ischaemic Heart: A Critical Review of Stem Cell Therapies. Rev Cardiovasc Med 2023; 24:122. [PMID: 39076280 PMCID: PMC11273058 DOI: 10.31083/j.rcm2404122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 03/16/2023] [Accepted: 03/20/2023] [Indexed: 07/31/2024] Open
Abstract
Ischaemic heart disease (IHD) remains the leading cause of mortality worldwide. Current pharmaceutical treatments focus on delaying, rather than preventing disease progression. The only curative treatment available is orthotopic heart transplantation, which is greatly limited by a lack of available donors and the possibility for immune rejection. As a result, novel therapies are consistently being sought to improve the quality and duration of life of those suffering from IHD. Stem cell therapies have garnered attention globally owing to their potential to replace lost cardiac cells, regenerate the ischaemic myocardium and to release protective paracrine factors. Despite recent advances in regenerative cardiology, one of the biggest challenges in the clinical translation of cell-based therapies is determining the most efficacious cell type for repair. Multiple cell types have been investigated in clinical trials; with inconsistent methodologies and isolation protocols making it difficult to draw strong conclusions. This review provides an overview of IHD focusing on pathogenesis and complications, followed by a summary of different stem cells which have been trialled for use in the treatment of IHD, and ends by exploring the known mechanisms by which stem cells mediate their beneficial effects on ischaemic myocardium.
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Affiliation(s)
- Devin Tonkin
- Department of Physiology, HeartOtago, School of Biomedical Sciences, University of Otago, 9010 Dunedin, New Zealand
| | - Anthony Yee-Goh
- Department of Physiology, HeartOtago, School of Biomedical Sciences, University of Otago, 9010 Dunedin, New Zealand
| | - Rajesh Katare
- Department of Physiology, HeartOtago, School of Biomedical Sciences, University of Otago, 9010 Dunedin, New Zealand
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4
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Farag A, Mandour AS, Hendawy H, Elhaieg A, Elfadadny A, Tanaka R. A review on experimental surgical models and anesthetic protocols of heart failure in rats. Front Vet Sci 2023; 10:1103229. [PMID: 37051509 PMCID: PMC10083377 DOI: 10.3389/fvets.2023.1103229] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2022] [Accepted: 03/13/2023] [Indexed: 03/29/2023] Open
Abstract
Heart failure (HF) is a serious health and economic burden worldwide, and its prevalence is continuously increasing. Current medications effectively moderate the progression of symptoms, and there is a need for novel preventative and reparative treatments. The development of novel HF treatments requires the testing of potential therapeutic procedures in appropriate animal models of HF. During the past decades, murine models have been extensively used in fundamental and translational research studies to better understand the pathophysiological mechanisms of HF and develop more effective methods to prevent and control congestive HF. Proper surgical approaches and anesthetic protocols are the first steps in creating these models, and each successful approach requires a proper anesthetic protocol that maintains good recovery and high survival rates after surgery. However, each protocol may have shortcomings that limit the study's outcomes. In addition, the ethical regulations of animal welfare in certain countries prohibit the use of specific anesthetic agents, which are widely used to establish animal models. This review summarizes the most common and recent surgical models of HF and the anesthetic protocols used in rat models. We will highlight the surgical approach of each model, the use of anesthesia, and the limitations of the model in the study of the pathophysiology and therapeutic basis of common cardiovascular diseases.
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Affiliation(s)
- Ahmed Farag
- Department of Veterinary Surgery, Faculty of Veterinary Medicine, Tokyo University of Agriculture and Technology, Fuchu, Japan
- Department of Surgery, Anesthesiology, and Radiology, Faculty of Veterinary Medicine, Zagazig University, Zagazig, Egypt
- *Correspondence: Ahmed Farag
| | - Ahmed S. Mandour
- Department of Animal Medicine (Internal Medicine), Faculty of Veterinary Medicine, Suez Canal University, Ismailia, Egypt
- Ahmed S. Mandour
| | - Hanan Hendawy
- Department of Veterinary Surgery, Faculty of Veterinary Medicine, Tokyo University of Agriculture and Technology, Fuchu, Japan
| | - Asmaa Elhaieg
- Department of Veterinary Surgery, Faculty of Veterinary Medicine, Tokyo University of Agriculture and Technology, Fuchu, Japan
| | - Ahmed Elfadadny
- Department of Animal Internal Medicine, Faculty of Veterinary Medicine, Damanhur University, Damanhur El-Beheira, Egypt
| | - Ryou Tanaka
- Department of Veterinary Surgery, Faculty of Veterinary Medicine, Tokyo University of Agriculture and Technology, Fuchu, Japan
- Ryou Tanaka
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5
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Teraoka S, Honda M, Makishima K, Shimizu R, Tsounapi P, Yumioka T, Iwamoto H, Li P, Morizane S, Hikita K, Hisatome I, Takenaka A. Early effects of an adipose-derived stem cell sheet against detrusor underactivity in a rat cryo-injury model. Life Sci 2022; 301:120604. [DOI: 10.1016/j.lfs.2022.120604] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2021] [Revised: 04/21/2022] [Accepted: 04/27/2022] [Indexed: 11/25/2022]
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6
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Affiliation(s)
- Eugene Braunwald
- TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, and Department of Medicine, Harvard Medical School, Hale Building for Transformative Medicine, Suite 7022, 60 Fenwood Road, Boston, MA 02115, USA
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7
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Garbern JC, Lee RT. Heart regeneration: 20 years of progress and renewed optimism. Dev Cell 2022; 57:424-439. [PMID: 35231426 PMCID: PMC8896288 DOI: 10.1016/j.devcel.2022.01.012] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 01/10/2022] [Accepted: 01/18/2022] [Indexed: 02/06/2023]
Abstract
Cardiovascular disease is a leading cause of death worldwide, and thus there remains great interest in regenerative approaches to treat heart failure. In the past 20 years, the field of heart regeneration has entered a renaissance period with remarkable progress in the understanding of endogenous heart regeneration, stem cell differentiation for exogenous cell therapy, and cell-delivery methods. In this review, we highlight how this new understanding can lead to viable strategies for human therapy. For the near term, drugs, electrical and mechanical devices, and heart transplantation will remain mainstays of cardiac therapies, but eventually regenerative therapies based on fundamental regenerative biology may offer more permanent solutions for patients with heart failure.
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Affiliation(s)
- Jessica C. Garbern
- Department of Stem Cell and Regenerative Biology and the Harvard Stem Cell Institute, Harvard University, 7 Divinity Ave, Cambridge, MA 02138, USA,Department of Cardiology, Boston Children’s Hospital, 300 Longwood Ave, Boston, MA 02115, USA
| | - Richard T. Lee
- Department of Stem Cell and Regenerative Biology and the Harvard Stem Cell Institute, Harvard University, 7 Divinity Ave, Cambridge, MA 02138, USA,Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, 75 Francis St, Boston, MA 02115, USA,Corresponding author and lead contact: Richard T. Lee, Department of Stem Cell and Regenerative Biology, Harvard University, 7 Divinity Ave, Cambridge, MA 02138, Phone: 617-496-5394, Fax: 617-496-8351,
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8
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Alam P, Maliken BD, Jones SM, Ivey MJ, Wu Z, Wang Y, Kanisicak O. Cardiac Remodeling and Repair: Recent Approaches, Advancements, and Future Perspective. Int J Mol Sci 2021; 22:ijms222313104. [PMID: 34884909 PMCID: PMC8658114 DOI: 10.3390/ijms222313104] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Revised: 11/29/2021] [Accepted: 11/30/2021] [Indexed: 12/12/2022] Open
Abstract
The limited ability of mammalian adult cardiomyocytes to proliferate following an injury to the heart, such as myocardial infarction, is a major factor that results in adverse fibrotic and myocardial remodeling that ultimately leads to heart failure. The continued high degree of heart failure-associated morbidity and lethality requires the special attention of researchers worldwide to develop efficient therapeutics for cardiac repair. Recently, various strategies and approaches have been developed and tested to extrinsically induce regeneration and restoration of the myocardium after cardiac injury have yielded encouraging results. Nevertheless, these interventions still lack adequate success to be used for clinical interventions. This review highlights and discusses both cell-based and cell-free therapeutic approaches as well as current advancements, major limitations, and future perspectives towards developing an efficient therapeutic method for cardiac repair.
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Affiliation(s)
- Perwez Alam
- Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA; (P.A.); (S.M.J.); (M.J.I.); (Z.W.); (Y.W.)
| | - Bryan D. Maliken
- Harrington Physician-Scientist Pathway, Department of Internal Medicine, University Hospitals Case Medical Center, Cleveland, OH 44106, USA;
| | - Shannon M. Jones
- Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA; (P.A.); (S.M.J.); (M.J.I.); (Z.W.); (Y.W.)
| | - Malina J. Ivey
- Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA; (P.A.); (S.M.J.); (M.J.I.); (Z.W.); (Y.W.)
| | - Zhichao Wu
- Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA; (P.A.); (S.M.J.); (M.J.I.); (Z.W.); (Y.W.)
| | - Yigang Wang
- Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA; (P.A.); (S.M.J.); (M.J.I.); (Z.W.); (Y.W.)
| | - Onur Kanisicak
- Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA; (P.A.); (S.M.J.); (M.J.I.); (Z.W.); (Y.W.)
- Correspondence: ; Tel.: +1-513-558-2029; Fax: +1-513-584-3892
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9
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Kasai-Brunswick TH, Carvalho AB, Campos de Carvalho AC. Stem cell therapies in cardiac diseases: Current status and future possibilities. World J Stem Cells 2021; 13:1231-1247. [PMID: 34630860 PMCID: PMC8474720 DOI: 10.4252/wjsc.v13.i9.1231] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 07/26/2021] [Accepted: 08/10/2021] [Indexed: 02/06/2023] Open
Abstract
Cardiovascular diseases represent the world's leading cause of death. In this heterogeneous group of diseases, ischemic cardiomyopathies are the most devastating and prevalent, estimated to cause 17.9 million deaths per year. Despite all biomedical efforts, there are no effective treatments that can replace the myocytes lost during an ischemic event or progression of the disease to heart failure. In this context, cell therapy is an emerging therapeutic alternative to treat cardiovascular diseases by cell administration, aimed at cardiac regeneration and repair. In this review, we will cover more than 30 years of cell therapy in cardiology, presenting the main milestones and drawbacks in the field and signaling future challenges and perspectives. The outcomes of cardiac cell therapies are discussed in three distinct aspects: The search for remuscularization by replacement of lost cells by exogenous adult cells, the endogenous stem cell era, which pursued the isolation of a progenitor with the ability to induce heart repair, and the utilization of pluripotent stem cells as a rich and reliable source of cardiomyocytes. Acellular therapies using cell derivatives, such as microvesicles and exosomes, are presented as a promising cell-free therapeutic alternative.
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Affiliation(s)
- Tais Hanae Kasai-Brunswick
- National Center of Structural Biology and Bioimaging, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
- National Institute of Science and Technology in Regenerative Medicine, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
| | - Adriana Bastos Carvalho
- National Institute of Science and Technology in Regenerative Medicine, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
- Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
| | - Antonio Carlos Campos de Carvalho
- National Center of Structural Biology and Bioimaging, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
- National Institute of Science and Technology in Regenerative Medicine, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
- Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil.
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10
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Gähwiler EKN, Motta SE, Martin M, Nugraha B, Hoerstrup SP, Emmert MY. Human iPSCs and Genome Editing Technologies for Precision Cardiovascular Tissue Engineering. Front Cell Dev Biol 2021; 9:639699. [PMID: 34262897 PMCID: PMC8273765 DOI: 10.3389/fcell.2021.639699] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Accepted: 03/31/2021] [Indexed: 12/12/2022] Open
Abstract
Induced pluripotent stem cells (iPSCs) originate from the reprogramming of adult somatic cells using four Yamanaka transcription factors. Since their discovery, the stem cell (SC) field achieved significant milestones and opened several gateways in the area of disease modeling, drug discovery, and regenerative medicine. In parallel, the emergence of clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein 9 (CRISPR-Cas9) revolutionized the field of genome engineering, allowing the generation of genetically modified cell lines and achieving a precise genome recombination or random insertions/deletions, usefully translated for wider applications. Cardiovascular diseases represent a constantly increasing societal concern, with limited understanding of the underlying cellular and molecular mechanisms. The ability of iPSCs to differentiate into multiple cell types combined with CRISPR-Cas9 technology could enable the systematic investigation of pathophysiological mechanisms or drug screening for potential therapeutics. Furthermore, these technologies can provide a cellular platform for cardiovascular tissue engineering (TE) approaches by modulating the expression or inhibition of targeted proteins, thereby creating the possibility to engineer new cell lines and/or fine-tune biomimetic scaffolds. This review will focus on the application of iPSCs, CRISPR-Cas9, and a combination thereof to the field of cardiovascular TE. In particular, the clinical translatability of such technologies will be discussed ranging from disease modeling to drug screening and TE applications.
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Affiliation(s)
- Eric K. N. Gähwiler
- Institute for Regenerative Medicine (IREM), University of Zurich, Zurich, Switzerland
| | - Sarah E. Motta
- Institute for Regenerative Medicine (IREM), University of Zurich, Zurich, Switzerland
- Wyss Zurich, University and ETH Zurich, Zurich, Switzerland
| | - Marcy Martin
- Division of Pediatric Cardiology, Department of Pediatrics, Stanford School of Medicine, Stanford, CA, United States
- Vera Moulton Wall Center for Pulmonary Vascular Disease, Stanford School of Medicine, Stanford, CA, United States
- Stanford Cardiovascular Institute, Stanford School of Medicine, Stanford, CA, United States
| | - Bramasta Nugraha
- Molecular Parasitology Lab, Institute of Parasitology, University of Zurich, Zurich, Switzerland
- Bioscience Cardiovascular, Research and Early Development, Cardiovascular, Renal and Metabolism, R&D BioPharmaceuticals, AstraZeneca, Gothenburg, Sweden
| | - Simon P. Hoerstrup
- Institute for Regenerative Medicine (IREM), University of Zurich, Zurich, Switzerland
- Wyss Zurich, University and ETH Zurich, Zurich, Switzerland
| | - Maximilian Y. Emmert
- Institute for Regenerative Medicine (IREM), University of Zurich, Zurich, Switzerland
- Wyss Zurich, University and ETH Zurich, Zurich, Switzerland
- Department of Cardiovascular Surgery, Charité Universitätsmedizin Berlin, Berlin, Germany
- Department of Cardiothoracic and Vascular Surgery, German Heart Center Berlin, Berlin, Germany
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11
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Elde S, Wang H, Woo YJ. Navigating the Crossroads of Cell Therapy and Natural Heart Regeneration. Front Cell Dev Biol 2021; 9:674180. [PMID: 34046410 PMCID: PMC8148343 DOI: 10.3389/fcell.2021.674180] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Accepted: 04/15/2021] [Indexed: 01/14/2023] Open
Abstract
Cardiovascular disease remains the leading cause of death worldwide despite significant advances in our understanding of the disease and its treatment. Consequently, the therapeutic potential of cell therapy and induction of natural myocardial regeneration have stimulated a recent surge of research and clinical trials aimed at addressing this challenge. Recent developments in the field have shed new light on the intricate relationship between inflammation and natural regeneration, an intersection that warrants further investigation.
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Affiliation(s)
- Stefan Elde
- Department of Cardiothoracic Surgery, Stanford University, Stanford, CA, United States
| | - Hanjay Wang
- Department of Cardiothoracic Surgery, Stanford University, Stanford, CA, United States.,Stanford Cardiovascular Institute, Stanford University, Stanford, CA, United States
| | - Y Joseph Woo
- Department of Cardiothoracic Surgery, Stanford University, Stanford, CA, United States.,Stanford Cardiovascular Institute, Stanford University, Stanford, CA, United States.,Department of Bioengineering, Stanford University, Stanford, CA, United States
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12
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Progress and Challenges of Amniotic Fluid Derived Stem Cells in Therapy of Ischemic Heart Disease. Int J Mol Sci 2020; 22:ijms22010102. [PMID: 33374215 PMCID: PMC7794729 DOI: 10.3390/ijms22010102] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Revised: 12/13/2020] [Accepted: 12/18/2020] [Indexed: 02/08/2023] Open
Abstract
Cardiovascular disease is the leading cause of deaths worldwide, claiming an estimated total of 17.9 million lives each year, of which one-third of the people are under the age of 70 years. Since adult cardiomyocytes fail to regenerate, the heart loses the ability to repair itself after an injury, making patients with heart disease suffer from poor prognosis. Pluripotent stem cells have the ability to differentiate into cardiomyocytes in vitro through a well-established process, which is a new advancement in cardiac regeneration therapy. However, pluripotent stem cell-derived cardiomyocytes have certain drawbacks, such as the risk of arrhythmia and immune incompatibility. Thus, amniotic fluid stem cells (AFSCs), a relatively novel source of stem cells, have been exploited for their ability of pluripotent differentiation. In addition, since AFSCs are weakly positive for the major histocompatibility class II molecules, they may have high immune tolerance. In summary, the possibility of development of cardiomyocytes from AFSCs, as well as their transplantation in host cells to produce mechanical contraction, has been discussed. Thus, this review article highlights the progress of AFSC therapy and its application in the treatment of heart diseases in recent years.
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13
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Birla RK. A methodological nine-step process to bioengineer heart muscle tissue. Tissue Cell 2020; 67:101425. [PMID: 32853859 DOI: 10.1016/j.tice.2020.101425] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Revised: 08/06/2020] [Accepted: 08/12/2020] [Indexed: 01/15/2023]
Abstract
Research in the field of heart muscle tissue engineering is focused on the fabrication of heart muscle tissue which can be utilized to repair, replace and/or augment functionality of damaged and/or diseased tissue. In the simplest embodiment, bioengineering heart muscle tissue constructs involves culture of cardiomyocytes within natural or synthetic scaffolds. Functional integration of the cells with the scaffold and subsequent remodeling lead to the formation of 3D heart muscle tissue and physiological cues like mechanical stretch, electrical stimulation and perfusion are necessary to guide tissue maturation and development. Potential applications for bioengineered heart muscle include use as grafts to repair or replace damaged tissue, as models for basic research and as tools for high-throughput screening of pharmacological agents. In this article, we provide a methodological process to bioengineer functional 3D heart muscle tissue and discuss state of the art and potential challenges in each of the nine-step tissue fabrication process.
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Affiliation(s)
- Ravi K Birla
- BIOLIFE4D, 2450 Holcombe Blvd; Houston, TX, 77204, United States.
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14
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He L, Chen X. Cardiomyocyte Induction and Regeneration for Myocardial Infarction Treatment: Cell Sources and Administration Strategies. Adv Healthc Mater 2020; 9:e2001175. [PMID: 33000909 DOI: 10.1002/adhm.202001175] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Revised: 09/15/2020] [Indexed: 02/06/2023]
Abstract
Occlusion of coronary artery and subsequent damage or death of myocardium can lead to myocardial infarction (MI) and even heart failure-one of the leading causes of deaths world wide. Notably, myocardium has extremely limited regeneration potential due to the loss or death of cardiomyocytes (i.e., the cells of which the myocardium is comprised) upon MI. A variety of stem cells and stem cell-derived cardiovascular cells, in situ cardiac fibroblasts and endogenous proliferative epicardium, have been exploited to provide renewable cellular sources to treat injured myocardium. Also, different strategies, including direct injection of cell suspensions, bioactive molecules, or cell-incorporated biomaterials, and implantation of artificial cardiac scaffolds (e.g., cell sheets and cardiac patches), have been developed to deliver renewable cells and/or bioactive molecules to the MI site for the myocardium regeneration. This article briefly surveys cell sources and delivery strategies, along with biomaterials and their processing techniques, developed for MI treatment. Key issues and challenges, as well as recommendations for future research, are also discussed.
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Affiliation(s)
- Lihong He
- Department of Cell Biology Medical College of Soochow University Suzhou 215123 China
| | - Xiongbiao Chen
- Department of Mechanical Engineering Division of Biomedical Engineering University of Saskatchewan Saskatoon S7N5A9 Canada
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15
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Mazzola M, Di Pasquale E. Toward Cardiac Regeneration: Combination of Pluripotent Stem Cell-Based Therapies and Bioengineering Strategies. Front Bioeng Biotechnol 2020; 8:455. [PMID: 32528940 PMCID: PMC7266938 DOI: 10.3389/fbioe.2020.00455] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Accepted: 04/21/2020] [Indexed: 12/12/2022] Open
Abstract
Cardiovascular diseases represent the major cause of morbidity and mortality worldwide. Multiple studies have been conducted so far in order to develop treatments able to prevent the progression of these pathologies. Despite progress made in the last decade, current therapies are still hampered by poor translation into actual clinical applications. The major drawback of such strategies is represented by the limited regenerative capacity of the cardiac tissue. Indeed, after an ischaemic insult, the formation of fibrotic scar takes place, interfering with mechanical and electrical functions of the heart. Hence, the ability of the heart to recover after ischaemic injury depends on several molecular and cellular pathways, and the imbalance between them results into adverse remodeling, culminating in heart failure. In this complex scenario, a new chapter of regenerative medicine has been opened over the past 20 years with the discovery of induced pluripotent stem cells (iPSCs). These cells share the same characteristic of embryonic stem cells (ESCs), but are generated from patient-specific somatic cells, overcoming the ethical limitations related to ESC use and providing an autologous source of human cells. Similarly to ESCs, iPSCs are able to efficiently differentiate into cardiomyocytes (CMs), and thus hold a real regenerative potential for future clinical applications. However, cell-based therapies are subjected to poor grafting and may cause adverse effects in the failing heart. Thus, over the last years, bioengineering technologies focused their attention on the improvement of both survival and functionality of iPSC-derived CMs. The combination of these two fields of study has burst the development of cell-based three-dimensional (3D) structures and organoids which mimic, more realistically, the in vivo cell behavior. Toward the same path, the possibility to directly induce conversion of fibroblasts into CMs has recently emerged as a promising area for in situ cardiac regeneration. In this review we provide an up-to-date overview of the latest advancements in the application of pluripotent stem cells and tissue-engineering for therapeutically relevant cardiac regenerative approaches, aiming to highlight outcomes, limitations and future perspectives for their clinical translation.
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Affiliation(s)
- Marta Mazzola
- Stem Cell Unit, Humanitas Clinical and Research Center - IRCCS, Rozzano, Italy
| | - Elisa Di Pasquale
- Stem Cell Unit, Humanitas Clinical and Research Center - IRCCS, Rozzano, Italy.,Institute of Genetic and Biomedical Research (IRGB) - UOS of Milan, National Research Council (CNR), Milan, Italy
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16
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ARH1 in Health and Disease. Cancers (Basel) 2020; 12:cancers12020479. [PMID: 32092898 PMCID: PMC7072381 DOI: 10.3390/cancers12020479] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2019] [Revised: 02/14/2020] [Accepted: 02/15/2020] [Indexed: 12/15/2022] Open
Abstract
Arginine-specific mono-adenosine diphosphate (ADP)-ribosylation is a nicotinamide adenine dinucleotide (NAD)+-dependent, reversible post-translational modification involving the transfer of an ADP-ribose from NAD+ by bacterial toxins and eukaryotic ADP-ribosyltransferases (ARTs) to arginine on an acceptor protein or peptide. ADP-ribosylarginine hydrolase 1 (ARH1) catalyzes the cleavage of the ADP-ribose-arginine bond, regenerating (arginine)protein. Arginine-specific mono-ADP-ribosylation catalyzed by bacterial toxins was first identified as a mechanism of disease pathogenesis. Cholera toxin ADP-ribosylates and activates the α subunit of Gαs, a guanine nucleotide-binding protein that stimulates adenylyl cyclase activity, increasing cyclic adenosine monophosphate (cAMP), and resulting in fluid and electrolyte loss. Arginine-specific mono-ADP-ribosylation in mammalian cells has potential roles in membrane repair, immunity, and cancer. In mammalian tissues, ARH1 is a cytosolic protein that is ubiquitously expressed. ARH1 deficiency increased tumorigenesis in a gender-specific manner. In the myocardium, in response to cellular injury, an arginine-specific mono-ADP-ribosylation cycle, involving ART1 and ARH1, regulated the level and cellular distribution of ADP-ribosylated tripartite motif-containing protein 72 (TRIM72). Confirmed substrates of ARH1 in vivo are Gαs and TRIM72, however, more than a thousand proteins, ADP-ribosylated on arginine, have been identified by proteomic analysis. This review summarizes the current understanding of the properties of ARH1, e.g., bacterial toxin action, myocardial membrane repair following injury, and tumorigenesis.
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17
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Ishiwata-Endo H, Kato J, Tonouchi A, Chung YW, Sun J, Stevens LA, Zhu J, Aponte AM, Springer DA, San H, Takeda K, Yu ZX, Hoffmann V, Murphy E, Moss J. Role of a TRIM72 ADP-ribosylation cycle in myocardial injury and membrane repair. JCI Insight 2018; 3:97898. [PMID: 30429362 DOI: 10.1172/jci.insight.97898] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2017] [Accepted: 10/11/2018] [Indexed: 12/29/2022] Open
Abstract
Mono-ADP-ribosylation of an (arginine) protein catalyzed by ADP-ribosyltransferase 1 (ART1) - i.e., transfer of ADP-ribose from NAD to arginine - is reversed by ADP-ribosylarginine hydrolase 1 (ARH1) cleavage of the ADP-ribose-arginine bond. ARH1-deficient mice developed cardiomyopathy with myocardial fibrosis, decreased myocardial function under dobutamine stress, and increased susceptibility to ischemia/reperfusion injury. The membrane repair protein TRIM72 was identified as a substrate for ART1 and ARH1; ADP-ribosylated TRIM72 levels were greater in ARH1-deficient mice following ischemia/reperfusion injury. To understand better the role of TRIM72 and ADP-ribosylation, we used C2C12 myocytes. ARH1 knockdown in C2C12 myocytes increased ADP-ribosylation of TRIM72 and delayed wound healing in a scratch assay. Mutant TRIM72 (R207K, R260K) that is not ADP-ribosylated interfered with assembly of TRIM72 repair complexes at a site of laser-induced injury. The regulatory enzymes ART1 and ARH1 and their substrate TRIM72 were found in multiple complexes, which were coimmunoprecipitated from mouse heart lysates. In addition, the mono-ADP-ribosylation inhibitors vitamin K1 and novobiocin inhibited oligomerization of TRIM72, the mechanism by which TRIM72 is recruited to the site of injury. We propose that a mono-ADP-ribosylation cycle involving recruitment of TRIM72 and other regulatory factors to sites of membrane damage is critical for membrane repair and wound healing following myocardial injury.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | - Hong San
- Animal Surgery and Resources Core, and
| | - Kazuyo Takeda
- Pathology Core, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland, USA
| | - Zu-Xi Yu
- Pathology Core, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland, USA
| | - Victoria Hoffmann
- Diagnostic and Research Service Branch, Division of Veterinary Resources, NIH, Bethesda, Maryland, USA
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18
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Rodrigues ICP, Kaasi A, Maciel Filho R, Jardini AL, Gabriel LP. Cardiac tissue engineering: current state-of-the-art materials, cells and tissue formation. ACTA ACUST UNITED AC 2018; 16:eRB4538. [PMID: 30281764 PMCID: PMC6178861 DOI: 10.1590/s1679-45082018rb4538] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2018] [Accepted: 07/24/2018] [Indexed: 12/23/2022]
Abstract
Cardiovascular diseases are the major cause of death worldwide. The heart has limited capacity of regeneration, therefore, transplantation is the only solution in some cases despite presenting many disadvantages. Tissue engineering has been considered the ideal strategy for regenerative medicine in cardiology. It is an interdisciplinary field combining many techniques that aim to maintain, regenerate or replace a tissue or organ. The main approach of cardiac tissue engineering is to create cardiac grafts, either whole heart substitutes or tissues that can be efficiently implanted in the organism, regenerating the tissue and giving rise to a fully functional heart, without causing side effects, such as immunogenicity. In this review, we systematically present and compare the techniques that have drawn the most attention in this field and that generally have focused on four important issues: the scaffold material selection, the scaffold material production, cellular selection and in vitro cell culture. Many studies used several techniques that are herein presented, including biopolymers, decellularization and bioreactors, and made significant advances, either seeking a graft or an entire bioartificial heart. However, much work remains to better understand and improve existing techniques, to develop robust, efficient and efficacious methods.
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Affiliation(s)
| | | | - Rubens Maciel Filho
- Instituto Nacional de Ciência e Tecnologia em Biofabricação, Campinas, SP, Brazil
| | - André Luiz Jardini
- Instituto Nacional de Ciência e Tecnologia em Biofabricação, Campinas, SP, Brazil
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19
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Gnecchi M. Cell Therapy for Heart Regeneration: Learning from the Past to Build a Brighter Future. Stem Cells Transl Med 2018; 7:702-704. [PMID: 30194808 PMCID: PMC6186267 DOI: 10.1002/sctm.18-0126] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2018] [Accepted: 06/18/2018] [Indexed: 12/17/2022] Open
Affiliation(s)
- Massimiliano Gnecchi
- Coronary Care Unit & Laboratory of Experimental Cardiology for Cell and Molecular Therapy, Fondazione IRCCS Policlinico San Matteo Foundation, Pavia, Italy.,Department of Molecular Medicine, Unit of Cardiology, University of Pavia, Pavia, Italy.,Department of Medicine, University of Cape Town, Cape Town, South Africa
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20
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An S, Wang X, Ruck MA, Rodriguez HJ, Kostyushev DS, Varga M, Luu E, Derakhshandeh R, Suchkov SV, Kogan SC, Hermiston ML, Springer ML. Age-Related Impaired Efficacy of Bone Marrow Cell Therapy for Myocardial Infarction Reflects a Decrease in B Lymphocytes. Mol Ther 2018; 26:1685-1693. [PMID: 29914756 DOI: 10.1016/j.ymthe.2018.05.015] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2018] [Revised: 05/17/2018] [Accepted: 05/18/2018] [Indexed: 12/19/2022] Open
Abstract
Treatment of myocardial infarction (MI) with bone marrow cells (BMCs) improves post-MI cardiac function in rodents. However, clinical trials of BMC therapy have been less effective. While most rodent experiments use young healthy donors, patients undergoing autologous cell therapy are older and post-MI. We previously demonstrated that BMCs from aged and post-MI donor mice are therapeutically impaired, and that donor MI induces inflammatory changes in BMC composition including reduced levels of B lymphocytes. Here, we hypothesized that B cell alterations in bone marrow account for the reduced therapeutic potential of post-MI and aged donor BMCs. Injection of BMCs from increasingly aged donor mice resulted in progressively poorer cardiac function and larger infarct size. Flow cytometry revealed fewer B cells in aged donor bone marrow. Therapeutic efficacy of young healthy donor BMCs was reduced by depletion of B cells. Implantation of intact or lysed B cells improved cardiac function, whereas intact or lysed T cells provided only minor benefit. We conclude that B cells play an important paracrine role in effective BMC therapy for MI. Reduction of bone marrow B cells because of age or MI may partially explain why clinical autologous cell therapy has not matched the success of rodent experiments.
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Affiliation(s)
- Songtao An
- Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143, USA; Division of Cardiology, Henan Provincial People's Hospital, Zhengzhou University, Zhengzhou, Henan 450003, China
| | - Xiaoyin Wang
- Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Melissa A Ruck
- Department of Pediatrics, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Hilda J Rodriguez
- Division of Cardiology, University of California, San Francisco, San Francisco, CA 94143, USA; Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Dmitry S Kostyushev
- Division of Cardiology, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Monika Varga
- Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Emmy Luu
- Division of Cardiology, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Ronak Derakhshandeh
- Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Sergey V Suchkov
- Center for Personalized Medicine, Sechenov University, Moscow, Russia; Department for Translational Medicine, Moscow Engineering Physical Institute, Moscow, Russia
| | - Scott C Kogan
- Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Michelle L Hermiston
- Department of Pediatrics, University of California, San Francisco, San Francisco, CA 94143, USA; Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Matthew L Springer
- Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143, USA; Division of Cardiology, University of California, San Francisco, San Francisco, CA 94143, USA; Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA.
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Tachibana A. [6. Application of MRI Technology to the Regenerative Medicine in Heart Disease Using Induced Pluripotent Stem Cells]. Nihon Hoshasen Gijutsu Gakkai Zasshi 2018; 74:491-498. [PMID: 29780049 DOI: 10.6009/jjrt.2018_jsrt_74.5.491] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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22
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Bianconi V, Sahebkar A, Kovanen P, Bagaglia F, Ricciuti B, Calabrò P, Patti G, Pirro M. Endothelial and cardiac progenitor cells for cardiovascular repair: A controversial paradigm in cell therapy. Pharmacol Ther 2017; 181:156-168. [PMID: 28827151 DOI: 10.1016/j.pharmthera.2017.08.004] [Citation(s) in RCA: 94] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/09/2023]
Abstract
Stem cells have the potential to differentiate into cardiovascular cell lineages and to stimulate tissue regeneration in a paracrine/autocrine manner; thus, they have been extensively studied as candidate cell sources for cardiovascular regeneration. Several preclinical and clinical studies addressing the therapeutic potential of endothelial progenitor cells (EPCs) and cardiac progenitor cells (CPCs) in cardiovascular diseases have been performed. For instance, autologous EPC transplantation and EPC mobilization through pharmacological agents contributed to vascular repair and neovascularization in different animal models of limb ischemia and myocardial infarction. Also, CPC administration and in situ stimulation of resident CPCs have been shown to improve myocardial survival and function in experimental models of ischemic heart disease. However, clinical studies using EPC- and CPC-based therapeutic approaches have produced mixed results. In this regard, intracoronary, intra-myocardial or intramuscular injection of either bone marrow-derived or peripheral blood progenitor cells has improved pathological features of tissue ischemia in humans, despite modest or no clinical benefit has been observed in most cases. Also, the intriguing scientific background surrounding the potential clinical applications of EPC capture stenting is still waiting for a confirmatory proof. Moreover, clinical findings on the efficacy of CPC-based cell therapy in heart diseases are still very preliminary and based on small-size studies. Despite promising evidence, widespread clinical application of both EPCs and CPCs remains delayed due to several unresolved issues. The present review provides a summary of the different applications of EPCs and CPCs for cardiovascular cell therapy and underlies their advantages and limitations.
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Affiliation(s)
- Vanessa Bianconi
- Unit of Internal Medicine, Department of Medicine, University of Perugia, Perugia, Italy
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Francesco Bagaglia
- Unit of Internal Medicine, Department of Medicine, University of Perugia, Perugia, Italy
| | - Biagio Ricciuti
- Department of Medical Oncology, S. Maria della Misericordia Hospital, Perugia, Italy
| | - Paolo Calabrò
- Division of Cardiology, Second University of Naples, Department of Cardio-Thoracic and Respiratory Sciences, Italy
| | - Giuseppe Patti
- Unit of Cardiovascular Science, Campus Bio-Medico University of Rome, Italy
| | - Matteo Pirro
- Unit of Internal Medicine, Department of Medicine, University of Perugia, Perugia, Italy.
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Abstract
Skeletal myoblasts function as precursors to adult skeletal myocytes. More so than other muscle progenitors, their capacity for de novo self-renewal and their positive functional effects in the cardiac environment have been demonstrated, even though they do not attain a cardiomyocyte phenotype. Autologous skeletal myoblasts are easily procured by established methods and can be administered into diseased myocardium safely and without technical difficulty, features that at this time set them apart from any other myogenic cell. Clinical studies in patients with chronic myocardial disease have consistently reported modest improvements in ventricular function and clinical status. Data from the Myogenesis Heart efficiency and Regeneration Trial (MYOHEART) trial are currently being evaluated. Larger, randomized, placebo-controlled studies in patients with congestive heart failure due to postinfarction systolic left ventricular dysfunction are under way, such as Myoblast Autologous Grafting in Ischemic Cardiomayopathy (MAGIC) and Multicenter Study of the Safety and Cardiovascular Effects Of Myoblasts in Congestive Heart Failure (MARVEL). The future role of skeletal myoblasts in the clinical setting will be determined by the results of randomized trials as well as by the investigation of subsequent generations of myoblasts, engineered for enhanced efficacy.
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Affiliation(s)
- Warren Sherman
- Division of Cardiology, Department of Medicine, College of Physicians & Surgeons, Columbia University, New York, NY, USA
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24
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Huwer H, Winning J, Vollmar B, Welter C, Löhbach C, Menger MD, Schäfers HJ. Long-Term Cell Survival and Hemodynamic Improvements after Neonatal Cardiomyocyte and Satellite Cell Transplantation into Healed Myocardial Cryoinfarcted Lesions in Rats. Cell Transplant 2017; 12:757-67. [PMID: 14653622 DOI: 10.3727/000000003108747361] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Cell engraftment is a new strategy for the repair of ischemic myocardial lesions. The hemodynamic effectiveness of this strategy, however, is not completely elucidated yet. In a rat model of cryothermia-induced myocardial dysfunction, we investigated whether syngeneic transplantation of neonatal cardiomyocytes or satellite cells is able to improve left ventricular performance. Myocardial infarction was induced in female Lewis rats by a standardized cryolesion to the obtuse margin of the left ventricle. After 4 weeks, 5 × 106 genetically male neonatal cardiomyocytes (n= 16) or satellite cells (n = 16) were engrafted into the myocardial scar. Sham-transplanted animals (n = 15) received injections with cell-free medium. Sham-operated animals (n = 15) served as controls. Left ventricular performance was analyzed 4 months after cell engraftment. Chimerism after this sex-mismatched transplantation was evaluated by detection of PCR-amplified DNA of the Y chromosome. The average heart weight of the infarcted animals significantly exceeded that of controls (p < 0.05). In sham-transplanted animals, mean aortic pressure, left ventricular systolic pressure, aortic flow (indicator of cardiac output), and left ventricular systolic reserve were significantly lower (p < 0.05) compared with sham-operated controls. This was associated with deterioration of ventricular diastolic function (maximal negative dP/dt, time constants of isovolumic relaxation; p < 0.05). Transplantation of satellite cells was found more effective than transplantation of neonatal cardiomyocytes, resulting in i) normalization of mean aortic pressure compared with sham-operated controls, and ii) significantly improved left ventricular systolic pressure and aortic flow (p < 0.05) compared with sham-transplanted animals. Left ventricular systolic reserve and diastolic function, however, were improved by neither satellite cell nor neonatal cardiomyocyte transplantation. Analysis of male genomic DNA revealed 3.98 ± 2.70 ng in hearts after neonatal cardiomyocyte engraftment and 6.16 ± 4.05 ng in hearts after satellite cell engraftment, representing approximately 103 viable engrafted cells per heart. Our study demonstrates i) long-term survival of both neonatal cardiomyocytes and satellite cells after transplantation into cryoinfarcted rat hearts, ii) slight superiority of satellite cells over neonatal cardiomyocytes in improving global left ventricular pump performance, and iii) no effect of both transplant procedures on diastolic dysfunction.
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Affiliation(s)
- Hanno Huwer
- Department of Thoracic and Cardiovascular Surgery, University of Saarland, D-66421 Homburg/Saar, Germany
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25
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Cambria E, Pasqualini FS, Wolint P, Günter J, Steiger J, Bopp A, Hoerstrup SP, Emmert MY. Translational cardiac stem cell therapy: advancing from first-generation to next-generation cell types. NPJ Regen Med 2017; 2:17. [PMID: 29302353 PMCID: PMC5677990 DOI: 10.1038/s41536-017-0024-1] [Citation(s) in RCA: 93] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2016] [Revised: 05/16/2017] [Accepted: 05/22/2017] [Indexed: 12/16/2022] Open
Abstract
Acute myocardial infarction and chronic heart failure rank among the major causes of morbidity and mortality worldwide. Except for heart transplantation, current therapy options only treat the symptoms but do not cure the disease. Stem cell-based therapies represent a possible paradigm shift for cardiac repair. However, most of the first-generation approaches displayed heterogeneous clinical outcomes regarding efficacy. Stemming from the desire to closely match the target organ, second-generation cell types were introduced and rapidly moved from bench to bedside. Unfortunately, debates remain around the benefit of stem cell therapy, optimal trial design parameters, and the ideal cell type. Aiming at highlighting controversies, this article provides a critical overview of the translation of first-generation and second-generation cell types. It further emphasizes the importance of understanding the mechanisms of cardiac repair and the lessons learned from first-generation trials, in order to improve cell-based therapies and to potentially finally implement cell-free therapies.
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Affiliation(s)
- Elena Cambria
- Institute for Regenerative Medicine, University of Zurich, Zurich, 8044 Switzerland.,Division of Surgical Research, University Hospital of Zurich, Zurich, 8091 Switzerland
| | | | - Petra Wolint
- Institute for Regenerative Medicine, University of Zurich, Zurich, 8044 Switzerland.,Division of Surgical Research, University Hospital of Zurich, Zurich, 8091 Switzerland
| | - Julia Günter
- Institute for Regenerative Medicine, University of Zurich, Zurich, 8044 Switzerland.,Division of Surgical Research, University Hospital of Zurich, Zurich, 8091 Switzerland
| | - Julia Steiger
- Institute for Regenerative Medicine, University of Zurich, Zurich, 8044 Switzerland.,Division of Surgical Research, University Hospital of Zurich, Zurich, 8091 Switzerland
| | - Annina Bopp
- Institute for Regenerative Medicine, University of Zurich, Zurich, 8044 Switzerland.,Division of Surgical Research, University Hospital of Zurich, Zurich, 8091 Switzerland
| | - Simon P Hoerstrup
- Institute for Regenerative Medicine, University of Zurich, Zurich, 8044 Switzerland.,Division of Surgical Research, University Hospital of Zurich, Zurich, 8091 Switzerland.,Heart Center Zurich, University Hospital of Zurich, Zurich, Switzerland.,Wyss Translational Center Zurich, Zurich, Switzerland
| | - Maximilian Y Emmert
- Institute for Regenerative Medicine, University of Zurich, Zurich, 8044 Switzerland.,Division of Surgical Research, University Hospital of Zurich, Zurich, 8091 Switzerland.,Heart Center Zurich, University Hospital of Zurich, Zurich, Switzerland.,Wyss Translational Center Zurich, Zurich, Switzerland
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26
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Wang Z, Dong N, Niu Y, Zhang Z, Zhang C, Liu M, Zhou T, Wu Q, Cheng K. Transplantation of human villous trophoblasts preserves cardiac function in mice with acute myocardial infarction. J Cell Mol Med 2017; 21:2432-2440. [PMID: 28524367 PMCID: PMC5618685 DOI: 10.1111/jcmm.13165] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2016] [Accepted: 02/05/2017] [Indexed: 12/13/2022] Open
Abstract
Over the past decade, cell therapies have provided promising strategies for the treatment of ischaemic cardiomyopathy. Particularly, the beneficial effects of stem cells, including bone marrow stem cells (BMSCs), endothelial progenitor cells (EPCs), mesenchymal stem cells (MSCs), embryonic stem cells (ESCs), and induced pluripotent stem cells (iPSCs), have been demonstrated by substantial preclinical and clinical studies. Nevertheless stem cell therapy is not always safe and effective. Hence, there is an urgent need for alternative sources of cells to promote cardiac regeneration. Human villous trophoblasts (HVTs) play key roles in embryonic implantation and placentation. In this study, we show that HVTs can promote tube formation of human umbilical vein endothelial cells (HUVECs) on Matrigel and enhance the resistance of neonatal rat cardiomyocytes (NRCMs) to oxidative stress in vitro. Delivery of HVTs to ischaemic area of heart preserved cardiac function and reduced fibrosis in a mouse model of acute myocardial infarction (AMI). Histological analysis revealed that transplantation of HVTs promoted angiogenesis in AMI mouse hearts. In addition, our data indicate that HVTs exert their therapeutic benefit through paracrine mechanisms. Meanwhile, injection of HVTs to mouse hearts did not elicit severe immune response. Taken together, our study demonstrates HVT may be used as a source for cell therapy or a tool to study cell-derived soluble factors for AMI treatment.
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Affiliation(s)
- Zegen Wang
- Cyrus Tang Hematology Center and Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Ningzheng Dong
- Cyrus Tang Hematology Center and Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China.,Thrombosis and Hemostasis Key Laboratory, Ministry of Education Engineering Center for Hematological Disease, Jiangsu Institute of Hematology, the First Affiliated Hospital of Soochow University, Suzhou, China
| | - Yayan Niu
- Cyrus Tang Hematology Center and Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Zhiwei Zhang
- Cyrus Tang Hematology Center and Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Ce Zhang
- Cyrus Tang Hematology Center and Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Meng Liu
- Cyrus Tang Hematology Center and Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Tiantian Zhou
- Cyrus Tang Hematology Center and Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Qingyu Wu
- Cyrus Tang Hematology Center and Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China.,Molecular Cardiology, Cleveland Clinic, Cleveland, OH, USA
| | - Ke Cheng
- Cyrus Tang Hematology Center and Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China.,Department of Molecular Biomedical Sciences and Comparative Medicine Institute, North Carolina State University, Raleigh, NC, USA.,Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Chapel Hill, NC, USA
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27
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Xu X, Wang W, Li Z, Kratz K, Ma N, Lendlein A. Surface geometry of poly(ether imide) boosts mouse pluripotent stem cell spontaneous cardiomyogenesis via modulating the embryoid body formation process. Clin Hemorheol Microcirc 2017; 64:367-382. [DOI: 10.3233/ch-168107] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Affiliation(s)
- Xun Xu
- Institute of Biomaterial Science and Berlin-Brandenburg Center for Regenerative Therapies, Helmholtz-Zentrum Geesthacht, Teltow, Germany
- Institute of Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany
| | - Weiwei Wang
- Institute of Biomaterial Science and Berlin-Brandenburg Center for Regenerative Therapies, Helmholtz-Zentrum Geesthacht, Teltow, Germany
| | - Zhengdong Li
- Institute of Biomaterial Science and Berlin-Brandenburg Center for Regenerative Therapies, Helmholtz-Zentrum Geesthacht, Teltow, Germany
- Institute of Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany
| | - Karl Kratz
- Institute of Biomaterial Science and Berlin-Brandenburg Center for Regenerative Therapies, Helmholtz-Zentrum Geesthacht, Teltow, Germany
- Helmholtz Virtual Institute - Multifunctional Materials in Medicine, Berlin and Teltow, Teltow, Germany
| | - Nan Ma
- Institute of Biomaterial Science and Berlin-Brandenburg Center for Regenerative Therapies, Helmholtz-Zentrum Geesthacht, Teltow, Germany
- Institute of Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany
- Helmholtz Virtual Institute - Multifunctional Materials in Medicine, Berlin and Teltow, Teltow, Germany
| | - Andreas Lendlein
- Institute of Biomaterial Science and Berlin-Brandenburg Center for Regenerative Therapies, Helmholtz-Zentrum Geesthacht, Teltow, Germany
- Institute of Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany
- Helmholtz Virtual Institute - Multifunctional Materials in Medicine, Berlin and Teltow, Teltow, Germany
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28
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Arbatlı S, Aslan GS, Kocabaş F. Stem Cells in Regenerative Cardiology. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 1079:37-53. [PMID: 29064067 DOI: 10.1007/5584_2017_113] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The common prevalence of heart failure and limitations in its treatment are leading cause of attention and interest towards the induction of cardiac regeneration with novel approaches. Recent studies provide growing evidence regarding bona fide cardiac regeneration post genetic manipulations, administration of stimulatory factors and myocardial injuries in animal models and human studies. To this end, stem cells of different sources have been tested to treat heart failure for the development of cellular therapies. Endogenous and exogenous stem cells sources used in regenerative cardiology have provided a proof of concept and applicability of cellular therapies in myocardial improvement. Recent clinical studies, especially, based on the endogenous cardiac progenitor and stem cells highlighted the possibility to regenerate lost cardiomyocytes in the myocardium. This review discusses emerging concepts in cardiac stem cell therapy, their sources and route of administration, and plausibility of de novo cardiomyocyte formation.
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Affiliation(s)
- Semih Arbatlı
- Regenerative Biology Research Laboratory, Department of Genetics and Bioengineering, Yeditepe University, Istanbul, Turkey
- Department of Biotechnology, Institute of Science, Yeditepe University, Istanbul, Turkey
| | - Galip Servet Aslan
- Regenerative Biology Research Laboratory, Department of Genetics and Bioengineering, Yeditepe University, Istanbul, Turkey
- Department of Biotechnology, Institute of Science, Yeditepe University, Istanbul, Turkey
| | - Fatih Kocabaş
- Regenerative Biology Research Laboratory, Department of Genetics and Bioengineering, Yeditepe University, Istanbul, Turkey.
- Department of Biotechnology, Institute of Science, Yeditepe University, Istanbul, Turkey.
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29
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Feyen DA, Gaetani R, Doevendans PA, Sluijter JP. Stem cell-based therapy: Improving myocardial cell delivery. Adv Drug Deliv Rev 2016; 106:104-115. [PMID: 27133386 DOI: 10.1016/j.addr.2016.04.023] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2016] [Revised: 04/19/2016] [Accepted: 04/20/2016] [Indexed: 12/15/2022]
Abstract
Stem cell-based therapies form an exciting new class of medicine that attempt to provide the body with the building blocks required for the reconstruction of damaged organs. However, delivering cells to the correct location, while preserving their integrity and functional properties, is a complex undertaking. These challenges have led to the development of a highly dynamic interdisciplinary research field, wherein medical, biological, and chemical sciences have collaborated to develop strategies to overcome the physiological barriers imposed on the cellular therapeutics. In this respect, improving the acute retention and subsequent survival of stem cells is key to effectively increase the effect of the therapy, while proper tissue integration is imperative for stem cells to functionally replace lost cells in damaged organs. In this review, we will use the heart as an example to highlight the current knowledge of therapeutic stem cell utilization, the existing pitfalls and limitations, and the approaches that have been developed to overcome them.
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Bruyneel AAN, Sehgal A, Malandraki-Miller S, Carr C. Stem Cell Therapy for the Heart: Blind Alley or Magic Bullet? J Cardiovasc Transl Res 2016; 9:405-418. [PMID: 27542008 PMCID: PMC5153828 DOI: 10.1007/s12265-016-9708-y] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2016] [Accepted: 08/05/2016] [Indexed: 12/15/2022]
Abstract
When stressed by ageing or disease, the adult human heart is unable to regenerate, leading to scarring and hypertrophy and eventually heart failure. As a result, stem cell therapy has been proposed as an ultimate therapeutic strategy, as stem cells could limit adverse remodelling and give rise to new cardiomyocytes and vasculature. Unfortunately, the results from clinical trials to date have been largely disappointing. In this review, we discuss the current status of the field and describe various limitations and how future work may attempt to resolve these to make way to successful clinical translation.
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Affiliation(s)
- Arne A N Bruyneel
- Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, UK
| | | | | | - Carolyn Carr
- Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, UK.
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31
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Meissner K, Heydrich B, Jedlitschky G, Meyer Zu Schwabedissen H, Mosyagin I, Dazert P, Eckel L, Vogelgesang S, Warzok RW, Böhm M, Lehmann C, Wendt M, Cascorbi I, Kroemer HK. The ATP-binding Cassette Transporter ABCG2 (BCRP), a Marker for Side Population Stem Cells, Is Expressed in Human Heart. J Histochem Cytochem 2016; 54:215-21. [PMID: 16116030 DOI: 10.1369/jhc.5a6750.2005] [Citation(s) in RCA: 69] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
Efforts to improve severely impaired myocardial function include transplantation of autologous hematopoietic side population (SP) stem cells. The transmembrane ABC-type (ATP binding cassette) half-transporter ABCG2 (BCRP) serves as a marker protein for SP cell selection. We have recently shown that other ABC transport proteins such as ABCB1 and ABCC5 are differentially expressed in normal and diseased human heart. Here we investigated localization and individual ABCG2 expression in 15 ventricular (including 10 cardiomyopathic) and 51 auricular heart tissue samples using immunohistochemistry, confocal laser scanning fluorescence microscopy, and real-time RT-PCR. Individual genotypes were assigned using PCR–restriction fragment length polymorphism (RFLP) analysis and subsequently correlated to ABCG2 mRNA levels. ABCG2 was localized in endothelial cells of capillaries and arterioles of all samples. Ventricular samples from cardiomyopathic hearts exhibited significantly increased levels of ABCG2 mRNA (ABCG2/18S rRNA: 1.08 ± 0.30 × 10−7; p = 0.028 (dilative cardiomyopathy) and 1.16 ± 0.46 × 10−7; p = 0.009 (ischemic cardiomyopathy) compared with 0.44 ± 0.26 × 10−7 in nonfailing hearts). The individual haplotypes were not associated with altered mRNA expression. ABCG2 is variably expressed in endothelial cells of human heart, where it may function as a protective barrier against cardiotoxic drugs such as anthracyclines or mitoxantrone. ABCG2 expression is induced in dilative and ischemic cardiomyopathies.
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Affiliation(s)
- Konrad Meissner
- Institut für Pharmakologie, Ernst-Moritz-Arndt-Universität Greifswald, Friedrich-Loeffler-Str. 23d, D-17487 Greifswald, Germany
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32
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Sun R, Li X, Liu M, Zeng Y, Chen S, Zhang P. Advances in stem cell therapy for cardiovascular disease (Review). Int J Mol Med 2016; 38:23-9. [PMID: 27220939 PMCID: PMC4899023 DOI: 10.3892/ijmm.2016.2607] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2015] [Accepted: 04/28/2016] [Indexed: 12/02/2022] Open
Abstract
Cardiovascular disease constitutes the primary cause of mortality and morbidity worldwide, and represents a group of disorders associated with the loss of cardiac function. Despite considerable advances in the understanding of the pathologic mechanisms of the disease, the majority of the currently available therapies remain at best palliative, since the problem of cardiac tissue loss has not yet been addressed. Indeed, few therapeutic approaches offer direct tissue repair and regeneration, whereas the majority of treatment options aim to limit scar formation and adverse remodeling, while improving myocardial function. Of all the existing therapeutic approaches, the problem of cardiac tissue loss is addressed uniquely by heart transplantation. Nevertheless, alternative options, particularly stem cell therapy, has emerged as a novel and promising approach. This approach involves the transplantation of healthy and functional cells to promote the renewal of damaged cells and repair injured tissue. Bone marrow precursor cells were the first cell type used in clinical studies, and subsequently, preclinical and clinical investigations have been extended to the use of various populations of stem cells. This review addresses the present state of research as regards stem cell therapy for cardiovascular disease.
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Affiliation(s)
- Rongrong Sun
- Xuzhou Central Hospital, The Affiliated Xuzhou Hospital of Medical College of Southest University, Xuzhou, Jiangsu 221009, P.R. China
| | - Xianchi Li
- Xuzhou Central Hospital, The Affiliated Xuzhou Hospital of Medical College of Southest University, Xuzhou, Jiangsu 221009, P.R. China
| | - Min Liu
- Xuzhou Central Hospital, The Affiliated Xuzhou Hospital of Medical College of Southest University, Xuzhou, Jiangsu 221009, P.R. China
| | - Yi Zeng
- Xuzhou Central Hospital, The Affiliated Xuzhou Hospital of Medical College of Southest University, Xuzhou, Jiangsu 221009, P.R. China
| | - Shuang Chen
- Xuzhou Central Hospital, The Affiliated Xuzhou Hospital of Medical College of Southest University, Xuzhou, Jiangsu 221009, P.R. China
| | - Peying Zhang
- Xuzhou Central Hospital, The Affiliated Xuzhou Hospital of Medical College of Southest University, Xuzhou, Jiangsu 221009, P.R. China
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33
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State-of-the-Art Review of 3D Bioprinting for Cardiovascular Tissue Engineering. Ann Biomed Eng 2016; 45:195-209. [DOI: 10.1007/s10439-016-1607-5] [Citation(s) in RCA: 159] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2016] [Accepted: 04/02/2016] [Indexed: 12/24/2022]
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Xu Y, Guan J. Biomaterial property-controlled stem cell fates for cardiac regeneration. Bioact Mater 2016; 1:18-28. [PMID: 29744392 PMCID: PMC5883968 DOI: 10.1016/j.bioactmat.2016.03.002] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2016] [Revised: 03/17/2016] [Accepted: 03/19/2016] [Indexed: 12/13/2022] Open
Abstract
Myocardial infarction (MI) affects more than 8 million people in the United States alone. Due to the insufficient regeneration capacity of the native myocardium, one widely studied approach is cardiac tissue engineering, in which cells are delivered with or without biomaterials and/or regulatory factors to fully regenerate the cardiac functions. Specifically, in vitro cardiac tissue engineering focuses on using biomaterials as a reservoir for cells to attach, as well as a carrier of various regulatory factors such as growth factors and peptides, providing high cell retention and a proper microenvironment for cells to migrate, grow and differentiate within the scaffolds before implantation. Many studies have shown that the full establishment of a functional cardiac tissue in vitro requires synergistic actions between the seeded cells, the tissue culture condition, and the biochemical and biophysical environment provided by the biomaterials-based scaffolds. Proper electrical stimulation and mechanical stretch during the in vitro culture can induce the ordered orientation and differentiation of the seeded cells. On the other hand, the various scaffolds biochemical and biophysical properties such as polymer composition, ligand concentration, biodegradability, scaffold topography and mechanical properties can also have a significant effect on the cellular processes.
Cell therapy is an attractive approach for cardiac regeneration after myocardial infarction. Biomaterials are used as cell carriers. This review highlights how biochemical and biophysical properties of biomaterials affect cell fates.
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Affiliation(s)
- Yanyi Xu
- Department of Materials Science and Engineering, The Ohio State University, Columbus, OH, USA
| | - Jianjun Guan
- Department of Materials Science and Engineering, The Ohio State University, Columbus, OH, USA
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35
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ASLAN GS, MISIR DG, KOCABAŞ F. Underlying mechanisms and prospects of heart regeneration. Turk J Biol 2016. [DOI: 10.3906/biy-1506-14] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
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36
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Jewhurst K, McLaughlin KA. Beyond the Mammalian Heart: Fish and Amphibians as a Model for Cardiac Repair and Regeneration. J Dev Biol 2015; 4:jdb4010001. [PMID: 29615574 PMCID: PMC5831815 DOI: 10.3390/jdb4010001] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2015] [Revised: 12/04/2015] [Accepted: 12/17/2015] [Indexed: 12/12/2022] Open
Abstract
The epidemic of heart disease, the leading cause of death worldwide, is made worse by the fact that the adult mammalian heart is especially poor at repair. Damage to the mammal heart-such as that caused by myocardial infarction-leads to scarring, resulting in cardiac dysfunction and heart failure. In contrast, the hearts of fish and urodele amphibians are capable of complete regeneration of cardiac tissue from multiple types of damage, with full restoration of functionality. In the last decades, research has revealed a wealth of information on how these animals are able to perform this remarkable feat, and non-mammalian models of heart repair have become a burgeoning new source of data on the morphological, cellular, and molecular processes necessary to heal cardiac damage. In this review we present the major findings from recent research on the underlying mechanisms of fish and amphibian heart regeneration. We also discuss the tools and techniques that have been developed to answer these important questions.
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Affiliation(s)
- Kyle Jewhurst
- Department of Biology, Tufts University, Medford, MA 02155, USA.
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37
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Le-Buu Pham T, Nguyen TT, Thi-Van Bui A, Pham HT, Phan NK, Thi-Thu Nguyen M, Van Pham P. Preliminary evaluation of treatment efficacy of umbilical cord blood-derived mesenchymal stem cell-differentiated cardiac progenitor cells in a myocardial injury mouse model. BIOMEDICAL RESEARCH AND THERAPY 2015. [DOI: 10.7603/s40730-015-0032-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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38
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Abstract
After decades of believing the heart loses the ability to regenerate soon after birth, numerous studies are now reporting that the adult heart may indeed be capable of regeneration, although the magnitude of new cardiac myocyte formation varies greatly. While this debate has energized the field of cardiac regeneration and led to a dramatic increase in our understanding of cardiac growth and repair, it has left much confusion in the field as to the prospects of regenerating the heart. Studies applying modern techniques of genetic lineage tracing and carbon-14 dating have begun to establish limits on the amount of endogenous regeneration after cardiac injury, but the underlying cellular mechanisms of this regeneration remained unclear. These same studies have also revealed an astonishing capacity for cardiac repair early in life that is largely lost with adult differentiation and maturation. Regardless, this renewed focus on cardiac regeneration as a therapeutic goal holds great promise as a novel strategy to address the leading cause of death in the developed world.
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Affiliation(s)
- Yiqiang Zhang
- Center for Cardiovascular Biology, Institute for Stem Cell Research and Division of Cardiology, Departments of Medicine and Pathology, University of Washington, Seattle, Washington
| | - John Mignone
- Center for Cardiovascular Biology, Institute for Stem Cell Research and Division of Cardiology, Departments of Medicine and Pathology, University of Washington, Seattle, Washington
| | - W Robb MacLellan
- Center for Cardiovascular Biology, Institute for Stem Cell Research and Division of Cardiology, Departments of Medicine and Pathology, University of Washington, Seattle, Washington
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39
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Preskey D, Allison TF, Jones M, Mamchaoui K, Unger C. Synthetically modified mRNA for efficient and fast human iPS cell generation and direct transdifferentiation to myoblasts. Biochem Biophys Res Commun 2015; 473:743-51. [PMID: 26449459 DOI: 10.1016/j.bbrc.2015.09.102] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2015] [Accepted: 09/18/2015] [Indexed: 10/22/2022]
Abstract
Synthetic mRNA transfection enables efficient and controlled gene expression in human cells, without genome integrations. Further, modifications to the mRNA and transfection protocol now allow for repeated transfection and long-term gene expression of an otherwise short-lived mRNA expression. This is mainly achieved through introducing modified nucleosides and interferon suppression. In this study we provide an overview and details of the advanced synthesis and modifications of mRNA originally developed for reprogramming. This mRNA allows for very efficient transfection of fibroblasts enabling the generation of high quality human iPS cells with a six-factor mRNA cocktail in 9 days. Furthermore, we synthesised and transfected modified MYOD1 mRNA to transdifferentiate human fibroblasts into myoblast-like cells without a transgene footprint. This efficient and integration-free mRNA technology opens the door for safe and controlled gene expression to reverse or redirect cell fate.
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Affiliation(s)
- David Preskey
- Centre for Stem Cell Biology, Department of Biomedical Science, The University of Sheffield, Sheffield, S10 2TN, UK
| | - Thomas F Allison
- Centre for Stem Cell Biology, Department of Biomedical Science, The University of Sheffield, Sheffield, S10 2TN, UK
| | - Mark Jones
- Centre for Stem Cell Biology, Department of Biomedical Science, The University of Sheffield, Sheffield, S10 2TN, UK
| | - Kamel Mamchaoui
- Sorbonne Universités, UPMC Univ Paris 06, INSERM UMRS974, CNRS FRE3617, Center for Research in Myology, 47 Boulevard de l'hôpital, 75013 Paris, France
| | - Christian Unger
- Centre for Stem Cell Biology, Department of Biomedical Science, The University of Sheffield, Sheffield, S10 2TN, UK.
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40
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Dynamic Support Culture of Murine Skeletal Muscle-Derived Stem Cells Improves Their Cardiogenic Potential In Vitro. Stem Cells Int 2015; 2015:247091. [PMID: 26357517 PMCID: PMC4556334 DOI: 10.1155/2015/247091] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2015] [Revised: 06/27/2015] [Accepted: 07/02/2015] [Indexed: 12/04/2022] Open
Abstract
Ischemic heart disease is the main cause of death in western countries and its burden is increasing worldwide. It typically involves irreversible degeneration and loss of myocardial tissue leading to poor prognosis and fatal outcome. Autologous cells with the potential to regenerate damaged heart tissue would be an ideal source for cell therapeutic approaches. Here, we compared different methods of conditional culture for increasing the yield and cardiogenic potential of murine skeletal muscle-derived stem cells. A subpopulation of nonadherent cells was isolated from skeletal muscle by preplating and applying cell culture conditions differing in support of cluster formation. In contrast to static culture conditions, dynamic culture with or without previous hanging drop preculture led to significantly increased cluster diameters and the expression of cardiac specific markers on the protein and mRNA level. Whole-cell patch-clamp studies revealed similarities to pacemaker action potentials and responsiveness to cardiac specific pharmacological stimuli. This data indicates that skeletal muscle-derived stem cells are capable of adopting enhanced cardiac muscle cell-like properties by applying specific culture conditions. Choosing this route for the establishment of a sustainable, autologous source of cells for cardiac therapies holds the potential of being clinically more acceptable than transgenic manipulation of cells.
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41
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Perbellini F, Carr CA. Uterine cells-an immunoprivileged cell source for therapy-but are they for everyone? J Mol Cell Cardiol 2015; 85:127-30. [PMID: 26027783 DOI: 10.1016/j.yjmcc.2015.05.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2015] [Revised: 05/21/2015] [Accepted: 05/22/2015] [Indexed: 10/23/2022]
Affiliation(s)
| | - Carolyn A Carr
- Department of Physiology, Anatomy & Genetics, University of Oxford, Oxford, UK.
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42
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Hastings CL, Roche ET, Ruiz-Hernandez E, Schenke-Layland K, Walsh CJ, Duffy GP. Drug and cell delivery for cardiac regeneration. Adv Drug Deliv Rev 2015; 84:85-106. [PMID: 25172834 DOI: 10.1016/j.addr.2014.08.006] [Citation(s) in RCA: 136] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2014] [Revised: 07/24/2014] [Accepted: 08/15/2014] [Indexed: 12/12/2022]
Abstract
The spectrum of ischaemic cardiomyopathy, encompassing acute myocardial infarction to congestive heart failure is a significant clinical issue in the modern era. This group of diseases is an enormous source of morbidity and mortality and underlies significant healthcare costs worldwide. Cardiac regenerative therapy, whereby pro-regenerative cells, drugs or growth factors are administered to damaged and ischaemic myocardium has demonstrated significant potential, especially preclinically. While some of these strategies have demonstrated a measure of success in clinical trials, tangible clinical translation has been slow. To date, the majority of clinical studies and a significant number of preclinical studies have utilised relatively simple delivery methods for regenerative therapeutics, such as simple systemic administration or local injection in saline carrier vehicles. Here, we review cardiac regenerative strategies with a particular focus on advanced delivery concepts as a potential means to enhance treatment efficacy and tolerability and ultimately, clinical translation. These include (i) delivery of therapeutic agents in biomaterial carriers, (ii) nanoparticulate encapsulation, (iii) multimodal therapeutic strategies and (iv) localised, minimally invasive delivery via percutaneous transcatheter systems.
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43
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On the existence of cardiomesenchymal stem cells. Med Hypotheses 2015; 84:511-5. [PMID: 25769705 DOI: 10.1016/j.mehy.2015.02.011] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2014] [Accepted: 02/20/2015] [Indexed: 11/21/2022]
Abstract
The most efficient cells for cardiac regeneration are myocardium-resident cardiac stem cells. However, the limited availability of these cells restricts their utility for cardiac cellular therapy. Mesenchymal stem cells can differentiate into a wide variety of tissues, but it is not simple to accurately direct cell differentiation into a specific lineage, such as cardiac tissue; this renders a low efficiency for cardiac regeneration therapy. Given the heterogeneity of mesenchymal stem cells, it may be possible to find specific stem cell subpopulations with a definite differentiation capacity toward cardiac lineage. A parameter to assess cardiac differentiation specificity could be surface marker expression; a population with an immunophenotype similar to cardiac stem cells may have a superior therapeutic value than unsorted mesenchymal stem cells. We hypothesize the existence of a cell line that combines the expression of cardiac stem cell surface markers with those of mesenchymal stem cells, a suitable name for this population is cardiomesenchymal stem cells (CMSC); such cells would be ideal for cardiac regeneration.
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44
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Antanavičiūtė I, Ereminienė E, Vysockas V, Račkauskas M, Skipskis V, Rysevaitė K, Treinys R, Benetis R, Jurevičius J, Skeberdis VA. Exogenous connexin43-expressing autologous skeletal myoblasts ameliorate mechanical function and electrical activity of the rabbit heart after experimental infarction. Int J Exp Pathol 2014; 96:42-53. [PMID: 25529770 DOI: 10.1111/iep.12109] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2014] [Accepted: 10/26/2014] [Indexed: 12/19/2022] Open
Abstract
Acute myocardial infarction is one of the major causes of mortality worldwide. For regeneration of the rabbit heart after experimentally induced infarction we used autologous skeletal myoblasts (SMs) due to their high proliferative potential, resistance to ischaemia and absence of immunological and ethical concerns. The cells were characterized with muscle-specific and myogenic markers. Cell transplantation was performed by injection of cell suspension (0.5 ml) containing approximately 6 million myoblasts into the infarction zone. The animals were divided into four groups: (i) no injection; (ii) sham injected; (iii) injected with wild-type SMs; and (iv) injected with SMs expressing connexin43 fused with green fluorescent protein (Cx43EGFP). Left ventricular ejection fraction (LVEF) was evaluated by 2D echocardiography in vivo before infarction, when myocardium has stabilized after infarction, and 3 months after infarction. Electrical activity in the healthy and infarction zones of the heart was examined ex vivo in Langendorff-perfused hearts by optical mapping using di-4-ANEPPS, a potential sensitive fluorescent dye. We demonstrate that SMs in the coculture can couple electrically not only to abutted but also to remote acutely isolated allogenic cardiac myocytes through membranous tunnelling tubes. The beneficial effect of cellular therapy on LVEF and electrical activity was observed in the group of animals injected with Cx43EGFP-expressing SMs. L-type Ca(2+) current amplitude was approximately fivefold smaller in the isolated SMs compared to healthy myocytes suggesting that limited recovery of LVEF may be related to inadequate expression or function of L-type Ca(2+) channels in transplanted differentiating SMs.
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Affiliation(s)
- Ieva Antanavičiūtė
- Institute of Cardiology, Medical Academy, Lithuanian University of Health Sciences, Kaunas, Lithuania
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45
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Cui Z, Li RK. Feel isolated? Bridging communication between host myocardium and skeletal myoblast grafts. J Thorac Cardiovasc Surg 2014; 149:357-9. [PMID: 25451494 DOI: 10.1016/j.jtcvs.2014.09.110] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2014] [Accepted: 09/27/2014] [Indexed: 10/24/2022]
Affiliation(s)
- Zhi Cui
- Division of Cardiovascular Surgery, Toronto General Research Institute, University Health Network; and Department of Surgery, Division of Cardiac Surgery, University of Toronto, Toronto, Ontario, Canada
| | - Ren-Ke Li
- Division of Cardiovascular Surgery, Toronto General Research Institute, University Health Network; and Department of Surgery, Division of Cardiac Surgery, University of Toronto, Toronto, Ontario, Canada.
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46
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Chong JJH, Murry CE. Cardiac regeneration using pluripotent stem cells--progression to large animal models. Stem Cell Res 2014; 13:654-65. [PMID: 25087896 PMCID: PMC4253057 DOI: 10.1016/j.scr.2014.06.005] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2014] [Revised: 06/18/2014] [Accepted: 06/28/2014] [Indexed: 12/23/2022] Open
Abstract
Pluripotent stem cells (PSCs) have indisputable cardiomyogenic potential and therefore have been intensively investigated as a potential cardiac regenerative therapy. Current directed differentiation protocols are able to produce high yields of cardiomyocytes from PSCs and studies in small animal models of cardiovascular disease have proven sustained engraftment and functional efficacy. Therefore, the time is ripe for cardiac regenerative therapies using PSC derivatives to be tested in large animal models that more closely resemble the hearts of humans. In this review, we discuss the results of our recent study using human embryonic stem cell derived cardiomyocytes (hESC-CM) in a non-human primate model of ischemic cardiac injury. Large scale remuscularization, electromechanical coupling and short-term arrhythmias demonstrated by our hESC-CM grafts are discussed in the context of other studies using adult stem cells for cardiac regeneration.
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Affiliation(s)
- James J H Chong
- Department of Cardiology Westmead Hospital, Sydney, NSW, Australia; School of Medicine, University of Sydney, Sydney, NSW, Australia; Westmead Millennium Institute for Medical Research, Sydney, NSW, Australia; Center for Cardiovascular Biology, University of Washington, Seattle, WA, USA; Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, USA.
| | - Charles E Murry
- Center for Cardiovascular Biology, University of Washington, Seattle, WA, USA; Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, USA; Department of Pathology, University of Washington, Seattle, WA, USA; Department of Medicine/Cardiology, University of Washington, Seattle, WA, USA; Department of Bioengineering, University of Washington, Seattle, WA, USA
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47
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The Current State of Stem Cell Therapeutics: Canadian Approaches in the International Context. Can J Cardiol 2014; 30:1361-9. [DOI: 10.1016/j.cjca.2014.04.031] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2014] [Revised: 04/24/2014] [Accepted: 04/27/2014] [Indexed: 11/22/2022] Open
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Turner WS, Sandhu N, McCloskey KE. Tissue engineering: construction of a multicellular 3D scaffold for the delivery of layered cell sheets. J Vis Exp 2014:e51044. [PMID: 25350752 DOI: 10.3791/51044] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
Many tissues, such as the adult human hearts, are unable to adequately regenerate after damage.(2,3) Strategies in tissue engineering propose innovations to assist the body in recovery and repair. For example, TE approaches may be able to attenuate heart remodeling after myocardial infarction (MI) and possibly increase total heart function to a near normal pre-MI level.(4) As with any functional tissue, successful regeneration of cardiac tissue involves the proper delivery of multiple cell types with environmental cues favoring integration and survival of the implanted cell/tissue graft. Engineered tissues should address multiple parameters including: soluble signals, cell-to-cell interactions, and matrix materials evaluated as delivery vehicles, their effects on cell survival, material strength, and facilitation of cell-to-tissue organization. Studies employing the direct injection of graft cells only ignore these essential elements.(2,5,6) A tissue design combining these ingredients has yet to be developed. Here, we present an example of integrated designs using layering of patterned cell sheets with two distinct types of biological-derived materials containing the target organ cell type and endothelial cells for enhancing new vessels formation in the "tissue". Although these studies focus on the generation of heart-like tissue, this tissue design can be applied to many organs other than heart with minimal design and material changes, and is meant to be an off-the-shelf product for regenerative therapies. The protocol contains five detailed steps. A temperature sensitive Poly(N-isopropylacrylamide) (pNIPAAM) is used to coat tissue culture dishes. Then, tissue specific cells are cultured on the surface of the coated plates/micropattern surfaces to form cell sheets with strong lateral adhesions. Thirdly, a base matrix is created for the tissue by combining porous matrix with neovascular permissive hydrogels and endothelial cells. Finally, the cell sheets are lifted from the pNIPAAM coated dishes and transferred to the base element, making the complete construct.
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Affiliation(s)
| | - Nabjot Sandhu
- School of Engineering, University of California, Merced
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Zhao Y, Feric NT, Thavandiran N, Nunes SS, Radisic M. The role of tissue engineering and biomaterials in cardiac regenerative medicine. Can J Cardiol 2014; 30:1307-22. [PMID: 25442432 DOI: 10.1016/j.cjca.2014.08.027] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2014] [Revised: 08/27/2014] [Accepted: 08/28/2014] [Indexed: 12/21/2022] Open
Abstract
In recent years, the development of 3-dimensional engineered heart tissue (EHT) has made large strides forward because of advances in stem cell biology, materials science, prevascularization strategies, and nanotechnology. As a result, the role of tissue engineering in cardiac regenerative medicine has become multifaceted as new applications become feasible. Cardiac tissue engineering has long been established to have the potential to partially or fully restore cardiac function after cardiac injury. However, EHTs may also serve as surrogate human cardiac tissue for drug-related toxicity screening. Cardiotoxicity remains a major cause of drug withdrawal in the pharmaceutical industry. Unsafe drugs reach the market because preclinical evaluation is insufficient to weed out cardiotoxic drugs in all their forms. Bioengineering methods could provide functional and mature human myocardial tissues, ie, physiologically relevant platforms, for screening the cardiotoxic effects of pharmaceutical agents and facilitate the discovery of new therapeutic agents. Finally, advances in induced pluripotent stem cells have made patient-specific EHTs possible, which opens up the possibility of personalized medicine. Herein, we give an overview of the present state of the art in cardiac tissue engineering, the challenges to the field, and future perspectives.
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Affiliation(s)
- Yimu Zhao
- Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, Ontario, Canada
| | - Nicole T Feric
- Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada
| | - Nimalan Thavandiran
- Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, Ontario, Canada; Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada
| | - Sara S Nunes
- Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada; Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Milica Radisic
- Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, Ontario, Canada; Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada.
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Xue X, Huang J, Wang H. The study of the intercellular trafficking of the fusion proteins of herpes simplex virus protein VP22. PLoS One 2014; 9:e100840. [PMID: 24955582 PMCID: PMC4067403 DOI: 10.1371/journal.pone.0100840] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2013] [Accepted: 05/30/2014] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND Genetic modifications can improve the therapeutic efficacy of mesenchymal stem cell (MSC) transplantation in myocardial infarction. However, so far, the efficiency of MSC modification is very low. Seeking for a more efficient way of MSC modification, we investigated the possibility of employing the intercellular trafficking capacity of the herpes simplex virus type-1 tegument protein VP22 on the enhancement of MSC modification. METHODS Plasmids pVP22-myc, pVP22-EGFP, pEGFP-VP22, pVP22-hBcl-xL and phBcl-xL-VP22 were constructed for the expressions of the myc-tagged VP22 and the fusion proteins VP22-EGFP, EGFP-VP22, VP22-hBcl-xL and hBcl-xL-VP22. MSCs were isolated from rat bone marrow and the surface markers were identified by Flowcytometry. COS-1 cells were transfected with the above plasmids and co-cultured with untransfected MSCs, the intercellular transportations of the constructed proteins were studied by immunofluorescence. The solubility of VP22-hBcl-xL and hBcl-xL-VP22 was analyzed by Western blot. RESULTS VP22-myc could be expressed in and spread between COS-1 cells, which indicates the validity of our VP22 expression construct. Flowcytometry analysis revealed that the isolated MSCs were CD29, CD44, and CD90 positive and were negative for the hematopoietic markers, CD34 and CD45. The co-culturing and immunofluorescence assay showed that VP22-myc, VP22-EGFP and EGFP-VP22 could traffic between COS-1 cells and MSCs, while the evidence of intercellular transportation of VP22-hBcl-xL and hBcl-xL-VP22 was not detected. Western blot analysis showed that VP22-hBcl-xL and hBcl-xL-VP22 were both insoluble in the cell lysate suggesting interactions of the fusion proteins with other cellular components. CONCLUSIONS The intercellular trafficking of VP22-myc, VP22-EGFP and EGFP-VP22 between COS-1 cells and MSCs presents an intriguing prospect in the therapeutic application of VP22 as a delivery vehicle which enhances genetic modifications of MSCs. However, VP22-hBcl-xL and hBcl-xL-VP22 failed to spread between cells, which are due to the insolubility of the fusion protein incurred by interactions with other cellular components.
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Affiliation(s)
- Xiaodong Xue
- Department of Cardiovascular Surgery, General Hospital of Shenyang Military Area Command, Shenyang, Liaoning, China
| | - Jianhua Huang
- Department of Cardiothoracic Surgery, Ningxia People’s Hospital, Yinchuan, Ningxia, China
| | - Huishan Wang
- Department of Cardiovascular Surgery, General Hospital of Shenyang Military Area Command, Shenyang, Liaoning, China
- * E-mail:
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