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1
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Shim GJ, Lee CO, Lee JT, Jung HM, Kwon TG. Potentiating effect of AMD3100 on bone morphogenetic protein-2 induced bone regeneration. Maxillofac Plast Reconstr Surg 2024; 46:22. [PMID: 38884872 PMCID: PMC11183024 DOI: 10.1186/s40902-024-00431-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Accepted: 06/10/2024] [Indexed: 06/18/2024] Open
Abstract
BACKGROUND AMD3100, a CXCR4 antagonist, is currently prescribed for activating the mobilization of hematopoietic stem cells. Recently, AMD3100 was shown to potentiate bone morphogenetic protein-2 (BMP-2)-induced bone formation by stimulating the trafficking of mesenchymal cells. However, optimization of the strategic combination of AMD3100 and BMP-2 has not yet been clearly established. The purpose of this study was to evaluate the effect of AMD3100 on BMP-2-induced bone regeneration in vitro and in a mouse calvarial defect healing model. METHODS In vitro osteoblastic differentiation and cell migration after sequential treatments with AMD3100 and BMP-2 were analyzed by alkaline phosphatase (ALP) activity, ALP staining, and calcium accumulation. Migration capacity was evaluated after treating mesenchymal cells with AMD3100 and/or BMP-2. A critical-size calvarial defect model was used to evaluate bone formation after sequential or continuous treatment with AMD3100 and BMP-2. The degree of bone formation in the defect was analyzed using micro-computed tomography (micro-CT) and histological staining. RESULTS Compared with single treatment using either AMD3100 or BMP-2 alone, sequential treatment with AMD3100 followed by BMP-2 on mesenchymal cells increased osteogenic differentiation. Application of AMD3100 and subsequent BMP-2 significantly activated cell migration on mesenchymal cell than BMP-2 alone or AMD3100 alone. Micro-CT and histomorphometric analysis showed that continuous intraperitoneal (IP) injection of AMD3100 resulted significantly increased new bone formation in BMP-2 loaded scaffold in calvarial defect than control groups without AMD3100 IP injection. Additionally, both single IP injection of AMD3100 and subsequent BMP-2 injection to the scaffold in calvarial defect showed pronounced new bone formation compared to continuous BMP-2 treatment without AMD3100 treatment. CONCLUSION Our data suggest that single or continuous injection of AMD3100 can potentiate BMP-2-induced osteoblastic differentiation and bone regeneration. This strategic combination of AMD3100 and BMP-2 may be a promising therapy for bone regeneration.
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Affiliation(s)
- Gyu-Jo Shim
- Department of Oral & Maxillofacial Surgery, School of Dentistry, Kyungpook National University, and Institute for Translational Research in Dentistry, Kyungpook National University, Daegu, Republic of Korea
| | - Chung O Lee
- Department of Oral & Maxillofacial Surgery, School of Dentistry, Kyungpook National University, and Institute for Translational Research in Dentistry, Kyungpook National University, Daegu, Republic of Korea
| | - Jung-Tae Lee
- Department of Oral & Maxillofacial Surgery, School of Dentistry, Kyungpook National University, and Institute for Translational Research in Dentistry, Kyungpook National University, Daegu, Republic of Korea
| | - Hong-Moon Jung
- Department of Radiologic Technology, Daegu Health College, Daegu, Republic of Korea
| | - Tae-Geon Kwon
- Department of Oral & Maxillofacial Surgery, School of Dentistry, Kyungpook National University, and Kyungpook National University Institute for Translational Research in Dentistry, 2177 Dalgubeol-daero, Jung-Gu, Daegu, 41940, Republic of Korea.
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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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Haridhasapavalan KK, Borthakur A, Thummer RP. Direct Cardiac Reprogramming: Current Status and Future Prospects. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1436:1-18. [PMID: 36662416 DOI: 10.1007/5584_2022_760] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Advances in cellular reprogramming articulated the path for direct cardiac lineage conversion, bypassing the pluripotent state. Direct cardiac reprogramming attracts major attention because of the low or nil regenerative ability of cardiomyocytes, resulting in permanent cell loss in various heart diseases. In the field of cardiology, balancing this loss of cardiomyocytes was highly challenging, even in the modern medical world. Soon after the discovery of cell reprogramming, direct cardiac reprogramming also became a promising alternative for heart regeneration. This review mainly focused on the various direct cardiac reprogramming approaches (integrative and non-integrative) for the derivation of induced autologous cardiomyocytes. It also explains the advancements in cardiac reprogramming over the decade with the pros and cons of each approach. Further, the review highlights the importance of clinically relevant (non-integrative) approaches and their challenges for the prospective applications for personalized medicine. Apart from direct cardiac reprogramming, it also discusses the other strategies for generating cardiomyocytes from different sources. The understanding of these strategies could pave the way for the efficient generation of integration-free functional autologous cardiomyocytes through direct cardiac reprogramming for various biomedical applications.
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Affiliation(s)
- Krishna Kumar Haridhasapavalan
- Laboratory for Stem Cell Engineering and Regenerative Medicine, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, India
| | - Atreyee Borthakur
- Laboratory for Stem Cell Engineering and Regenerative Medicine, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, India
| | - Rajkumar P Thummer
- Laboratory for Stem Cell Engineering and Regenerative Medicine, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, India.
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Healing the Broken Hearts: A Glimpse on Next Generation Therapeutics. HEARTS 2022. [DOI: 10.3390/hearts3040013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Cardiovascular diseases are the leading cause of death worldwide, accounting for 32% of deaths globally and thus representing almost 18 million people according to WHO. Myocardial infarction, the most prevalent adult cardiovascular pathology, affects over half a million people in the USA according to the last records of the AHA. However, not only adult cardiovascular diseases are the most frequent diseases in adulthood, but congenital heart diseases also affect 0.8–1.2% of all births, accounting for mild developmental defects such as atrial septal defects to life-threatening pathologies such as tetralogy of Fallot or permanent common trunk that, if not surgically corrected in early postnatal days, they are incompatible with life. Therefore, both congenital and adult cardiovascular diseases represent an enormous social and economic burden that invariably demands continuous efforts to understand the causes of such cardiovascular defects and develop innovative strategies to correct and/or palliate them. In the next paragraphs, we aim to briefly account for our current understanding of the cellular bases of both congenital and adult cardiovascular diseases, providing a perspective of the plausible lines of action that might eventually result in increasing our understanding of cardiovascular diseases. This analysis will come out with the building blocks for designing novel and innovative therapeutic approaches to healing the broken hearts.
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6
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Hall RC, Ramaseshan R, Reid A, Jones DA, Mathur A. Case report: Cytokine therapy and an intracoronary autologous bone marrow-derived cell infusion with Impella support in a patient with dilated cardiomyopathy and a severely reduced ejection fraction. Front Cardiovasc Med 2022; 9:1002508. [PMID: 36172585 PMCID: PMC9510980 DOI: 10.3389/fcvm.2022.1002508] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Accepted: 08/25/2022] [Indexed: 11/24/2022] Open
Abstract
Introduction This is the first reported case of a patient with dilated cardiomyopathy (DCM) and severely impaired left ventricular function to receive a combined treatment of granulocyte colony-stimulating factor therapy and an intracoronary delivery of autologous bone marrow-derived mononuclear cells with percutaneous circulatory assistance (the Impella CP device; Abiomed, Danvers, MA). Main symptoms and outcome Three months post-treatment, the gentleman in his early 70s demonstrated an improvement in left ventricular ejection fraction (13–17%) and a reduction in New York Heart Association class from III to class I. There was also an improvement in his 6-minute walk test (147–357 meters), N-terminal pro-brain natriuretic peptide level (14,099–7,129 ng/l) and quality of life scores. There were no safety concerns during the treatment or follow-up. Conclusion This case report suggests combined cell and cytokine therapy with adjunctive circulatory support could be a safe and promising treatment for patients with DCM and severely reduced ejection fraction.
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Affiliation(s)
| | - Rohini Ramaseshan
- Barts Heart Centre, Barts Health NHS Trust, London, United Kingdom
- Centre for Cardiovascular Medicine and Devices, William Harvey Research Institute, Queen Mary University of London, London, United Kingdom
| | - Alice Reid
- Centre for Cardiovascular Medicine and Devices, William Harvey Research Institute, Queen Mary University of London, London, United Kingdom
| | - Daniel A. Jones
- Barts Heart Centre, Barts Health NHS Trust, London, United Kingdom
- Centre for Cardiovascular Medicine and Devices, William Harvey Research Institute, Queen Mary University of London, London, United Kingdom
| | - Anthony Mathur
- Barts Heart Centre, Barts Health NHS Trust, London, United Kingdom
- Centre for Cardiovascular Medicine and Devices, William Harvey Research Institute, Queen Mary University of London, London, United Kingdom
- *Correspondence: Anthony Mathur
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7
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Tu Z, Karnoub AE. Mesenchymal stem/stromal cells in breast cancer development and management. Semin Cancer Biol 2022; 86:81-92. [PMID: 36087857 DOI: 10.1016/j.semcancer.2022.09.002] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 09/02/2022] [Accepted: 09/03/2022] [Indexed: 11/17/2022]
Abstract
Mesenchymal stem/stromal cells (MSCs) encompass a heterogeneous population of fibroblastic progenitor cells that reside in multiple tissues around the body. They are endowed with capacities to differentiate into multiple connective tissue lineages, including chondrocytes, adipocytes, and osteoblasts, and are thought to function as trophic cells recruited to sites of injury and inflammation where they contribute to tissue regeneration. In keeping with these roles, MSCs also to home to sites of breast tumorigenesis, akin to their migration to wounds, and participate in tumor stroma formation. Mounting evidence over the past two decades has described the critical regulatory roles for tumor-associated MSCs in various aspects of breast tumor pathogenesis, be it tumor initiation, growth, angiogenesis, tumor microenvironment formation, immune evasion, cancer cell migration, invasion, survival, therapeutic resistance, dissemination, and metastatic colonization. In this review, we present a brief summary of the role of MSCs in breast tumor development and progression, highlight some of the molecular frameworks underlying their pro-malignant contributions, and present evidence of their promising utility in breast cancer therapy.
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Affiliation(s)
- Zhenbo Tu
- Department of Pathology and Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Antoine E Karnoub
- Department of Pathology and Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Boston Veterans Affairs Research Institute, West Roxbury, MA 02132, USA.
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8
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Rafiee Z, Orazizadeh M, Nejad Dehbashi F, Neisi N, Babaahmadi-Rezaei H, Mansouri E. Mesenchymal stem cells derived from the kidney can ameliorate diabetic nephropathy through the TGF-β/Smad signaling pathway. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2022; 29:53212-53224. [PMID: 35278177 DOI: 10.1007/s11356-021-17954-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Accepted: 12/01/2021] [Indexed: 06/14/2023]
Abstract
Diabetic nephropathy (DN) has been introduced as one of the main microvascular complications in diabetic patients, the most common cause of end-stage renal disease (ESRD). Based on the therapeutic potential of mesenchymal stem cells in tissue repair, we aimed to test the hypothesis that kidney stem cells (KSCs) might be effective in the kidney regeneration process. Stem cells from rat kidney were separated, and the surface stem cell markers were determined by flow cytometry analysis. Thirty-two Sprague Dawley rats were divided into four groups (control, control that received kidney stem cells, diabetic, diabetic treated with stem cells). To establish diabetic, model STZ (streptozotocin) (60 mg/kg) was used. The KSCs were injected into experimental groups via tail vein (2 × 106 cells/rat). In order to determine the impact of stem cells on the function and structure of the kidney, biochemical and histological parameters were measured. Further, the expression of miRNA-29a, miR-192, IL-1β, and TGF-β was determined through the real-time PCR technique. Phosphorylation of Smad2/3 was evaluated by using the standard western blotting. The KSCs significantly reduced blood nitrogen (BUN), serum creatinine (Scr), and 24-h urinary proteins in DN (P < 0.05). IL-1β and TGF-β significantly increased in the kidney of diabetic rats. In addition, the expression of miR-29a is significantly increased, whereas miR-192 decreased after treatment with KSCs (P < 0.05). Diabetic rats showed an increased level of phosphorylation of both Smad2 and Smad3 (P < 0.05). Periodic acid-Schiff (PAS) staining showed improved histopathological changes in the presence of KSCs. Stem cells derived from adult rat kidney may be an option for treating the early DN to improve the functions and structure of kidneys in rats with DN.
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Affiliation(s)
- Zeinab Rafiee
- Medical Basic Sciences Research Institute, Cellular and Molecular Research Center, Department of Anatomical Sciences, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, 61335, Ahvaz, Iran
| | - Mahmoud Orazizadeh
- Medical Basic Sciences Research Institute, Cellular and Molecular Research Center, Department of Anatomical Sciences, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, 61335, Ahvaz, Iran
| | - Fereshteh Nejad Dehbashi
- Medical Basic Sciences Research Institute, Cellular and Molecular Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Niloofar Neisi
- Alimentary Tract Research Center, Imam Khomeini Hospital Clinical Research Development Unit, Infectious and Tropical Diseases Research Center, Department of Virology, the School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Hossein Babaahmadi-Rezaei
- Hyperlipidemia Research Center, Department of Clinical Biochemistry, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Esrafil Mansouri
- Medical Basic Sciences Research Institute, Cellular and Molecular Research Center, Department of Anatomical Sciences, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, 61335, Ahvaz, Iran.
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9
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Wang K, Han P, Huang L, Xiao Y, Hou J, Yang P, Xie Y, Cai J, Wang H, Kang YJ. An Improved Monkey Model of Myocardial Ischemic Infarction for Cardiovascular Drug Development. Cardiovasc Toxicol 2022; 22:787-801. [PMID: 35739384 DOI: 10.1007/s12012-022-09754-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Accepted: 05/25/2022] [Indexed: 02/05/2023]
Abstract
Non-human primate monkey model of myocardial ischemic infarction is precious for translational medicine research. Ligation of the left anterior descending (LAD) artery is a common procedure to induce myocardial ischemic infarction. However, the consistency of the myocardial infarction thus generated remains problematic. The present study was undertaken to critically evaluate the monkey model of myocardial ischemic infarction to develop a procedure for a consistent cross-study comparison. Forty male Rhesus monkeys were divided into 4 groups and subjected to LAD artery ligation at different levels along the artery. In addition, the major diagonal branch was selectively ligated parallel to the ligation site of the LAD artery according to the diagonal branch distribution. Analyses of MRI, echocardiography, cardiac hemodynamics, electrocardiography, histopathology, and cardiac injury biomarkers were undertaken to characterize the monkeys with myocardial infarction. Ligation at 40% of the total length of the artery, measured from the apex end, produced variable infarct areas with inconsistent functional alterations. Ligation at 60% or above coupled with selective ligation of diagonal branches produced a consistent myocardial infarction with uniform dysfunction. However, ligation at 70% caused a lethal threat. After a thorough analysis, it is concluded that ligation at 60% of the total length coupled with selective ligation of diagonal branches, enables standardization of the location of occlusion and the subsequent ischemic area, as well as avoids the influence of the diagonal branches, are ideal to produce a consistent monkey model of myocardial ischemic infarction.
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Affiliation(s)
- Keke Wang
- Regenerative Medicine Research Center, Sichuan University West China Hospital, Chengdu, 610041, Sichuan, China
| | - Pengfei Han
- Regenerative Medicine Research Center, Sichuan University West China Hospital, Chengdu, 610041, Sichuan, China
| | - Lu Huang
- Regenerative Medicine Research Center, Sichuan University West China Hospital, Chengdu, 610041, Sichuan, China
| | - Ying Xiao
- Regenerative Medicine Research Center, Sichuan University West China Hospital, Chengdu, 610041, Sichuan, China
| | - Jianglong Hou
- Regenerative Medicine Research Center, Sichuan University West China Hospital, Chengdu, 610041, Sichuan, China
- Department of Cardiovascular Surgery, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Pingliang Yang
- Regenerative Medicine Research Center, Sichuan University West China Hospital, Chengdu, 610041, Sichuan, China
- Department of Anesthesiology, First Affiliated Hospital of Chengdu Medical College, Xindu, 610050, Sichuan, China
| | - Yuping Xie
- Regenerative Medicine Research Center, Sichuan University West China Hospital, Chengdu, 610041, Sichuan, China
- Department of Oncology, Chengdu First People's Hospital, Chengdu, 610041, Sichuan, China
| | - Jindan Cai
- Regenerative Medicine Research Center, Sichuan University West China Hospital, Chengdu, 610041, Sichuan, China
- Department of Cardiology, Affiliated Renhe Hospital, China Three Gorges University, Yichang, 443001, Hubei, China
| | - Hongge Wang
- Regenerative Medicine Research Center, Sichuan University West China Hospital, Chengdu, 610041, Sichuan, China
| | - Y James Kang
- Regenerative Medicine Research Center, Sichuan University West China Hospital, Chengdu, 610041, Sichuan, China.
- Tennessee Institute of Regenerative Medicine, University of Tennessee Health Science Center, Memphis, TN, USA.
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Costa A, Pasquinelli G. Air Pollution Exposure Induces Vascular Injury and Hampers Endothelial Repair by Altering Progenitor and Stem Cells Functionality. Front Cell Dev Biol 2022; 10:897831. [PMID: 35712669 PMCID: PMC9197257 DOI: 10.3389/fcell.2022.897831] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Accepted: 04/20/2022] [Indexed: 11/13/2022] Open
Abstract
Extensive evidence indicates an association of air pollution exposure with an increased risk of cardiovascular disease (CVD) development. Fine particulate matter (PM) represents one of the main components of urban pollution, but the mechanisms by which it exerts adverse effects on cardiovascular system remain partially unknown and under investigation. The alteration of endothelial functions and inflammation are among the earliest pathophysiological impacts of environmental exposure on the cardiovascular system and represent critical mediators of PM-induced injury. In this context, endothelial stem/progenitor cells (EPCs) play an important role in vascular homeostasis, endothelial reparative capacity, and vasomotor functionality modulation. Several studies indicate the impairment of EPCs' vascular reparative capacity due to PM exposure. Since a central source of EPCs is bone marrow (BM), their number and function could be related to the population and functional status of stem cells (SCs) of this district. In this review, we provide an overview of the potential mechanisms by which PM exposure hinders vascular repair by the alteration of progenitor and stem cells' functionality.
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Affiliation(s)
- Alice Costa
- Laboratory of Clinical Pathology, Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy
| | - Gianandrea Pasquinelli
- Laboratory of Clinical Pathology, Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy.,IRCCS Azienda Ospedaliero Universitaria di Bologna, Bologna, Italy
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11
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Romero-Trevejo JL, Fernández-Romero L, Delgado J, Muñoz-García E, Sánchez-Pérez A, Murri M, Gutiérrez-Bedmar M, Jiménez-Navarro MF. Choroidal thickness and granulocyte colony-stimulating factor in tears improve the prediction model for coronary artery disease. Cardiovasc Diabetol 2022; 21:103. [PMID: 35681222 PMCID: PMC9185942 DOI: 10.1186/s12933-022-01538-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Accepted: 05/27/2022] [Indexed: 11/23/2022] Open
Abstract
BACKGROUND Coronary artery disease (CAD) detection in asymptomatic patients still remains controversial. The aim of our study was to evaluate the usefulness of ophthalmologic findings as predictors of the presence of CAD when added to cardiovascular classic risk factors (CRF) in patients with acute coronary cardiopathy suspicion. METHODS After clinical stabilization, 96 patients with acute coronary cardiopathy suspicion were selected and divided in two groups: 69 patients with coronary lesions and 27 patients without coronary lesions. Their 192 eyes were subjected to a complete routine ophthalmologic examination. Samples of tear fluid were also collected to be used in the detection of cytokines and inflammatory mediators. Logistic regression models, receiver operating characteristic curves and their area under the curve (AUC) were analysed. RESULTS Suggestive predictors were choroidal thickness (CT) (OR: 1.02, 95% CI 1.01-1.03) and tear granulocyte colony-stimulating factor (G-CSF) (OR: 0.97, 95% CI 0.95-0.99). We obtained an AUC of 0.9646 (95% CI 0.928-0.999) when CT and tear G-CSF were added as independent variables to the logistic regression model with cardiovascular CRF: sex, age, diabetes, high blood pressure, hypercholesterolemia, smoking habit and obesity. This AUC was significantly higher (p = 0.003) than the prediction derived from the same logistic regression model without CT and tear G-CSF (AUC = 0.828, 95% CI 0.729-0.927). CONCLUSIONS CT and tear G-CSF improved the predictive model for CAD when added to cardiovascular CRF in our sample of symptomatic patients. Subsequent studies are needed for validation of these findings in asymptomatic patients.
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Affiliation(s)
- José Lorenzo Romero-Trevejo
- Department of Ophthalmology, Virgen de la Victoria University Hospital, Campus de Teatinos, s/n. 29010, Malaga, Spain
- Department of Medicine and Dermatology. School of Medicine, University of Malaga, Campus de Teatinos, s/n. 29010, Malaga, Spain
- Malaga Biomedical Research Institute-IBIMA, Virgen de La Victoria University Hospital, Campus de Teatinos, s/n. 29010, Malaga, Spain
| | - Lourdes Fernández-Romero
- Malaga Biomedical Research Institute-IBIMA, Virgen de La Victoria University Hospital, Campus de Teatinos, s/n. 29010, Malaga, Spain
| | - Josué Delgado
- Malaga Biomedical Research Institute-IBIMA, Virgen de La Victoria University Hospital, Campus de Teatinos, s/n. 29010, Malaga, Spain
- Department of Heart and Cardiovascular Pathology, Virgen de La Victoria University Hospital, Campus de Teatinos, s/n. 29010, Malaga, Spain
- CIBERCV Cardiovascular Diseases, Carlos III Health Institute, Madrid, Spain
| | - Erika Muñoz-García
- Malaga Biomedical Research Institute-IBIMA, Virgen de La Victoria University Hospital, Campus de Teatinos, s/n. 29010, Malaga, Spain
- Department of Heart and Cardiovascular Pathology, Virgen de La Victoria University Hospital, Campus de Teatinos, s/n. 29010, Malaga, Spain
- CIBERCV Cardiovascular Diseases, Carlos III Health Institute, Madrid, Spain
| | - Andrés Sánchez-Pérez
- Malaga Biomedical Research Institute-IBIMA, Virgen de La Victoria University Hospital, Campus de Teatinos, s/n. 29010, Malaga, Spain
- Department of Heart and Cardiovascular Pathology, Virgen de La Victoria University Hospital, Campus de Teatinos, s/n. 29010, Malaga, Spain
| | - Mora Murri
- Malaga Biomedical Research Institute-IBIMA, Virgen de La Victoria University Hospital, Campus de Teatinos, s/n. 29010, Malaga, Spain
- CIBEROBN Obesity and Nutrition, Carlos III Health Institute, Madrid, Spain
| | - Mario Gutiérrez-Bedmar
- Malaga Biomedical Research Institute-IBIMA, Virgen de La Victoria University Hospital, Campus de Teatinos, s/n. 29010, Malaga, Spain.
- CIBERCV Cardiovascular Diseases, Carlos III Health Institute, Madrid, Spain.
- Department of Preventive Medicine and Public Health. School of Medicine, University of Malaga, Campus de Teatinos, s/n. 29010, Malaga, Spain.
| | - Manuel Francisco Jiménez-Navarro
- Department of Medicine and Dermatology. School of Medicine, University of Malaga, Campus de Teatinos, s/n. 29010, Malaga, Spain.
- Malaga Biomedical Research Institute-IBIMA, Virgen de La Victoria University Hospital, Campus de Teatinos, s/n. 29010, Malaga, Spain.
- Department of Heart and Cardiovascular Pathology, Virgen de La Victoria University Hospital, Campus de Teatinos, s/n. 29010, Malaga, Spain.
- CIBERCV Cardiovascular Diseases, Carlos III Health Institute, Madrid, Spain.
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12
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Canjuga D, Steinle H, Mayer J, Uhde AK, Klein G, Wendel HP, Schlensak C, Avci-Adali M. Homing of mRNA-Modified Endothelial Progenitor Cells to Inflamed Endothelium. Pharmaceutics 2022; 14:pharmaceutics14061194. [PMID: 35745767 PMCID: PMC9229815 DOI: 10.3390/pharmaceutics14061194] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Revised: 05/28/2022] [Accepted: 05/30/2022] [Indexed: 01/25/2023] Open
Abstract
Endothelial progenitor cells (EPCs) are one of the most important stem cells for the neovascularization of tissues damaged by ischemic diseases such as myocardial infarction, ischemic stroke, or critical limb ischemia. However, their low homing efficiency in the treatment of ischemic tissues limits their potential clinical applications. The use of synthetic messenger RNA (mRNA) for cell engineering represents a novel and promising technology for the modulation of cell behavior and tissue regeneration. To improve the therapeutic potential of EPCs, in this study, murine EPCs were engineered with synthetic mRNAs encoding C-X-C chemokine receptor 4 (CXCR4) and P-selectin glycoprotein ligand 1 (PSGL-1) to increase the homing and migration efficiency of EPCs to inflamed endothelium. Flow cytometric measurements revealed that the transfection of EPCs with CXCR4 and PSGL-1 mRNA resulted in increased expressions of CXCR4 and PSGL-1 on the cell surface compared with the unmodified EPCs. The transfection of EPCs with mRNAs did not affect cell viability. CXCR4-mRNA-modified EPCs showed significantly higher migration potential than unmodified cells in a chemotactic migration assay. The binding strength of the EPCs to inflamed endothelium was determined with single-cell atomic force microscopy (AFM). This showed that the mRNA-modified EPCs required a three-fold higher detachment force to be released from the TNF-α-activated endothelium than unmodified EPCs. Furthermore, in a dynamic flow model, significantly increased binding of the mRNA-modified EPCs to inflamed endothelium was detected. This study showed that the engineering of EPCs with homing factors encoding synthetic mRNAs increases the homing and migration potentials of these stem cells to inflamed endothelium. Thus, this strategy represents a promising strategy to increase the therapeutic potential of EPCs for the treatment of ischemic tissues.
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Affiliation(s)
- Denis Canjuga
- Department of Thoracic and Cardiovascular Surgery, University Hospital Tuebingen, Calwerstraße 7/1, 72076 Tuebingen, Germany; (D.C.); (H.S.); (J.M.); (A.-K.U.); (H.P.W.); (C.S.)
| | - Heidrun Steinle
- Department of Thoracic and Cardiovascular Surgery, University Hospital Tuebingen, Calwerstraße 7/1, 72076 Tuebingen, Germany; (D.C.); (H.S.); (J.M.); (A.-K.U.); (H.P.W.); (C.S.)
| | - Jana Mayer
- Department of Thoracic and Cardiovascular Surgery, University Hospital Tuebingen, Calwerstraße 7/1, 72076 Tuebingen, Germany; (D.C.); (H.S.); (J.M.); (A.-K.U.); (H.P.W.); (C.S.)
| | - Ann-Kristin Uhde
- Department of Thoracic and Cardiovascular Surgery, University Hospital Tuebingen, Calwerstraße 7/1, 72076 Tuebingen, Germany; (D.C.); (H.S.); (J.M.); (A.-K.U.); (H.P.W.); (C.S.)
| | - Gerd Klein
- Center for Medical Research, Department of Medicine II, University of Tuebingen, Waldhörnlestraße 22, 72072 Tuebingen, Germany;
| | - Hans Peter Wendel
- Department of Thoracic and Cardiovascular Surgery, University Hospital Tuebingen, Calwerstraße 7/1, 72076 Tuebingen, Germany; (D.C.); (H.S.); (J.M.); (A.-K.U.); (H.P.W.); (C.S.)
| | - Christian Schlensak
- Department of Thoracic and Cardiovascular Surgery, University Hospital Tuebingen, Calwerstraße 7/1, 72076 Tuebingen, Germany; (D.C.); (H.S.); (J.M.); (A.-K.U.); (H.P.W.); (C.S.)
| | - Meltem Avci-Adali
- Department of Thoracic and Cardiovascular Surgery, University Hospital Tuebingen, Calwerstraße 7/1, 72076 Tuebingen, Germany; (D.C.); (H.S.); (J.M.); (A.-K.U.); (H.P.W.); (C.S.)
- Correspondence: ; Tel.: +49-7071-29-86605; Fax: +49-7071-29-3617
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13
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Wang W, Tayier B, Guan L, Yan F, Mu Y. Pre-transplantation of Bone Marrow Mesenchymal Stem Cells Amplifies the Therapeutic Effect of Ultrasound-Targeted Microbubble Destruction-Mediated Localized Combined Gene Therapy in Post-Myocardial Infarction Heart Failure Rats. ULTRASOUND IN MEDICINE & BIOLOGY 2022; 48:830-845. [PMID: 35246339 DOI: 10.1016/j.ultrasmedbio.2022.01.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 01/06/2022] [Accepted: 01/07/2022] [Indexed: 06/14/2023]
Abstract
Although stem cell transplantation and single-gene therapy have been intensively discussed separately as treatments for myocardial infarction (MI) hearts and have exhibited ideal therapeutic efficiency in animal models, clinical trials turned out to be disappointing. Here, we deliver sarcoplasmic reticulum Ca2+-ATPase 2a (SERCA2a) and connexin 43 (Cx43) genes simultaneously via an ultrasound-targeted microbubble destruction (UTMD) approach to chronic MI hearts that have been pre-treated with bone marrow mesenchymal stem cells (BMSCs) to amplify cardiac repair. First, biotinylated microbubbles (BMBs) were fabricated, and biotinylated recombinant adenoviruses carrying the SERCA2a or Cx43 gene were conjugated to the surface of self-assembled BMBs to form SERCA2a-BMBs, Cx43-BMBs or dual gene-loaded BMBs. Then, the general characteristics of these bubbles, including particle size, concentration, contrast signal and gene loading capacity, were examined. Second, a rat myocardial infarction model was created by ligating the left anterior descending coronary artery and injecting BMSCs into the infarct and border zones. Four weeks later, co-delivery of SERCA2a and Cx43 genes to the infarcted heart were delivered together to the infarcted heart using the UTMD approach. Cardiac mechano-electrical function was determined 4 wk after gene transfection, and the infarcted hearts were collected for myocardial infarct size measurement and detection of expression of SERCA2a, Cx43 and cardiac-specific markers. Finally, to validate the role of BMSC transplantation, MI rats transplanted or not with BMSCs were transfected with SERCA2a and Cx43, and the cardiac mechano-electrical function of these two groups of rats was recorded and compared. General characteristics of the self-assembled gene-loaded BMBs were qualified, and the gene loading rate was satisfactory. The self-assembled gene-loaded BMBs were in microscale and exhibit satisfactory dual-gene loading capacity. High transfection efficiency was achieved under ultrasound irradiation in vitro. In addition, rats in which SERCA2a and Cx43 were overexpressed simultaneously had the best contractile function and electrical stability among all experimental groups. Immunofluorescence assay revealed that the levels of SERCA2a and/or Cx43 proteins were significantly elevated, especially in the border zone. Moreover, compared with rats that did not receive BMSCs, rats pre-treated with BMSCs have better mechano-electrical function after transfection with SERCA2a and Cx43. Collectively, we report a promising cardiac repair strategy for post-MI hearts that exploits the providential advantages of stem cell therapy and UTMD-mediated localized co-delivery of specific genes.
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Affiliation(s)
- Wei Wang
- Department of Echocardiography, Xinjiang Medical University First Affiliated Hospital, Urumqi, China; Xinjiang Key Laboratory of Ultrasound Medicine, Urumqi, China
| | - Baihetiya Tayier
- Department of Echocardiography, Xinjiang Medical University First Affiliated Hospital, Urumqi, China; Xinjiang Key Laboratory of Ultrasound Medicine, Urumqi, China
| | - Lina Guan
- Department of Echocardiography, Xinjiang Medical University First Affiliated Hospital, Urumqi, China; Xinjiang Key Laboratory of Ultrasound Medicine, Urumqi, China
| | - Fei Yan
- CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Yuming Mu
- Department of Echocardiography, Xinjiang Medical University First Affiliated Hospital, Urumqi, China; Xinjiang Key Laboratory of Ultrasound Medicine, Urumqi, China.
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14
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Buja LM, Mitchell RN. Basic pathobiology of cell-based therapies and cardiac regenerative medicine. Cardiovasc Pathol 2022. [DOI: 10.1016/b978-0-12-822224-9.00016-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
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15
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Tajabadi M, Goran Orimi H, Ramzgouyan MR, Nemati A, Deravi N, Beheshtizadeh N, Azami M. Regenerative strategies for the consequences of myocardial infarction: Chronological indication and upcoming visions. Biomed Pharmacother 2021; 146:112584. [PMID: 34968921 DOI: 10.1016/j.biopha.2021.112584] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 12/20/2021] [Accepted: 12/21/2021] [Indexed: 12/13/2022] Open
Abstract
Heart muscle injury and an elevated troponin level signify myocardial infarction (MI), which may result in defective and uncoordinated segments, reduced cardiac output, and ultimately, death. Physicians apply thrombolytic therapy, coronary artery bypass graft (CABG) surgery, or percutaneous coronary intervention (PCI) to recanalize and restore blood flow to the coronary arteries, albeit they were not convincingly able to solve the heart problems. Thus, researchers aim to introduce novel substitutional therapies for regenerating and functionalizing damaged cardiac tissue based on engineering concepts. Cell-based engineering approaches, utilizing biomaterials, gene, drug, growth factor delivery systems, and tissue engineering are the most leading studies in the field of heart regeneration. Also, understanding the primary cause of MI and thus selecting the most efficient treatment method can be enhanced by preparing microdevices so-called heart-on-a-chip. In this regard, microfluidic approaches can be used as diagnostic platforms or drug screening in cardiac disease treatment. Additionally, bioprinting technique with whole organ 3D printing of human heart with major vessels, cardiomyocytes and endothelial cells can be an ideal goal for cardiac tissue engineering and remarkable achievement in near future. Consequently, this review discusses the different aspects, advancements, and challenges of the mentioned methods with presenting the advantages and disadvantages, chronological indications, and application prospects of various novel therapeutic approaches.
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Affiliation(s)
- Maryam Tajabadi
- School of Metallurgy and Materials Engineering, Iran University of Science and Technology (IUST), Narmak, Tehran 16844, Iran
| | - Hanif Goran Orimi
- School of Metallurgy and Materials Engineering, Iran University of Science and Technology (IUST), Narmak, Tehran 16844, Iran; Regenerative Medicine Group (REMED), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Maryam Roya Ramzgouyan
- Department of Tissue Engineering, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Iran; Regenerative Medicine Group (REMED), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Alireza Nemati
- Department of Biomedical Engineering, Amirkabir University of Technology (Tehran Polytechnic), Tehran, Iran; Regenerative Medicine Group (REMED), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Niloofar Deravi
- Student Research Committee, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Regenerative Medicine Group (REMED), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Nima Beheshtizadeh
- Department of Tissue Engineering, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Iran; Regenerative Medicine Group (REMED), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Mahmoud Azami
- Department of Tissue Engineering, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Iran; Regenerative Medicine Group (REMED), Universal Scientific Education and Research Network (USERN), Tehran, Iran.
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16
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Fujioka N, Kitabatake M, Ouji-Sageshima N, Ibaraki T, Kumamoto M, Fujita Y, Hontsu S, Yamauchi M, Yoshikawa M, Muro S, Ito T. Human Adipose-Derived Mesenchymal Stem Cells Ameliorate Elastase-Induced Emphysema in Mice by Mesenchymal-Epithelial Transition. Int J Chron Obstruct Pulmon Dis 2021; 16:2783-2793. [PMID: 34675503 PMCID: PMC8517419 DOI: 10.2147/copd.s324952] [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: 06/15/2021] [Accepted: 09/13/2021] [Indexed: 11/23/2022] Open
Abstract
Purpose Chronic obstructive pulmonary disease (COPD) is a worldwide problem because of its high prevalence and mortality. However, there is no fundamental treatment to ameliorate their pathological change in COPD lung. Recently, adipose-derived mesenchymal stem cells (ADSCs) have attracted attention in the field of regenerative medicine to repair damaged organs. Moreover, their utility in treating respiratory diseases has been reported in some animal models. However, the detailed mechanism by which ADSCs improve chronic respiratory diseases, including COPD, remains to be elucidated. We examined whether human ADSCs (hADSCs) ameliorated elastase-induced emphysema and whether hADSCs differentiated into alveolar epithelial cells in a murine model of COPD. Methods Female SCID-beige mice (6 weeks old) were divided into the following four groups according to whether they received an intratracheal injection of phosphate-buffered saline or porcine pancreatic elastase, and whether they received an intravenous injection of saline or hADSCs 3 days after intratracheal injection; Control group, hADSC group, Elastase group, and Elastase-hADSC group. We evaluated the lung function, assessed histological changes, and compared gene expression between hADSCs isolated from the lung of Elastase-hADSC group and naïve hADSCs 28 days after saline or elastase administration. Results hADSCs improved the pathogenesis of COPD, including the mean linear intercept and forced expiratory volume, in an elastase-induced emphysema model in mice. Furthermore, hADSCs were observed in the lungs of elastase-treated mice at 25 days after administration. These cells expressed genes related to mesenchymal–epithelial transition and surface markers of alveolar epithelial cells, such as TTF-1, β-catenin, and E-cadherin. Conclusion hADSCs have the potential to improve the pathogenesis of COPD by differentiating into alveolar epithelial cells by mesenchymal–epithelial transition.
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Affiliation(s)
- Nobuhiro Fujioka
- Department of Respiratory Medicine, Nara Medical University, Kashihara, Nara, Japan
| | | | | | - Takahiro Ibaraki
- Department of Respiratory Medicine, Nara Medical University, Kashihara, Nara, Japan
| | - Makiko Kumamoto
- Department of Respiratory Medicine, Nara Medical University, Kashihara, Nara, Japan
| | - Yukio Fujita
- Department of Respiratory Medicine, Nara Medical University, Kashihara, Nara, Japan
| | - Shigeto Hontsu
- Department of Respiratory Medicine, Nara Medical University, Kashihara, Nara, Japan
| | - Motoo Yamauchi
- Department of Respiratory Medicine, Nara Medical University, Kashihara, Nara, Japan
| | - Masanori Yoshikawa
- Department of Respiratory Medicine, Nara Medical University, Kashihara, Nara, Japan
| | - Shigeo Muro
- Department of Respiratory Medicine, Nara Medical University, Kashihara, Nara, Japan
| | - Toshihiro Ito
- Department of Immunology, Nara Medical University, Kashihara, Nara, Japan
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17
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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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18
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Begley CG, Ashton M, Baell J, Bettess M, Brown MP, Carter B, Charman WN, Davis C, Fisher S, Frazer I, Gautam A, Jennings MP, Kearney P, Keeffe E, Kelly D, Lopez AF, McGuckin M, Parker MW, Rayner C, Roberts B, Rush JS, Sullivan M. Drug repurposing: Misconceptions, challenges, and opportunities for academic researchers. Sci Transl Med 2021; 13:eabd5524. [PMID: 34550729 DOI: 10.1126/scitranslmed.abd5524] [Citation(s) in RCA: 77] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
[Figure: see text].
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Affiliation(s)
| | - Mark Ashton
- UniQuest Pty Ltd., University of Queensland, Brisbane, Queensland, Australia
| | - Jonathan Baell
- Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia
| | | | - Michael P Brown
- Cancer Clinical Trials Unit, Royal Adelaide Hospital, Adelaide, South Australia, Australia
| | - Brett Carter
- Bioseer Pty Ltd., Glen Iris, Victoria, Australia
| | - William N Charman
- Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia
| | - Christopher Davis
- Institute for Glycomics, Griffith University, Gold Coast campus, Queensland, Australia
| | - Simon Fisher
- Novartis Pharmaceuticals Australia Pty Ltd., Macquarie Park, New South Wales, Australia
| | - Ian Frazer
- University of Queensland Diamantina Institute, Woolloongabba, Queensland, Australia
| | | | - Michael P Jennings
- Institute for Glycomics, Griffith University, Gold Coast campus, Queensland, Australia
| | - Philip Kearney
- Merck Sharp & Dohme, Macquarie Park, New South Wales, Australia
| | - Eloise Keeffe
- Institute for Glycomics, Griffith University, Gold Coast campus, Queensland, Australia
| | - Darren Kelly
- Department of Medicine, University of Melbourne, Parkville, Victoria, Australia
| | - Angel F Lopez
- Centre for Cancer Biology, Adelaide, South Australia, Australia
| | | | - Michael W Parker
- Bio21 Molecular Science and Biotechnology Institute, Parkville, Victoria, Australia
| | | | - Brett Roberts
- Novartis Pharmaceuticals Australia Pty Ltd., Macquarie Park, New South Wales, Australia
| | | | - Mark Sullivan
- Medicines Development for Global Health, Southbank, Victoria, Australia
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19
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Mufarrih SH, Mahmood F, Qureshi NQ, Yunus R, Quraishi I, Baribeau V, Sharkey A, Matyal R, Khabbaz KR. Three-Dimensional Printing of Patient-Specific Heart Valves: Separating Facts From Fiction and Myth From Reality. J Cardiothorac Vasc Anesth 2021; 36:2643-2655. [PMID: 34654635 DOI: 10.1053/j.jvca.2021.09.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Revised: 08/05/2021] [Accepted: 09/08/2021] [Indexed: 11/11/2022]
Abstract
The development of prosthetic heart valves by Dr. Charles Hufnagel in 1952 was a major clinical innovation; however, it was not an ideal solution. Mechanical prosthetic heart valves are rigid, immunogenic, require anticoagulation, do not grow with the patient, and have a finite life.1 An ideal prosthetic valve should overcome all these limitations. Considering the prevalence of valvular heart disorders, there is considerable interest in the creation of patient-specific heart valves. Following the introduction of three-dimensional (3D) printing in 1986 by Chuck Hill, rapid advances in multimodality 3D imaging and modeling have led to a generation of tangible replicas of patient-specific anatomy. The science of organogenesis has gained importance for a multitude of valid reasons: as an alternate source of organs, for realistic drug testing, as an alternative to animal testing, and for transplants that grow with the patient. What scientists imagined to be seemingly impossible in the past now seems just a step away from becoming a reality. However, due to the disruptive nature of this technology, often there are commercially-motivated claims of originality and overstatement of the scope and applicability of 3D printing. It often is difficult to separate fact from fiction and myth from reality. In this manuscript, the authors have reviewed the historic perspective, status of the basic techniques of organogenesis with specific reference to heart valves, and their potential.
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Affiliation(s)
- Syed Hamza Mufarrih
- Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
| | - Feroze Mahmood
- Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
| | - Nada Qaisar Qureshi
- Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
| | - Rayaan Yunus
- Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
| | - Ibrahim Quraishi
- Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
| | - Vincent Baribeau
- Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
| | - Aidan Sharkey
- Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
| | - Robina Matyal
- Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
| | - Kamal R Khabbaz
- Department of Surgery, Division of Cardiothoracic Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
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20
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Iannolo G, Sciuto MR, Cuscino N, Carcione C, Coronnello C, Chinnici CM, Raffa GM, Pilato M, Conaldi PG. miRNA expression analysis in the human heart: Undifferentiated progenitors vs. bioptic tissues-Implications for proliferation and ageing. J Cell Mol Med 2021; 25:8687-8700. [PMID: 34390171 PMCID: PMC8435455 DOI: 10.1111/jcmm.16824] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Revised: 06/07/2021] [Accepted: 07/20/2021] [Indexed: 12/30/2022] Open
Abstract
In developed countries, cardiovascular diseases are currently the first cause of death. Cardiospheres (CSs) and cardiosphere-derived cells (CDCs) have been found to have the ability to regenerate the myocardium after myocardial infarction (MI). In recent years, much effort has been made to gain insight into the human heart repair mechanisms, in which miRNAs have been shown to play an important role. In this regard, to elucidate the involvement of miRNAs, we evaluated the miRNA expression profile across human heart biopsy, CSs and CDCs using microarray and next-generation sequencing (NGS) technologies. We identified several miRNAs more represented in the progenitors, where some of them can be responsible for the proliferation or the maintenance of an undifferentiated state, while others have been found to be downregulated in the undifferentiated progenitors compared with the biopsies. Moreover, we also found a correlation between downregulated miRNAs in CSs/CDCs and patient age (eg miR-490) and an inverse correlation among miRNAs upregulated in CSs/CDCs (eg miR-31).
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Affiliation(s)
- Gioacchin Iannolo
- Department of Research, Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione (ISMETT-IRCCS), Palermo, Italy
| | - Maria Rita Sciuto
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Nicola Cuscino
- Department of Research, Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione (ISMETT-IRCCS), Palermo, Italy
| | | | | | - Cinzia Maria Chinnici
- Department of Research, Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione (ISMETT-IRCCS), Palermo, Italy.,Fondazione Ri.MED, Palermo, Italy
| | - Giuseppe Maria Raffa
- Cardiac Surgery and Heart Transplantation Unit, Department for the Treatment and Study of Cardiothoracic Diseases and Cardiothoracic Transplantation, Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione (ISMETT-IRCCS), Palermo, Italy
| | - Michele Pilato
- Cardiac Surgery and Heart Transplantation Unit, Department for the Treatment and Study of Cardiothoracic Diseases and Cardiothoracic Transplantation, Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione (ISMETT-IRCCS), Palermo, Italy
| | - Pier Giulio Conaldi
- Department of Research, Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione (ISMETT-IRCCS), Palermo, Italy
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21
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Chen Y, Shen H, Ding Y, Yu Y, Shao L, Shen Z. The application of umbilical cord-derived MSCs in cardiovascular diseases. J Cell Mol Med 2021; 25:8103-8114. [PMID: 34378345 PMCID: PMC8419197 DOI: 10.1111/jcmm.16830] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Revised: 06/29/2021] [Accepted: 07/13/2021] [Indexed: 02/06/2023] Open
Abstract
Transplantation of stem cells is a promising, emerging treatment for cardiovascular diseases in the modern era. Mesenchymal stem cells (MSCs) derived from the umbilical cord are one of the most promising cell sources because of their capacity for differentiation into cardiomyocytes, endothelial cells and vascular smooth muscle cells in vitro/in vivo. In addition, umbilical cord‐derived MSCs (UC‐MSCs) secrete many effective molecules regulating apoptosis, fibrosis and neovascularization. Another important and specific characteristic of UC‐MSCs is their low immunogenicity and immunomodulatory properties. However, the application of UC‐MSCs still faces some challenges, such as low survivability and tissue retention in a harmful disease environment. Gene engineering and pharmacological studies have been implemented to overcome these difficulties. In this review, we summarize the differentiation ability, secretion function, immunoregulatory properties and preclinical/clinical studies of UC‐MSCs, highlighting the advantages of UC‐MSCs for the treatment of cardiovascular diseases.
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Affiliation(s)
- Yueqiu Chen
- Institute for Cardiovascular Science, Soochow University, Suzhou, China.,Department of Cardiovascular Surgery of The First Affiliated Hospital, Soochow University, Suzhou, China
| | - Han Shen
- Department of Cardiovascular Surgery of The First Affiliated Hospital, Soochow University, Suzhou, China
| | - Yinglong Ding
- Department of Cardiovascular Surgery of The First Affiliated Hospital, Soochow University, Suzhou, China
| | - You Yu
- Institute for Cardiovascular Science, Soochow University, Suzhou, China.,Department of Cardiovascular Surgery of The First Affiliated Hospital, Soochow University, Suzhou, China
| | - Lianbo Shao
- Institute for Cardiovascular Science, Soochow University, Suzhou, China.,Department of Cardiovascular Surgery of The First Affiliated Hospital, Soochow University, Suzhou, China
| | - Zhenya Shen
- Institute for Cardiovascular Science, Soochow University, Suzhou, China.,Department of Cardiovascular Surgery of The First Affiliated Hospital, Soochow University, Suzhou, China
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22
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Dudek J, Kutschka I, Maack C. Metabolic and Redox Regulation of Cardiovascular Stem Cell Biology and Pathology. Antioxid Redox Signal 2021; 35:163-181. [PMID: 33121253 DOI: 10.1089/ars.2020.8201] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Significance: Cardiovascular stem cells are important for regeneration and repair of damaged tissue. Recent Advances: Pluripotent stem cells have a unique metabolism, which is adopted for their energetic and biosynthetic demand as rapidly proliferating cells. Stem cell differentiation requires an exceptional metabolic flexibility allowing for metabolic remodeling between glycolysis and oxidative phosphorylation. Critical Issues: Respiration is associated with the generation of reactive oxygen species (ROS) by the mitochondrial respiratory chain. But also the membrane-bound protein nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase, NOX) contributes to ROS levels. ROS not only play a significant role in stem cell differentiation and tissue renewal but also cause senescence and contribute to tissue aging. Future Directions: For utilization of stem cells in therapeutic approaches, a deep understanding of the molecular mechanisms how metabolism and the cellular redox state regulate stem cell differentiation is required. Modulating the redox state of stem cells using antioxidative agents may be suitable to enhance activity of endothelial progenitor cells. Antioxid. Redox Signal. 35, 163-181.
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Affiliation(s)
- Jan Dudek
- Department of Translational Research, Comprehensive Heart Failure Center (CHFC), University Clinic Würzburg, Würzburg, Germany
| | - Ilona Kutschka
- Department of Translational Research, Comprehensive Heart Failure Center (CHFC), University Clinic Würzburg, Würzburg, Germany
| | - Christoph Maack
- Department of Translational Research, Comprehensive Heart Failure Center (CHFC), University Clinic Würzburg, Würzburg, Germany.,Department of Internal Medicine I, University Hospital Würzburg, Würzburg, Germany
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23
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Abstract
Manipulation of microRNA (miRNA) expression has been shown to induce cardiac regeneration, consolidating their therapeutic potential. However, studies often validate only a few miRNA targets in each experiment and hold these targets entirely accountable for the miRNAs' action, ignoring the other potential molecular and cellular events involved. In this report, experimentally validated miRNAs are used as a window of discovery for the possible genes and signaling pathways that are implicated in cardiac regeneration. A thorough evidence search was conducted, and identified miRNAs were submitted for in silico dissection using reliable bioinformatics tools. A total of 46 miRNAs were retrieved from existing literature. Shared targets between miRNAs included well-recognized genes such as BCL-2, CCND1, and PTEN. Transcription factors that are possibly involved in the regeneration process such as SP1, CTCF, and ZNF263 were also identified. The analysis confirmed well-established signaling pathways involved in cardiac regeneration such as Hippo, MAPK, and AKT signaling, and revealed new pathways such as ECM-receptor interaction, and FoxO signaling on top of hormonal pathways such as thyroid, adrenergic, and estrogen signaling pathways. Additionally, a set of differentially expressed miRNAs were identified as potential future experimental candidates.
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24
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Rusch RM, Ogawa Y, Sato S, Morikawa S, Inagaki E, Shimizu E, Tsubota K, Shimmura S. MSCs Become Collagen-Type I Producing Cells with Different Phenotype in Allogeneic and Syngeneic Bone Marrow Transplantation. Int J Mol Sci 2021; 22:4895. [PMID: 34063118 PMCID: PMC8125797 DOI: 10.3390/ijms22094895] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 04/24/2021] [Accepted: 04/28/2021] [Indexed: 11/17/2022] Open
Abstract
Mesenchymal stem cells (MSCs) have been widely used in therapeutic applications for many decades. However, more and more evidence suggests that factors such as the site of origin and pre-implantation treatment have a crucial impact on the result. This study investigates the role of freshly isolated MSCs in the lacrimal gland after allogeneic transplantation. For this purpose, MSCs from transgenic GFP mice were isolated and transplanted into allogeneic and syngeneic recipients. While the syngeneic MSCs maintained a spherical shape, allogeneic MSCs engrafted into the tissue as spindle-shaped cells in the interstitial stroma. Furthermore, the MSCs produced collagen type I in more than 85% to 95% of the detected GFP+ MSCs in the recipients of both models, supposedly contributing to pathogenic fibrosis in allogeneic recipients compared to syngeneic models. These findings indicate that allogeneic MSCs act completely differently from syngeneic MSCs, highlighting the importance of understanding the exact mechanisms behind MSCs.
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Affiliation(s)
- Robert Maximilian Rusch
- Department of Ophthalmology, Keio University School of Medicine 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan; (R.M.R.); (S.S.); (E.I.); (E.S.); (K.T.)
| | - Yoko Ogawa
- Department of Ophthalmology, Keio University School of Medicine 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan; (R.M.R.); (S.S.); (E.I.); (E.S.); (K.T.)
| | - Shinri Sato
- Department of Ophthalmology, Keio University School of Medicine 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan; (R.M.R.); (S.S.); (E.I.); (E.S.); (K.T.)
| | - Satoru Morikawa
- Department of Dentistry and Oral Surgery, Keio University School of Medicine 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan;
| | - Emi Inagaki
- Department of Ophthalmology, Keio University School of Medicine 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan; (R.M.R.); (S.S.); (E.I.); (E.S.); (K.T.)
| | - Eisuke Shimizu
- Department of Ophthalmology, Keio University School of Medicine 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan; (R.M.R.); (S.S.); (E.I.); (E.S.); (K.T.)
| | - Kazuo Tsubota
- Department of Ophthalmology, Keio University School of Medicine 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan; (R.M.R.); (S.S.); (E.I.); (E.S.); (K.T.)
| | - Shigeto Shimmura
- Department of Ophthalmology, Keio University School of Medicine 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan; (R.M.R.); (S.S.); (E.I.); (E.S.); (K.T.)
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25
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Denu RA, Hematti P. Optimization of oxidative stress for mesenchymal stromal/stem cell engraftment, function and longevity. Free Radic Biol Med 2021; 167:193-200. [PMID: 33677063 DOI: 10.1016/j.freeradbiomed.2021.02.042] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 02/24/2021] [Accepted: 02/26/2021] [Indexed: 12/18/2022]
Abstract
Mesenchymal stromal/stem cells (MSCs) are multipotent cells that possess great potential as a cellular therapeutic based on their ability to differentiate to different lineages and to modulate immune responses. However, their potential is limited by their low tissue abundance, and thus the need for robust ex vivo expansion prior to their application. This creates its own issues, namely replicative senescence, which could lead to reduced MSC functionality and negatively impact their engraftment. Ex vivo expansion and MSC aging are associated with greater oxidative stress. Therefore, there is great need to identify strategies to reduce oxidative stress in MSCs. This review summarizes the achievements made to date in addressing oxidative stress in MSCs and speculates about interesting avenues of future investigation to solve this critical problem.
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Affiliation(s)
- Ryan A Denu
- Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
| | - Peiman Hematti
- Departments of Medicine, Pediatrics, Surgery and Biomedical Engineering, Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA
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26
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Application of genetic cell-lineage tracing technology to study cardiovascular diseases. J Mol Cell Cardiol 2021; 156:57-68. [PMID: 33745891 DOI: 10.1016/j.yjmcc.2021.03.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 03/03/2021] [Accepted: 03/15/2021] [Indexed: 12/12/2022]
Abstract
Cardiovascular diseases are leading causes that threaten people's life. To investigate cells that are involved in disease development and tissue repair, various technologies have been introduced. Among these technologies, lineage tracing is a powerful tool to track the fate of cells in vivo, providing deep insights into cellular behavior and plasticity. In cardiac diseases, newly formed cardiomyocytes and endothelial cells are found from proliferation of local cells, while fibroblasts and macrophages are originated from diverse cell sources. Similarly, in response to vascular injury, various sources of cells including media smooth muscle cells, endothelium, resident progenitors and bone marrow cells are involved in lesion formation and/or vessel regeneration. In summary, current review summarizes the development of lineage tracing techniques and their utilizations in investigating roles of different cell types in cardiovascular diseases.
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27
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The efficacy of bone marrow mononuclear stem cell transplantation in patients with non-ischemic dilated cardiomyopathy-a meta analysis. Heart Fail Rev 2021; 27:811-820. [PMID: 33587248 DOI: 10.1007/s10741-021-10082-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/03/2021] [Indexed: 10/22/2022]
Abstract
Cardiomyopathy refers to a wide spectrum of heart pathologies that interfere with normal heart function. Management options of patients with cardiomyopathy depended mainly on the severity of the condition. Lifestyle modifications and regular exercise together with a healthy diet is compatible for mild conditions. Severe conditions, however, rely on medications or surgery. Here, we aim to investigate the efficacy of bone marrow mononuclear stem cell transplantation in patients with dilated cardiomyopathy. We searched PubMed, Scopus, and Cochrane CENTRAL for relevant clinical trials and excluded observational studies. We performed the quality assessment of this study following GRADE guidelines. The assessment of the risk of bias was performed by the Cochrane's risk of bias tool. We present an analysis of the following outcomes: left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter (LVEDD), and six minutes walking test. Data were pooled as mean differences (MD) and relative confidence intervals (CI). The analysis of 667 patients from 11 studies receiving autologous bone marrow cell therapy for non-ischemic dilated cardiomyopathy is presented. A total of 338 patients were allocated to the treatment group, and 329 participants entered the control group. The mean age of the patients in the treatment group is 52.4 ± 4.3 years, while that of the control is 53.7 ± 3.7 years. Seven studies (14.18-23) reported transplantation through the intracoronary route. Table 1 shows a summary of the baseline characteristics of the included studies and participants, the number of injected cells, and the type of injected cells in each trial. Table 2 summarizes and illustrates the previous treatment history of included patients in each trial, as well as the baseline values of different scores used as outcome measures in this analysis. We found that bone marrow mononuclear stem cell therapy leads to significantly increased LVEF (MD = 4.54%, 95% CI [3.52, 5.56], P < 0.0001). Patients in the transplant group experienced less left ventricular end-diastolic diameter (millimeter) than the control arm (MD = -1.86 mm, 95% CI [-4.01, 0.29], P = 0.09). Additionally, Patients in the transplant group could walk 28.53 m more than the controls (MD = 28.53 m, 95% CI [2.51, 54.55], P = 0.03). Transplantation of bone marrow stem cells yields acceptable results regarding left ventricular ejection fraction and lowers the left ventricular end-diastolic diameter. Additionally, the six minutes walking test is improved in the transplant group. Table 1 Demographic data about the included participants Study Year Sample size Age, years Males, n (%) Diabetics, n (%) Route of administration Number of injected cells Type of injected cells TTT Control TTT Control TTT Control TTT Control Bartolucci 2015 12 11 58 ± 14 57 ± 11 8 (66.7) 9 (81.8) 2 (16.7) 1 (9.1) Intracoronary 1.94 × 10^6 CD34 + Bocchi 2010 8 15 51 ± 15 NR NR NR NR Intracoronary NR NR Frljak 2018 30 30 56 ± 9 54 ± 11 27 (90) 26 (87) 3 (10) 2 (6) Trans-endocardial NR CD34 + Hamshere 2015 15 14 57.67 ± 12.32 56.79 ± 9.8 10 12 9(59.9%) 8(57.1%) Intracoronary 4.91 × 10^6 CD34 + Hu 2011 31 29 56.61 ± 9.72 58.27 ± 8.86 NR NR NR NR NR NR NR Matrino 2015 82 78 51 ± 11.1 49.6 ± 11.1 73.1 68.3 NR NR Intracoronary 10^8 TTT, CD45, CD105, and CD133 Sant'Anna 2014 20 10 48.3 ± 8.71 51.6 ± 7.79 13(65) 5 (50%) NR NR Intra-myocardial 1.06 × 108 CD3, CD4, CD14, CD34, CD38, and CD45 Seth 2010 41 40 45 ± 15 49 ± 9 33 35 NR NR NR 168 × 10^6 Bone marrow mononuclear cells Vrtovec 2011 28 27 52 ± 8 54 ± 7 26 (93) 23 (85) NR NR Intracoronary 123 × 10^6 CD34 + Vrtovec 2013 55 55 53 ± 8 55 ± 7 45 (82) 44 (80) NR NR Intracoronary NR NR Xiao 2017 16 20 49.5 ± 11.6 54.4 ± 11.6 9 (56.3) 14 (70.0) 6 (37.5) 5 (29.4) Intracoronary infusion (4.9 ± 1.7) × 108 (CD29, CD34, CD44, CD45, and CD166) Data are reported as mean ± SD or n (%) unless proved otherwise TTT treatment group, NR not reported Table 2 Previous history of treatment and drug intake by the patients Study Year Medical therapy, n (%) Baseline scores, mean (SD) Beta blockers ACE inhibitors Digoxin Diuretics LVEF, % LVEDD, mm Six minutes-walk test* TTT Control TTT Control TTT Control TTT Control TTT Control TTT Control TTT Control Bartolucci 2015 10 (83.3) 8 (72.7) NR NR 3 (25) 3 (27.3) 11 (91.6) 10 (90.9) 26.8 ± 4.9 30.3 ± 6.3 NR NR NR NR Bocchi 2010 NR NR NR NR NR NR NR NR 21.8 ± 3.8 30.6 ± 7.3 79 (10) 78 (12) NR NR Frljak 2018 30 (100) 30 (100) 31 (100) 32 (100) 2 (7) 3 (10) 32 (100) 33 (100) 32.2 ± 9.3 31.1 ± 7.8 NR NR NR NR Hamshere 2015 13 14 15 13 6 2 9 8 32.93 ± 16.46 29.75 ± 9.2 NR NR NR NR Hu* 2011 NR NR NR NR NR NR NR NR NR NR NR NR 466 (402, 495) 448 (383, 497) Matrino 2015 9 (11) 8 (10.2) 53 (64.1) 48 (61.1) 63 (77) 62 (79) 74 (89.7) 69 (88.9) 23.8 ± 7.2 24.7 ± 7.0 NR NR 347.3(146.7) 349.8(139.7) Sant'Anna 2014 NR NR NR NR NR NR NR NR NR NR NR NR 358.5 (88.69) 353 (86.67) Seth 2010 29 (70) 29 (72) 41 (100) 40 (100) NR NR NR NR NR NR NR NR NR NR Vrtovec 2011 21 (75) 22 (81) NR NR 5 (18) 6 (22) 26 (93) 24 (88) 25.6 ± 5.1 26.7 ± 3.9 69 ± 10 70 ± 7 NR NR Vrtovec 2013 43 (79) 46 (84) 51 (93) 54 (98) 9 (16) 11 (20) 51 (93) 20 (91) 24.3 ± 6.5 25.7 ± 4.1 69 ± 10 70 ± 7 NR NR Xiao 2017 16 (100) 20 (100) 16 (100) 19 (95) 4 (25.0) 8 (40.0) 5 (31.3) 6 (30.0) 33.1 ± 3.9 33.7 ± 4.0 NR NR 355.0 ± 91.2 323.3 ± 89.4 Data are reported as mean ± SD or n (%) unless proved otherwise TTT treatment group, NR not reported *Data are reported as median (IQR).
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28
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Li Y, Chen X, Jin R, Chen L, Dang M, Cao H, Dong Y, Cai B, Bai G, Gooding JJ, Liu S, Zou D, Zhang Z, Yang C. Injectable hydrogel with MSNs/microRNA-21-5p delivery enables both immunomodification and enhanced angiogenesis for myocardial infarction therapy in pigs. SCIENCE ADVANCES 2021; 7:7/9/eabd6740. [PMID: 33627421 PMCID: PMC7904259 DOI: 10.1126/sciadv.abd6740] [Citation(s) in RCA: 129] [Impact Index Per Article: 32.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/05/2020] [Accepted: 01/11/2021] [Indexed: 05/05/2023]
Abstract
Current therapeutic strategies such as angiogenic therapy and anti-inflammatory therapy for treating myocardial infarction have limited success. An effective approach may benefit from resolution of excessive inflammation combined with enhancement of angiogenesis. Here, we developed a microRNA-21-5p delivery system using functionalized mesoporous silica nanoparticles (MSNs) with additional intrinsic therapeutic effects. These nanocarriers were encapsulated into an injectable hydrogel matrix (Gel@MSN/miR-21-5p) to enable controlled on-demand microRNA-21 delivery triggered by the local acidic microenvironment. In a porcine model of myocardial infarction, we demonstrated that the released MSN complexes notably inhibited the inflammatory response by inhibiting the polarization of M1 macrophage within the infarcted myocardium, while further microRNA-21-5p delivery by MSNs to endothelial cells markedly promoted local neovascularization and rescued at-risk cardiomyocytes. The synergy of anti-inflammatory and proangiogenic effects effectively reduced infarct size in a porcine model of myocardial infarction.
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Affiliation(s)
- Yan Li
- National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology and Shanghai Research Institute of Stomatology, Department of Oral Surgery, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Key Laboratory of Oral Diseases, Department of Prosthodontics, School of Stomatology, The Fourth Military Medical University, Xi'an 710032, China
| | - Xin Chen
- School of Chemical Engineering and Technology, Shaanxi Key Laboratory of Energy Chemical Process Intensification, Institute of Polymer Science in Chemical Engineering, Xi'an Jiao Tong University, Xi'an 710049, China
| | - Ronghua Jin
- School of Chemical Engineering and Technology, Shaanxi Key Laboratory of Energy Chemical Process Intensification, Institute of Polymer Science in Chemical Engineering, Xi'an Jiao Tong University, Xi'an 710049, China
| | - Lu Chen
- National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology and Shanghai Research Institute of Stomatology, Department of Oral Surgery, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
| | - Ming Dang
- School of Dentistry, University of Michigan, Ann Arbor, MI 48109, USA
| | - Hao Cao
- Department of Cardiac Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
| | - Yun Dong
- Department of Cardiac Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
| | - Bolei Cai
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Key Laboratory of Oral Diseases, Department of Prosthodontics, School of Stomatology, The Fourth Military Medical University, Xi'an 710032, China
| | - Guo Bai
- National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology and Shanghai Research Institute of Stomatology, Department of Oral Surgery, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
| | - J Justin Gooding
- School of Chemistry, Australian Centre for NanoMedicine and ARC Australian, Centre of Excellence in Convergent Bio-Nano Science and Technology, University of New South Wales, Sydney 2052, Australia
| | - Shiyu Liu
- Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Key Laboratory of Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Duohong Zou
- National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology and Shanghai Research Institute of Stomatology, Department of Oral Surgery, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
| | - Zhiyuan Zhang
- National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology and Shanghai Research Institute of Stomatology, Department of Oral Surgery, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
| | - Chi Yang
- National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology and Shanghai Research Institute of Stomatology, Department of Oral Surgery, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
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29
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Sharma P, Kumar A, Dey AD, Behl T, Chadha S. Stem cells and growth factors-based delivery approaches for chronic wound repair and regeneration: A promise to heal from within. Life Sci 2021; 268:118932. [PMID: 33400933 DOI: 10.1016/j.lfs.2020.118932] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Revised: 12/03/2020] [Accepted: 12/12/2020] [Indexed: 02/06/2023]
Abstract
The sophisticated chain of cellular and molecular episodes during wound healing includes cell migration, cell proliferation, deposition of extracellular matrix, and remodelling and are onerous to replicate. Encapsulation of growth factors (GFs) and Stem cell-based (SCs) has been proclaimed to accelerate healing by transforming every phase associated with wound healing to enhance skin regeneration. Therapeutic application of mesenchymal stem cells (MSCs), embryonic stem cells (ESCs) and induced pluripotent stem cells (PSCs) provides aid in wound fixing, tissue integrity restoration and function of impaired tissue. Several scientific studies have established the essential role GFs in wound healing and their reduced degree in the chronic wound. The overall limitation includes half-life, unfriendly microhabitat abundant with protease, and inadequate delivery approaches results in decreased delivery of effective amounts in a suitable time-based fashion. Advancements in the area of reformative medicine as well as tissue engineering have offered techniques competent of dispensing SCs and GFs in site-oriented manner. The progress in nanotechnology-based approaches attracts researcher to study and evaluate the potential of this SCs and GFs based therapy in chronic wounds. These techniques embrace the polymeric regime viz., nano-formulations, hydrogels, liposomes, scaffolds, nanofibers, metallic nanoparticles, lipid-based nanoparticles and dendrimers that have established better retort through targeting tissues when GFs and SCs are transported via these humans made devices. Assumed the current problems, improvements in delivery approaches and difficulties offered by chronic wounds, we hope to show that encapsulation of SCs and GFs loaded nanoformulations therapies is the rational next step in improving wound care.
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Affiliation(s)
- Preety Sharma
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Arun Kumar
- Chitkara College of Pharmacy, Chitkara University, Punjab, India.
| | - Asmita Deka Dey
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Tapan Behl
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Swati Chadha
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
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30
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Rasheed A, Shawky SA, Tsai R, Jung RG, Simard T, Saikali MF, Hibbert B, Rayner KJ, Cummins CL. The secretome of liver X receptor agonist-treated early outgrowth cells decreases atherosclerosis in Ldlr-/- mice. Stem Cells Transl Med 2020; 10:479-491. [PMID: 33231376 PMCID: PMC7900590 DOI: 10.1002/sctm.19-0390] [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: 11/16/2019] [Revised: 09/11/2020] [Accepted: 09/26/2020] [Indexed: 12/14/2022] Open
Abstract
Endothelial progenitor cells (EPCs) promote the maintenance of the endothelium by secreting vasoreparative factors. A population of EPCs known as early outgrowth cells (EOCs) is being investigated as novel cell‐based therapies for the treatment of cardiovascular disease. We previously demonstrated that the absence of liver X receptors (LXRs) is detrimental to the formation and function of EOCs under hypercholesterolemic conditions. Here, we investigate whether LXR activation in EOCs is beneficial for the treatment of atherosclerosis. EOCs were differentiated from the bone marrow of wild‐type (WT) and LXR‐knockout (Lxrαβ−/−) mice in the presence of vehicle or LXR agonist (GW3965). WT EOCs treated with GW3965 throughout differentiation showed reduced mRNA expression of endothelial lineage markers (Cd144, Vegfr2) compared with WT vehicle and Lxrαβ−/− EOCs. GW3965‐treated EOCs produced secreted factors that reduced monocyte adhesion to activated endothelial cells in culture. When injected into atherosclerosis‐prone Ldlr−/− mice, GW3965‐treated EOCs, or their corresponding conditioned media (CM) were both able to reduce aortic sinus plaque burden compared with controls. Furthermore, when human EOCs (obtained from patients with established CAD) were treated with GW3965 and the CM applied to endothelial cells, monocyte adhesion was decreased, indicating that our results in mice could be translated to patients. Ex vivo LXR agonist treatment of EOCs therefore produces a secretome that decreases early atherosclerosis in Ldlr−/− mice, and additionally, CM from human EOCs significantly inhibits monocyte to endothelial adhesion. Thus, active factor(s) within the GW3965‐treated EOC secretome may have the potential to be useful for the treatment of atherosclerosis.
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Affiliation(s)
- Adil Rasheed
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada
| | - Sarah A Shawky
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada
| | - Ricky Tsai
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada
| | - Richard G Jung
- Capital Research Group, University of Ottawa Heart Institute, Ottawa, Ontario, Canada.,Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.,University of Ottawa Heart Institute, Ottawa, Ontario, Canada
| | - Trevor Simard
- Capital Research Group, University of Ottawa Heart Institute, Ottawa, Ontario, Canada.,Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.,University of Ottawa Heart Institute, Ottawa, Ontario, Canada.,Division of Cardiology, University of Ottawa Heart Institute, Ottawa, Ontario, Canada
| | - Michael F Saikali
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada
| | - Benjamin Hibbert
- Capital Research Group, University of Ottawa Heart Institute, Ottawa, Ontario, Canada.,Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.,University of Ottawa Heart Institute, Ottawa, Ontario, Canada.,Division of Cardiology, University of Ottawa Heart Institute, Ottawa, Ontario, Canada
| | - Katey J Rayner
- University of Ottawa Heart Institute, Ottawa, Ontario, Canada.,Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada
| | - Carolyn L Cummins
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.,Banting and Best Diabetes Centre, Toronto, Ontario, Canada.,The Heart and Stroke Richard Lewar Centre of Excellence in Cardiovascular Research, Toronto, Ontario, Canada
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31
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Duddu S, Chakrabarti R, Ghosh A, Shukla PC. Hematopoietic Stem Cell Transcription Factors in Cardiovascular Pathology. Front Genet 2020; 11:588602. [PMID: 33193725 PMCID: PMC7596349 DOI: 10.3389/fgene.2020.588602] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Accepted: 09/21/2020] [Indexed: 12/14/2022] Open
Abstract
Transcription factors as multifaceted modulators of gene expression that play a central role in cell proliferation, differentiation, lineage commitment, and disease progression. They interact among themselves and create complex spatiotemporal gene regulatory networks that modulate hematopoiesis, cardiogenesis, and conditional differentiation of hematopoietic stem cells into cells of cardiovascular lineage. Additionally, bone marrow-derived stem cells potentially contribute to the cardiovascular cell population and have shown potential as a therapeutic approach to treat cardiovascular diseases. However, the underlying regulatory mechanisms are currently debatable. This review focuses on some key transcription factors and associated epigenetic modifications that modulate the maintenance and differentiation of hematopoietic stem cells and cardiac progenitor cells. In addition to this, we aim to summarize different potential clinical therapeutic approaches in cardiac regeneration therapy and recent discoveries in stem cell-based transplantation.
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Affiliation(s)
| | | | | | - Praphulla Chandra Shukla
- School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur, India
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Cacciapuoti M, Johnson B, Kapdia A, Powell S, Gallicano GI. The Role of Neuregulin and Stem Cells as Therapy Post-Myocardial Infarction. Stem Cells Dev 2020; 29:1266-1274. [PMID: 32731805 DOI: 10.1089/scd.2020.0099] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Coronary artery disease, including myocardial infarction (MI), is a leading cause of morbidity and mortality in the United States. Due to the limited self-renewal capacity of cardiac tissue, MIs can lead to progressive heart disease with a lasting impact on health and quality of life. The recent discovery of cardiac stem cells has incited research into their potential therapeutic applications for patients suffering from cardiovascular disease. Studies have demonstrated the ability of stem cells to both generate cardiac tissues in vitro and aid in the recovery of cardiovascular function in vivo in animal models. However, the long-term efficacy of stem cells as regenerative therapy is still unknown. Exploration of alternative therapies is underway, including the use of cardiac growth factor neuregulin-1 (NRG-1). Research has demonstrated that NRG-1 not only has direct effects on cardiomyocytes (CM) but also acts within the tissues supporting the CM. Transplantation of NRG-1 into ischemic cardiac tissue mitigates the progression of heart failure and can reverse cardiac remodeling. Recent publications have sought to study the combined use of these agents, and while the results are promising, they do warrant further research. This review aims to consider these therapies separately as well as in combination.
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Affiliation(s)
- Maria Cacciapuoti
- Georgetown University School of Medicine, Washington, District of Columbia, USA
| | - Bria Johnson
- Georgetown University School of Medicine, Washington, District of Columbia, USA
| | - Anjani Kapdia
- Georgetown University School of Medicine, Washington, District of Columbia, USA
| | - Sarah Powell
- Georgetown University School of Medicine, Washington, District of Columbia, USA
| | - G Ian Gallicano
- Georgetown University School of Medicine, Washington, District of Columbia, USA
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Shen J, Mu C, Wang H, Huang Z, Yu K, Zoetendal EG, Zhu W. Stimulation of Gastric Transit Function Driven by Hydrolyzed Casein Increases Small Intestinal Carbohydrate Availability and Its Microbial Metabolism. Mol Nutr Food Res 2020; 64:e2000250. [PMID: 32945612 DOI: 10.1002/mnfr.202000250] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2020] [Revised: 08/07/2020] [Indexed: 11/07/2022]
Abstract
Gastrointestinal (GI) functions affect gut nutrient flow and microbial metabolism. Dietary peptides modulate GI functions and improve small intestinal health, but the mechanism remains elusive. This study aims to investigate whether dietary peptides affect small intestinal microbial metabolism, and the underlying mechanisms. An ileal-cannulated pig model is adopted to explore the relationship between gut nutrient flow and microbial metabolism after treatment with hydrolyzed casein (peptides) or intact casein (Control)-based diet. The results demonstrate that hydrolyzed casein enhances microbial carbohydrate metabolism with higher Streptococcus abundance and higher lactate level in the ileum. Meanwhile, hydrolyzed casein increases ileal flows of nutrients, especially carbohydrate, leading to a higher carbohydrate availability in ileal digesta. To unveil the mechanisms, it is found that the hydrolyzed casein enhances the ghrelin signal and improves development of interstitial cells of Cajal and muscular layer in gastric corpus, indicating the enhanced upper GI transit function. In addition, hydrolyzed casein improves small intestinal health, as indicated by higher villus heights and luminal lactate concentrations in the jejunum and ileum. In conclusion, hydrolyzed casein stimulates upper GI transit function, enhances gut nutrient flow, and increases small intestinal carbohydrate availability and its microbial metabolism, which favor the small intestinal health.
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Affiliation(s)
- Junhua Shen
- Laboratory of Gastrointestinal Microbiology, Jiangsu Key Laboratory of Gastrointestinal Nutrition and Animal Health, College of Animal Science and Technology, National Center for International Research on Animal Gut Nutrition, Nanjing Agricultural University, Nanjing, 210095, China
| | - Chunlong Mu
- Laboratory of Gastrointestinal Microbiology, Jiangsu Key Laboratory of Gastrointestinal Nutrition and Animal Health, College of Animal Science and Technology, National Center for International Research on Animal Gut Nutrition, Nanjing Agricultural University, Nanjing, 210095, China
| | - Huisong Wang
- Laboratory of Gastrointestinal Microbiology, Jiangsu Key Laboratory of Gastrointestinal Nutrition and Animal Health, College of Animal Science and Technology, National Center for International Research on Animal Gut Nutrition, Nanjing Agricultural University, Nanjing, 210095, China
| | - Zan Huang
- Laboratory of Gastrointestinal Microbiology, Jiangsu Key Laboratory of Gastrointestinal Nutrition and Animal Health, College of Animal Science and Technology, National Center for International Research on Animal Gut Nutrition, Nanjing Agricultural University, Nanjing, 210095, China
| | - Kaifan Yu
- Laboratory of Gastrointestinal Microbiology, Jiangsu Key Laboratory of Gastrointestinal Nutrition and Animal Health, College of Animal Science and Technology, National Center for International Research on Animal Gut Nutrition, Nanjing Agricultural University, Nanjing, 210095, China
| | - Erwin G Zoetendal
- Laboratory of Microbiology, Wageningen University, Wageningen, 6703 HB, The Netherlands
| | - Weiyun Zhu
- Laboratory of Gastrointestinal Microbiology, Jiangsu Key Laboratory of Gastrointestinal Nutrition and Animal Health, College of Animal Science and Technology, National Center for International Research on Animal Gut Nutrition, Nanjing Agricultural University, Nanjing, 210095, China
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He L, Nguyen NB, Ardehali R, Zhou B. Heart Regeneration by Endogenous Stem Cells and Cardiomyocyte Proliferation: Controversy, Fallacy, and Progress. Circulation 2020; 142:275-291. [PMID: 32687441 DOI: 10.1161/circulationaha.119.045566] [Citation(s) in RCA: 90] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Ischemic heart disease is the leading cause of death worldwide. Myocardial infarction results in an irreversible loss of cardiomyocytes with subsequent adverse remodeling and heart failure. Identifying new sources for cardiomyocytes and promoting their formation represents a goal of cardiac biology and regenerative medicine. Within the past decade, many types of putative cardiac stem cells (CSCs) have been reported to regenerate the injured myocardium by differentiating into new cardiomyocytes. Some of these CSCs have been translated from bench to bed with reported therapeutic effectiveness. However, recent basic research studies on stem cell tracing have begun to question their fundamental biology and mechanisms of action, raising serious concerns over the myogenic potential of CSCs. We review the history of different types of CSCs within the past decade and provide an update of recent cell tracing studies that have challenged the origin and existence of CSCs. In addition to the potential role of CSCs in heart regeneration, proliferation of preexisting cardiomyocytes has recently gained more attention. This review will also evaluate the methodologic and technical aspects of past and current studies on CSCs and cardiomyocyte proliferation, with emphasis on technical strengths, advantages, and potential limitations of research approaches. While our understanding of cardiomyocyte generation and regeneration continues to evolve, it is important to address the shortcomings and inaccuracies in this field. This is best achieved by embracing technological advancements and improved methods to label single cardiomyocytes/progenitors and accurately investigate their developmental potential and fate/lineage commitment.
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Affiliation(s)
- Lingjuan He
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China (L.H., B.Z.)
| | - Ngoc B Nguyen
- Division of Cardiology, Department of Internal Medicine, David Geffen School of Medicine (N.B.N., R.A.), University of California, Los Angeles.,Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research (N.B.N., R.A.), University of California, Los Angeles
| | - Reza Ardehali
- Division of Cardiology, Department of Internal Medicine, David Geffen School of Medicine (N.B.N., R.A.), University of California, Los Angeles.,Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research (N.B.N., R.A.), University of California, Los Angeles
| | - Bin Zhou
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China (L.H., B.Z.).,School of Life Science and Technology, ShanghaiTech University, Shanghai, China (B.Z.).,School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China (B.Z.).,Key Laboratory of Regenerative Medicine of Ministry of Education, Jinan University, Guangzhou, China (B.Z.)
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Fahmy HM, Abd El-Daim TM, Mohamed HAAENE, Mahmoud EAAEQ, Abdallah EAS, Mahmoud Hassan FEZ, Maihop DI, Amin AEAE, Mustafa ABE, Hassan FMA, Mohamed DME, Shams-Eldin EMM. Multifunctional nanoparticles in stem cell therapy for cellular treating of kidney and liver diseases. Tissue Cell 2020; 65:101371. [PMID: 32746989 DOI: 10.1016/j.tice.2020.101371] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2019] [Revised: 04/22/2020] [Accepted: 04/23/2020] [Indexed: 12/13/2022]
Abstract
The review gives an overview of the mechanisms of internalization and distribution of nanoparticles in stem cells this is achieved via providing analysis of the methods used in exploring the migration routes of stem cells, and their reciprocity. In addition, exploring microenvironment target in the body, and tracking the fate of exogenously transplanted stem cells by using innovative and non-invasive techniques will also be discussed. Such techniques like magnetic resonance imaging (MRI), multimodality tracking, optical imaging, and nuclear medicine imaging, which were designed to follow up stem cell migration. This review will explain the various distinctive strategies to enhance homing of labeled stem cells with nanoparticles into damaged hepatic and renal tissues, this purpose was obtained by inducing a specific gene into stem cells, various chemokines, and applying an external magnetic field. Also, this work illustrates how to improve nanoparticles uptake by using transfection agents or covalently binding an exogenous protein (i.e., Human immunodeficiency virus-Tat protein) or conjugating a receptor-specific monoclonal antibody or make modifications to iron coat. It contains stem cell labeling methods such as extracellular labeling and internalization approaches. Ultimately, our review indicates trails of researchers in nanoparticles utilization in stem cell therapy in both kidney and liver diseases.
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Wing TT, Erikson DW, Burghardt RC, Bazer FW, Bayless KJ, Johnson GA. OPN binds alpha V integrin to promote endothelial progenitor cell incorporation into vasculature. Reproduction 2020; 159:465-478. [PMID: 31990676 PMCID: PMC10792589 DOI: 10.1530/rep-19-0358] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2019] [Accepted: 01/28/2020] [Indexed: 11/08/2022]
Abstract
Angiogenesis is fundamental to the expansion of the placental vasculature during pregnancy. Integrins are associated with vascular formation; and osteopontin is a candidate ligand for integrins to promote angiogenesis. Endothelial progenitor cells (EPCs) are released from bone marrow into the blood and incorporate into newly vascularized tissue where they differentiate into mature endothelium. Results of studies in women suggest that EPCs may play an important role in maintaining placental vascular integrity during pregnancy, although little is known about how EPCs are recruited to these tissues. Our goal was to determine the αv integrin mediated effects of osteopontin on EPC adhesion and incorporation into angiogenic vascular networks. EPCs were isolated from 6 h old piglets. RT-PCR revealed that EPCs initially had a monocyte-like phenotype in culture that became more endothelial-like with cell passage. Immunofluorescence microscopy confirmed that the EPCs express platelet endothelial cell adhesion molecule, vascular endothelial cadherin, and von Willebrand factor. When EPCs were cultured on OPN-coated slides, the αv integrin subunit was observed in focal adhesions at the basal surface of EPCs. Silencing of αv integrin reduced EPC binding to OPN and focal adhesion assembly. In vitro siRNA knockdown in EPCs,demonstrated that OPN stimulates EPC incorporation into human umbilical vein endothelial cell (HUVEC) networks via αv-containing integrins. Finally, in situ hybridization and immunohistochemistry localized osteopontin near placental blood vessels. In summary, OPN binds the αv integrin subunit on EPCs to support EPC adhesion and increase EPC incorporation into angiogenic vascular networks.
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Affiliation(s)
- Theodore T. Wing
- Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843
| | - David W. Erikson
- Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843
| | - Robert C. Burghardt
- Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843
| | - Fuller W. Bazer
- Department of Animal Science, Texas A&M University, College Station, TX 77843
| | - Kayla J. Bayless
- Department of Molecular and Cellular Medicine, Texas A&M Health Science Center, College Station, TX 77843
| | - Greg A. Johnson
- Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843
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Nakao S, Tsukamoto T, Ueyama T, Kawamura T. STAT3 for Cardiac Regenerative Medicine: Involvement in Stem Cell Biology, Pathophysiology, and Bioengineering. Int J Mol Sci 2020; 21:ijms21061937. [PMID: 32178385 PMCID: PMC7139789 DOI: 10.3390/ijms21061937] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2020] [Revised: 03/07/2020] [Accepted: 03/10/2020] [Indexed: 12/28/2022] Open
Abstract
Heart disease is the most common cause of death in developed countries, but the medical treatments for heart failure remain limited. In this context, the development of cardiac regeneration therapy for severe heart failure is important. Owing to their unique characteristics, including multiple differentiation and infinitive self-renewal, pluripotent stem cells can be considered as a novel source for regenerative medicine. Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) signaling plays critical roles in the induction, maintenance, and differentiation of pluripotent stem cells. In the heart, JAK/STAT3 signaling has diverse cellular functions, including myocardial differentiation, cell cycle re-entry of matured myocyte after injury, and anti-apoptosis in pathological conditions. Therefore, regulating STAT3 activity has great potential as a strategy of cardiac regeneration therapy. In this review, we summarize the current understanding of STAT3, focusing on stem cell biology and pathophysiology, as they contribute to cardiac regeneration therapy. We also introduce a recently reported therapeutic strategy for myocardial regeneration that uses engineered artificial receptors that trigger endogenous STAT3 signal activation.
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Affiliation(s)
- Shu Nakao
- Department of Biomedical Sciences, College of Life Sciences, Ritsumeikan University, Kusatsu 525-8577, Japan; (S.N.); (T.T.); (T.U.)
- Ritsumeikan Global Innovation Research Institute, Ritsumeikan University, Kusatsu 525-8577, Japan
| | - Tasuku Tsukamoto
- Department of Biomedical Sciences, College of Life Sciences, Ritsumeikan University, Kusatsu 525-8577, Japan; (S.N.); (T.T.); (T.U.)
- Ritsumeikan Global Innovation Research Institute, Ritsumeikan University, Kusatsu 525-8577, Japan
| | - Tomoe Ueyama
- Department of Biomedical Sciences, College of Life Sciences, Ritsumeikan University, Kusatsu 525-8577, Japan; (S.N.); (T.T.); (T.U.)
- Ritsumeikan Global Innovation Research Institute, Ritsumeikan University, Kusatsu 525-8577, Japan
| | - Teruhisa Kawamura
- Department of Biomedical Sciences, College of Life Sciences, Ritsumeikan University, Kusatsu 525-8577, Japan; (S.N.); (T.T.); (T.U.)
- Ritsumeikan Global Innovation Research Institute, Ritsumeikan University, Kusatsu 525-8577, Japan
- Correspondence: ; Tel.: +81-75-599-4327
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Ghanimati R, Rajabi H, Ramezani F, Ramez M, Bapiran M, Nasirinezhad F. The effect of preconditioning with high-intensity training on tissue levels of G-CSF, its receptor and C-kit after an acute myocardial infarction in male rats. BMC Cardiovasc Disord 2020; 20:75. [PMID: 32046645 PMCID: PMC7011373 DOI: 10.1186/s12872-020-01380-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Accepted: 02/06/2020] [Indexed: 02/13/2023] Open
Abstract
BACKGROUND Exercise training is known as a practical way to increase cardioprotection against stress, and it seems that stem cell recruitment is one of its mechanisms. The purpose of the present study was to investigate the effect of preconditioning with High-intensity interval training (HIIT) on tissue levels of G-CSF, its receptor and C-Kit following acute myocardial infarction in male rats. METHODS Twenty Male Wistar rats were randomly divided into 4 groups of control, MI, HIIT, and HIIT+MI. Training groups performed 2 weeks of high intensity interval training in 4 sections. The first section consisted training in 3 days and 2 sessions in each day (4 × 2 min with 35-40 m/min and 3 × 2 min with 25-30 m/min between high intervals. The second part included 2 days of training (4 × 2 min with 40 to 45 m/min and 3 × 2 min with 28 to 32 m /min). The third part was performed in 3 days with one more repetition. The fourth section consisted 2 days of training and with one more repetition compared to section 3. For induction of myocardial infarction, subcutaneous injection of isoprenaline was used. CK, total CK, LDH, and troponin T were measured in serum and G-CSF, G-CSFR and C-Kit proteins were measured by the Western Blot method in the heart tissue. RESULTS The results of this study showed that enzymes of CK, total CK, LDH, troponin T had a significant increase in both MI and HIIT+MI groups compared to the other two groups (P < 0.001) and these indices in the MI group were significantly higher than the HIIT+MI group. Also, the results demonstrated that G-CSF, G-CSFR and C-Kit protein expression in the heart tissue significantly increased after MI. As well as, 2 weeks of HIIT training significantly increased G-CSF and C-kit in the training group compared to the control group, but the training caused that these proteins does not increase in HIIT+MI group as much as MI group. CONCLUSIONS Along with other protective pathways, high intensity interval training can increase cardioprotection and decrease heart injuries through the increase in G-CSF, G-CSFR and C-kit level.
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Affiliation(s)
- Reza Ghanimati
- Department of Exercise physiology, Faculty of Physical Education and Sport Sciences, Kharazmi University, Tehran, Iran
| | - Hamid Rajabi
- Department of Exercise physiology, Faculty of Physical Education and Sport Sciences, Kharazmi University, Tehran, Iran
| | - Fatemeh Ramezani
- Physiology Research Center and Physiology Department, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Maral Ramez
- Department of Exercise physiology, Faculty of Physical Education and Sport Sciences, Kharazmi University, Tehran, Iran
| | - Mohsen Bapiran
- Department of Exercise physiology, Faculty of Physical Education and Sport Sciences, Kharazmi University, Tehran, Iran
| | - Farinaz Nasirinezhad
- Physiology Research Center and Physiology Department, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
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Xiang H, Chen R, Wu S, Xi D, Long S, Shen Y, Fan Z, Ren L. [Construction of three-dimensional dermoid tissue based on cell sheets technology in vitro]. ZHONGGUO XIU FU CHONG JIAN WAI KE ZA ZHI = ZHONGGUO XIUFU CHONGJIAN WAIKE ZAZHI = CHINESE JOURNAL OF REPARATIVE AND RECONSTRUCTIVE SURGERY 2020; 34:116-123. [PMID: 31939246 PMCID: PMC8171817 DOI: 10.7507/1002-1892.201904039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Revised: 11/05/2019] [Indexed: 11/03/2022]
Abstract
OBJECTIVE To explore a new strategy for constructing three-dimensional dermoid tissue in vitro by using cell sheets technology. METHODS Rabbit bone marrow mesenchymal stem cells (rBMSCs) were isolated from bone marrow of New Zealand white rabbits and cultured by whole bone marrow adherent method. Human dermal fibroblasts (HDFs) were cultured and passaged in vitro. The 2nd generation rBMSCs and the 3rd generation HDFs were cultured in a culture dish for 2 weeks with cell sheets conditioned medium respectively to obtain a monolayer cell sheets. Human umbilical vein endothelial cells (HUVECs) were inoculated on rBMSCs sheet to construct pre-vascularized cell sheet. During the culture period, the morphological changes of the cell sheet were observed under an inverted phase contrast microscope. At 1, 3, 7, and 14 days, HE staining and CD31 immunofluorescence staining were performed to observe the cell distribution and microvascular network formation. The rBMSCs sheet was used as control. The pre-vascularized cell sheet (experimental group) and rBMSCs sheet (control group) cultured for 7 days were placed in the middle of two HDFs sheets, respectively, to prepare three-dimensional dermoid tissues. After 24 hours of culture, CD31 immunofluorescence staining and collagen type Ⅰ and collagen type Ⅲ immunohistochemical stainings were performed to evaluate cell distribution and collagen expression. RESULTS HDFs and rBMSCs sheets were successfully prepared after 2 weeks of cell culture. After inoculation of HUVECs on rBMSCs sheet for 3 days, HUVECs could be seen to rearrange on rBMSCs sheet and forming vacuoles. The reticular structure was visible at 7 days and more obvious at 14 days. The formation of vacuoles between the cell sheets was observed by HE staining, and the vacuoles became more and more obvious, the thickness of the membranes increased significantly with time. CD31 immunofluorescence staining showed the microvascular lumen formation. However, only the thickness of rBMSCs sheet increasing was observed, with no changes in cell morphology or cavitation structure. The three-dimensional dermoid tissue observation showed that the endothelial cells in the experimental group were positive expressions, and the rBMSCs, HDFs, and HUVECs cells were arranged neatly. The endothelial cells were negative expressions and randomly arranged in the control group. The collagen type Ⅰ and collagen type Ⅲ were positive expression in the experimental group and the control group. But compared with control group, experimental group presented a "honeycomb" network connection, where the matrix was distributed regularly, and cells were arranged tightly. The difference in the expression of collagen type Ⅰ and collagen type Ⅲ between the experimental group and the control group was not significant ( P>0.05). CONCLUSION Three-dimensional dermoid tissue is successfully constructed by using cell sheet technology. The cell matrix distribution of the pre-vascularized cell sheet constructed by HUVECs and rBMSCs sheet is relatively regular, which has the potential to form tissue engineered dermis.
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Affiliation(s)
- Hua Xiang
- School of Stomatology, Lanzhou University, Lanzhou Gansu, 730000, P.R.China
| | - Rui Chen
- School of Stomatology, Lanzhou University, Lanzhou Gansu, 730000, P.R.China
| | - Shan Wu
- School of Stomatology, Lanzhou University, Lanzhou Gansu, 730000, P.R.China
| | - Dali Xi
- Department of Pathology, the First Affiliated Hospital of Lanzhou University, Lanzhou Gansu, 730000, P.R.China
| | - Siqi Long
- School of Stomatology, Lanzhou University, Lanzhou Gansu, 730000, P.R.China
| | - Yuan Shen
- School of Stomatology, Lanzhou University, Lanzhou Gansu, 730000, P.R.China
| | - Zengjie Fan
- School of Stomatology, Lanzhou University, Lanzhou Gansu, 730000, P.R.China
| | - Liling Ren
- School of Stomatology, Lanzhou University, Lanzhou Gansu, 730000,
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Gao L, Mei S, Zhang S, Qin Q, Li H, Liao Y, Fan H, Liu Z, Zhu H. Cardio-renal Exosomes in Myocardial Infarction Serum Regulate Proangiogenic Paracrine Signaling in Adipose Mesenchymal Stem Cells. Am J Cancer Res 2020; 10:1060-1073. [PMID: 31938051 PMCID: PMC6956822 DOI: 10.7150/thno.37678] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2019] [Accepted: 10/21/2019] [Indexed: 12/22/2022] Open
Abstract
Rationale: Mesenchymal stem cells (MSCs) play important roles in tissue repair and regeneration. However, the molecular mechanisms underlying MSCs activation remain largely unknown, thus hindering their clinical translation. Exosomes are small vesicles that act as intercellular messengers, and their potential for stem cell activation in pathological conditions has not been fully characterized yet. Here, we aim to investigate whether serum exosomes are involved in the remote activation of MSCs after myocardial infarction (MI). Methods: We established MI mouse model by ligating the left anterior descending branch of the coronary artery. Afterwards, serum exosomes were isolated from control (Con Exo) and MI mice (MI Exo) by differential centrifugation. Exosomes were characterized through transmission electron microscopy and nanoparticle tracking analysis. The cell proliferation rate was evaluated by CCK-8 and EdU incorporation assays. Exosomal miRNA and protein levels were assessed using qRT-PCR and western blotting, respectively. VEGF levels in the supernatant and serum were quantified by ELISA. Matrigel plug and tube formation assays were used to evaluate angiogenesis. To explore miR-1956 roles, overexpression and knock-down experiments were performed using mimic and inhibitor, respectively. Finally, miR-1956 target genes were confirmed using the luciferase reporter assay. Results: Both types of exosomes exhibited typical characteristics and could be internalized by adipose-derived MSCs (ADMSCs). MI Exo enhanced ADMSCs proliferation through the activation of ERK1/2. Gain- and loss-of-function studies allowed the validation of miR-1956 (enriched in MI Exo) as the functional messenger that stimulates ADMSCs-mediated angiogenesis and paracrine VEGF signaling, by downregulating Notch-1. Finally, we found that the ischemic myocardium and kidney may be the main sources that release serum exosomes after MI. Conclusions: Cardio-renal exosomes deliver miR-1956 and activate paracrine proangiogenic VEGF signaling in ADMSCs after MI; this process also involves Notch-1, which functions as the core mediator.
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Plenter RJ, Coulombe MG, Roybal HM, Lin CM, Gill RG, Zamora MR, Grazia TJ. C-kit-derived CD11b + cells are critical for cardiac allograft prolongation by autologous C-kit + progenitor cells. Cell Immunol 2020; 347:104023. [PMID: 31836133 DOI: 10.1016/j.cellimm.2019.104023] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2019] [Revised: 11/06/2019] [Accepted: 11/25/2019] [Indexed: 10/25/2022]
Abstract
Autologous C-kit+ cells robustly prolong cardiac allografts. As C-kit+ cells can transdifferentiate to hematopoietic cells as well as non-hematopoietic cells, we aimed to clarify the class(es) of C-kit-derived cell(s) required for cardiac allograft prolongation. Autologous C-kit+ cells were administered post-cardiac transplantation and allografts were evaluated for C-kit+ inoculum-derived cells. Results suggested that alloimmunity was a major signal for trafficking of C-kit-derived cells to the allograft and demonstrated that C-kit+ inoculum-derived cells expressed CD11b early after transfer. Allograft survival studies with CD11b-DTR C-kit+ cells demonstrated a requirement for C-kit+-derived CD11b+ cells. Co-therapy studies demonstrated near complete abrogation of acute rejection with concomitant CTLA4-Ig therapy and no loss of prolongation in combination with Cyclosporine A. These results strongly implicate a C-kit-derived myeloid population as critical for allograft preservation and demonstrate the potential therapeutic application of autologous C-kit+ progenitor cells as calcineurin inhibitor-sparing agents and possibly as co-therapeutics for durable graft survival.
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Affiliation(s)
- R J Plenter
- Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado, Aurora, CO, USA; Department of Surgery, University of Colorado, Aurora, CO, USA.
| | - M G Coulombe
- Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado, Aurora, CO, USA; Department of Surgery, University of Colorado, Aurora, CO, USA.
| | - H M Roybal
- Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado, Aurora, CO, USA.
| | - C M Lin
- Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado, Aurora, CO, USA.
| | - R G Gill
- Department of Microbiology and Immunology, University of Colorado, Aurora, CO, USA; Department of Surgery, University of Colorado, Aurora, CO, USA.
| | - M R Zamora
- Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado, Aurora, CO, USA.
| | - T J Grazia
- Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado, Aurora, CO, USA; Department of Microbiology and Immunology, University of Colorado, Aurora, CO, USA; Division of Pulmonary Diseases, Section of Advanced Lung Disease and Lung Transplantation, Baylor University Medical Center, Dallas, TX, USA.
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Chen CW, Wang LL, Zaman S, Gordon J, Arisi MF, Venkataraman CM, Chung JJ, Hung G, Gaffey AC, Spruce LA, Fazelinia H, Gorman RC, Seeholzer SH, Burdick JA, Atluri P. Sustained release of endothelial progenitor cell-derived extracellular vesicles from shear-thinning hydrogels improves angiogenesis and promotes function after myocardial infarction. Cardiovasc Res 2019; 114:1029-1040. [PMID: 29566124 DOI: 10.1093/cvr/cvy067] [Citation(s) in RCA: 152] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2017] [Accepted: 03/15/2018] [Indexed: 12/14/2022] Open
Abstract
Aims Previous studies have demonstrated improved cardiac function following myocardial infarction (MI) after administration of endothelial progenitor cells (EPCs) into ischaemic myocardium. A growing body of literature supports paracrine effectors, including extracellular vesicles (EVs), as the main mediators of the therapeutic benefits of EPCs. The direct use of paracrine factors is an attractive strategy that harnesses the effects of cell therapy without concerns of cell engraftment or viability. We aim to reproduce the beneficial effects of EPC treatment through delivery of EPC-derived EVs within a shear-thinning gel (STG) for precise localization and sustained delivery. Methods and results EVs were harvested from EPCs isolated from adult male Rattus norvegicus (Wistar) rats and characterized by electron microscopy, nanoparticle tracking analysis (NTA), and mass spectrometry. EVs were incorporated into the STG and injected at the border zone in rat models of MI. Haemodynamic function, angiogenesis, and myocardial remodelling were analyzed in five groups: phosphate buffered saline (PBS) control, STG control, EVs in PBS, EVs in STG, and EPCs in STG. Electron microscopy and NTA of EVs showed uniform particles of 50-200 nm. EV content analysis revealed several key angiogenic mediators. EV uptake by endothelial cells was confirmed and followed by robust therapeutic angiogenesis. In vivo animal experiments demonstrated that delivery of EVs within the STG resulted in increased peri-infarct vascular proliferation, preservation of ventricular geometry, and improved haemodynamic function post-MI. Conclusions EPC-derived EVs delivered into ischaemic myocardium via an injectable hydrogel enhanced peri-infarct angiogenesis and myocardial haemodynamics in a rat model of MI. The STG greatly increased therapeutic efficiency and efficacy of EV-mediated myocardial preservation.
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Affiliation(s)
- Carol W Chen
- Division of Cardiovascular Surgery, Department of Surgery, University of Pennsylvania, Silverstein 6, 3400 Spruce Street, Philadelphia, PA 19104, USA
| | - Leo L Wang
- Department of Bioengineering, University of Pennsylvania, 240 Skirkanich, 210 S 33rd Street, Philadelphia, PA 19104
| | - Samir Zaman
- Division of Cardiovascular Surgery, Department of Surgery, University of Pennsylvania, Silverstein 6, 3400 Spruce Street, Philadelphia, PA 19104, USA
| | - Jon Gordon
- Division of Cardiovascular Surgery, Department of Surgery, University of Pennsylvania, Silverstein 6, 3400 Spruce Street, Philadelphia, PA 19104, USA
| | - Maria F Arisi
- Division of Cardiovascular Surgery, Department of Surgery, University of Pennsylvania, Silverstein 6, 3400 Spruce Street, Philadelphia, PA 19104, USA
| | - Chantel M Venkataraman
- Division of Cardiovascular Surgery, Department of Surgery, University of Pennsylvania, Silverstein 6, 3400 Spruce Street, Philadelphia, PA 19104, USA
| | - Jennifer J Chung
- Division of Cardiovascular Surgery, Department of Surgery, University of Pennsylvania, Silverstein 6, 3400 Spruce Street, Philadelphia, PA 19104, USA
| | - George Hung
- Division of Cardiovascular Surgery, Department of Surgery, University of Pennsylvania, Silverstein 6, 3400 Spruce Street, Philadelphia, PA 19104, USA
| | - Ann C Gaffey
- Division of Cardiovascular Surgery, Department of Surgery, University of Pennsylvania, Silverstein 6, 3400 Spruce Street, Philadelphia, PA 19104, USA
| | - Lynn A Spruce
- Protein and Proteomics Core Facility, The Children's Hospital of Philadelphia Research Institute, 3615 Civic Center Boulevard, Philadelphia, PA 19104, USA
| | - Hossein Fazelinia
- Protein and Proteomics Core Facility, The Children's Hospital of Philadelphia Research Institute, 3615 Civic Center Boulevard, Philadelphia, PA 19104, USA
| | - Robert C Gorman
- Division of Cardiovascular Surgery, Department of Surgery, University of Pennsylvania, Silverstein 6, 3400 Spruce Street, Philadelphia, PA 19104, USA
| | - Steven H Seeholzer
- Protein and Proteomics Core Facility, The Children's Hospital of Philadelphia Research Institute, 3615 Civic Center Boulevard, Philadelphia, PA 19104, USA
| | - Jason A Burdick
- Department of Bioengineering, University of Pennsylvania, 240 Skirkanich, 210 S 33rd Street, Philadelphia, PA 19104
| | - Pavan Atluri
- Division of Cardiovascular Surgery, Department of Surgery, University of Pennsylvania, Silverstein 6, 3400 Spruce Street, Philadelphia, PA 19104, USA
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Sant'Anna RT, Eibel B, Markoski MM, Rodrigues CG, de Salles FB, Giusti II, Nesralla IA, Nardi NB, Kalil RAK. Gene therapy for refractory angina and cell therapy for heart failure: experience of a Brazilian research group. Gene Ther 2019; 27:40-50. [PMID: 31278371 DOI: 10.1038/s41434-019-0087-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2018] [Revised: 05/01/2019] [Accepted: 05/02/2019] [Indexed: 12/11/2022]
Abstract
Cell therapy has shown impressive effects in experimental cardiomyopathy models. To a lesser extent, gene therapy has also been studied. In both cases, translation to clinical therapy has been disappointing. This paper is intended to describe the experience and achievements of a multicenter working group located in Porto Alegre, southern Brazil, in experimental and translational research projects for cell-based and gene therapy methods in the treatment of dilated and ischemic cardiomyopathies. The results of preclinical and clinical studies showed that bone marrow mononuclear stem cells indeed have an effect in improving myocardial perfusion and contractile function, but the overall results are poorly translated to the clinical level. Gene therapy studies with direct myocardial injections of naked VEGF 165 plasmid showed improvement in myocardial perfusion and function in animal models. A randomized clinical trial found that this method is safe and improved myocardial perfusion, but the benefits disappeared after 1 year. An animal experiment associating VEGF 165 with angiopoietin was undertaken in mini pigs to extend the durability of that therapy. In conclusion, our efforts to better understand the mechanisms and functions of gene and cell-based therapies in cardiology resulted in significant findings and propose a future look at cell-free therapeutic approaches.
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Affiliation(s)
- Roberto Tofani Sant'Anna
- Instituto de Cardiologia do Rio Grande do Sul, Av Princesa Isabel 395, 90620-001, Porto Alegre, RS, Brazil
| | - Bruna Eibel
- Instituto de Cardiologia do Rio Grande do Sul, Av Princesa Isabel 395, 90620-001, Porto Alegre, RS, Brazil
| | - Melissa Medeiros Markoski
- Universidade Federal de Ciências da Saúde de Porto Alegre, Rua Sarmento Leite 245, 90050-170, Porto Alegre, RS, Brazil
| | - Clarissa Garcia Rodrigues
- Global Research and Innovation Network - GRINN, Rua Doutor João Colin 1285, Sala 03, 89204-001, Joinville, SC, Brazil
| | - Felipe Borsu de Salles
- Instituto de Cardiologia do Rio Grande do Sul, Av Princesa Isabel 395, 90620-001, Porto Alegre, RS, Brazil
| | - Imarilde Inês Giusti
- Instituto de Cardiologia do Rio Grande do Sul, Av Princesa Isabel 395, 90620-001, Porto Alegre, RS, Brazil
| | - Ivo Abrahão Nesralla
- Instituto de Cardiologia do Rio Grande do Sul, Av Princesa Isabel 395, 90620-001, Porto Alegre, RS, Brazil
| | - Nance Beyer Nardi
- Instituto de Cardiologia do Rio Grande do Sul, Av Princesa Isabel 395, 90620-001, Porto Alegre, RS, Brazil.,Universidade Luterana do Brasil, Av Farroupilha, 8001, 92425-900, Canoas, RS, Brazil
| | - Renato Abdala Karam Kalil
- Instituto de Cardiologia do Rio Grande do Sul, Av Princesa Isabel 395, 90620-001, Porto Alegre, RS, Brazil.
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Rajendran S, Shen X, Glawe J, Kolluru GK, Kevil CG. Nitric Oxide and Hydrogen Sulfide Regulation of Ischemic Vascular Growth and Remodeling. Compr Physiol 2019; 9:1213-1247. [PMID: 31187898 DOI: 10.1002/cphy.c180026] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Ischemic vascular remodeling occurs in response to stenosis or arterial occlusion leading to a change in blood flow and tissue perfusion. Altered blood flow elicits a cascade of molecular and cellular physiological responses leading to vascular remodeling of the macro- and micro-circulation. Although cellular mechanisms of vascular remodeling such as arteriogenesis and angiogenesis have been studied, therapeutic approaches in these areas have had limited success due to the complexity and heterogeneous constellation of molecular signaling events regulating these processes. Understanding central molecular players of vascular remodeling should lead to a deeper understanding of this response and aid in the development of novel therapeutic strategies. Hydrogen sulfide (H2 S) and nitric oxide (NO) are gaseous signaling molecules that are critically involved in regulating fundamental biochemical and molecular responses necessary for vascular growth and remodeling. This review examines how NO and H2 S regulate pathophysiological mechanisms of angiogenesis and arteriogenesis, along with important chemical and experimental considerations revealed thus far. The importance of NO and H2 S bioavailability, their synthesis enzymes and cofactors, and genetic variations associated with cardiovascular risk factors suggest that they serve as pivotal regulators of vascular remodeling responses. © 2019 American Physiological Society. Compr Physiol 9:1213-1247, 2019.
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Affiliation(s)
| | - Xinggui Shen
- Departments of Pathology, LSU Health Sciences Center, Shreveport
| | - John Glawe
- Departments of Pathology, LSU Health Sciences Center, Shreveport
| | - Gopi K Kolluru
- Departments of Pathology, LSU Health Sciences Center, Shreveport
| | - Christopher G Kevil
- Departments of Pathology, LSU Health Sciences Center, Shreveport.,Departments of Cellular Biology and Anatomy, LSU Health Sciences Center, Shreveport.,Departments of Molecular and Cellular Physiology, LSU Health Sciences Center, Shreveport
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45
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Endothelial progenitor cells: Potential novel therapeutics for ischaemic stroke. Pharmacol Res 2019; 144:181-191. [DOI: 10.1016/j.phrs.2019.04.017] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Revised: 04/08/2019] [Accepted: 04/16/2019] [Indexed: 01/15/2023]
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46
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Huang K, Li Z, Su T, Shen D, Hu S, Cheng K. Bispecific Antibody Therapy for Effective Cardiac Repair through Redirection of Endogenous Stem Cells. ADVANCED THERAPEUTICS 2019. [DOI: 10.1002/adtp.201900009] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Affiliation(s)
- Ke Huang
- Department of Molecular Biomedical Sciences North Carolina University Raleigh NC 27607 USA
| | - Zhenhua Li
- Department of Molecular Biomedical Sciences North Carolina University Raleigh NC 27607 USA
- Joint Department of Biomedical Engineering University of North Carolina at Chapel Hill and North Carolina State University Raleigh NC 27695 USA
| | - Teng Su
- Department of Molecular Biomedical Sciences North Carolina University Raleigh NC 27607 USA
- Joint Department of Biomedical Engineering University of North Carolina at Chapel Hill and North Carolina State University Raleigh NC 27695 USA
| | - Deliang Shen
- Department of Cardiology The First Affiliated Hospital of Zhengzhou University Zhengzhou Henan 450052 China
| | - Shiqi Hu
- Department of Molecular Biomedical Sciences North Carolina University Raleigh NC 27607 USA
- Joint Department of Biomedical Engineering University of North Carolina at Chapel Hill and North Carolina State University Raleigh NC 27695 USA
| | - Ke Cheng
- Department of Molecular Biomedical Sciences North Carolina University Raleigh NC 27607 USA
- Joint Department of Biomedical Engineering University of North Carolina at Chapel Hill and North Carolina State University Raleigh NC 27695 USA
- Division of Pharmacoengineering and Molecular Pharmaceutics Eshelman School of Pharmacy University of North Carolina at Chapel Hill Chapel Hill NC 27599 USA
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Pourtaji A, Jahani V, Moallem SMH, Karimani A, Mohammadpour AH. Application of G-CSF in Congestive Heart Failure Treatment. Curr Cardiol Rev 2019; 15:83-90. [PMID: 30378501 PMCID: PMC6520582 DOI: 10.2174/1573403x14666181031115118] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2018] [Revised: 10/17/2018] [Accepted: 10/24/2018] [Indexed: 12/23/2022] Open
Abstract
INTRODUCTION Congestive Heart Failure (CHF) is a disorder in which the heart is unable to supply enough blood for body tissues. Since heart is an adaptable organ, it overcomes this condition by going under remodeling process. Considering cardiac myocytes are capable of proliferation after MI, stimulation of neovascularization as well as their regeneration might serve as a novel target in cardiac remodeling prevention and CHF treatment. Granulocyte Colony-Stimulating Factor (G-CSF), is a hematopoietic cytokine that promotes proliferation and differentiation of neutrophils and is involved in cardiac repair after MI. So far, this is the first review to focus on GCSF as a novel treatment for heart failure. METHODS We conducted a search of some databases such as PubMed for articles and reviews published between 2003 and 2017, with different keywords including "G-CSF", "congestive heart failure", "new therapies for CHF", "filgrastim", "in vivo study". RESULTS GCSF exerts its beneficial effects on cardiac repair through either stem cell mobilization or direct angiogenesis promotion. All of which are capable of promoting cardiac cell repair. CONCLUSION GCSF is a promising target in CHF-therapy by means of cardiac repair and remodeling prevention through multiple mechanisms, which are effective enough to be used in clinical practice.
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Affiliation(s)
- Atena Pourtaji
- Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Vajiheh Jahani
- Department of Clinical Pharmacy, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Asieh Karimani
- Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amir Hooshang Mohammadpour
- Department of Clinical Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.,Pharmaceutical Research Center, Institute of Pharmaceutical Technology, Mashhad University of Medical Sciences, Mashhad, Iran
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Gao F, Kataoka M, Liu N, Liang T, Huang ZP, Gu F, Ding J, Liu J, Zhang F, Ma Q, Wang Y, Zhang M, Hu X, Kyselovic J, Hu X, Pu WT, Wang J, Chen J, Wang DZ. Therapeutic role of miR-19a/19b in cardiac regeneration and protection from myocardial infarction. Nat Commun 2019; 10:1802. [PMID: 30996254 PMCID: PMC6470165 DOI: 10.1038/s41467-019-09530-1] [Citation(s) in RCA: 199] [Impact Index Per Article: 33.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2017] [Accepted: 03/11/2019] [Indexed: 12/20/2022] Open
Abstract
The primary cause of heart failure is the loss of cardiomyocytes in the diseased adult heart. Previously, we reported that the miR-17-92 cluster plays a key role in cardiomyocyte proliferation. Here, we report that expression of miR-19a/19b, members of the miR-17-92 cluster, is induced in heart failure patients. We show that intra-cardiac injection of miR-19a/19b mimics enhances cardiomyocyte proliferation and stimulates cardiac regeneration in response to myocardial infarction (MI) injury. miR-19a/19b protected the adult heart in two distinctive phases: an early phase immediately after MI and long-term protection. Genome-wide transcriptome analysis demonstrates that genes related to the immune response are repressed by miR-19a/19b. Using an adeno-associated virus approach, we validate that miR-19a/19b reduces MI-induced cardiac damage and protects cardiac function. Finally, we confirm the therapeutic potential of miR-19a/19b in protecting cardiac function by systemically delivering miR-19a/19b into mice post-MI. Our study establishes miR-19a/19b as potential therapeutic targets to treat heart failure.
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Affiliation(s)
- Feng Gao
- Department of Cardiology, The Second Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, 310029, Hangzhou, China
| | - Masaharu Kataoka
- Department of Cardiology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA, 02115, USA
- Department of Cardiology, Keio University School of Medicine, Tokyo, 160-8582, Japan
| | - Ning Liu
- Department of Cardiology, The Second Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, 310029, Hangzhou, China
| | - Tian Liang
- Department of Cardiology, The Second Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, 310029, Hangzhou, China
| | - Zhan-Peng Huang
- Department of Cardiology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA, 02115, USA
- Center for Translational Medicine, The First Affiliated Hospital, NHC Key Laboratory of Assisted Circulation, Sun Yat-sen University, Guangzhou, 510080, China
| | - Fei Gu
- Department of Cardiology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA, 02115, USA
| | - Jian Ding
- Department of Cardiology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA, 02115, USA
| | - Jianming Liu
- Department of Cardiology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA, 02115, USA
| | - Feng Zhang
- Department of Cardiology, The Second Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, 310029, Hangzhou, China
| | - Qing Ma
- Department of Cardiology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA, 02115, USA
| | - Yingchao Wang
- Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, 310009, Hangzhou, China
| | - Mingming Zhang
- Department of Cardiology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA, 02115, USA
| | - Xiaoyun Hu
- Department of Cardiology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA, 02115, USA
| | - Jan Kyselovic
- Faculty of Pharmacy, Comenius University, Bratislava, 832 32, Slovak Republic
| | - Xinyang Hu
- Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, 310009, Hangzhou, China
| | - William T Pu
- Department of Cardiology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA, 02115, USA
- Harvard Stem Cell Institute, Harvard University, Cambridge, MA, 02138, USA
| | - Jian'an Wang
- Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, 310009, Hangzhou, China
| | - Jinghai Chen
- Department of Cardiology, The Second Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, 310029, Hangzhou, China.
| | - Da-Zhi Wang
- Department of Cardiology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA, 02115, USA.
- Harvard Stem Cell Institute, Harvard University, Cambridge, MA, 02138, USA.
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Zubkova ES, Beloglazova IB, Evtushenko EG, Kopylov AT, Shevchenko EK, Dergilev KV, Ratner EI, Parfenova EV, Men'shikov MY. Application of Adeno-Associated Virus Vectors for Engineering SCF-Containing Extracellular Vesicles of Mesenchymal Stromal Cells. Bull Exp Biol Med 2019; 166:527-534. [PMID: 30793234 DOI: 10.1007/s10517-019-04387-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2018] [Indexed: 12/12/2022]
Abstract
Mesenchymal stromal cells from rat adipose tissue were transduced with adeno-associated viral (AAV) vector encoding stem cell factor SCF that stimulates proliferation of cardiac c-kit+ cells and improved cardiac function and survival of animals after myocardial infarction. Extracellular vesicles isolated from the medium conditioned by mesenchymal stromal cells by ultracentrifugation were characterized by Western blotting, transmission electron microscopy, nanoparticle tracking analysis, immunostaining, and mass spectrometry analysis. Using proteomic analysis, we identified transgenic SCF in extracellular vesicles released by AAV-modified mesenchymal stromal cells and detected some proteins specific of extracellular vesicles secreted by transduced cells. Extracellular vesicles from AAV-transduced mesenchymal stromal cells could be used for delivery of transgenic proteins as they were readily endocytosed by both cardiosphere-derived cells and cardiac-progenitor cells.
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Affiliation(s)
- E S Zubkova
- National Medical Research Center for Cardiology, Ministry of Health of the Russian Federation, Moscow, Russia. .,M. V. Lomonosov Moscow State University, Moscow, Russia.
| | - I B Beloglazova
- National Medical Research Center for Cardiology, Ministry of Health of the Russian Federation, Moscow, Russia.,M. V. Lomonosov Moscow State University, Moscow, Russia
| | - E G Evtushenko
- National Medical Research Center for Cardiology, Ministry of Health of the Russian Federation, Moscow, Russia
| | | | - E K Shevchenko
- National Medical Research Center for Cardiology, Ministry of Health of the Russian Federation, Moscow, Russia
| | - K V Dergilev
- National Medical Research Center for Cardiology, Ministry of Health of the Russian Federation, Moscow, Russia.,M. V. Lomonosov Moscow State University, Moscow, Russia
| | - E I Ratner
- National Medical Research Center for Cardiology, Ministry of Health of the Russian Federation, Moscow, Russia
| | - E V Parfenova
- National Medical Research Center for Cardiology, Ministry of Health of the Russian Federation, Moscow, Russia.,M. V. Lomonosov Moscow State University, Moscow, Russia
| | - M Yu Men'shikov
- National Medical Research Center for Cardiology, Ministry of Health of the Russian Federation, Moscow, Russia
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50
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Regenerating the field of cardiovascular cell therapy. Nat Biotechnol 2019; 37:232-237. [PMID: 30778231 DOI: 10.1038/s41587-019-0042-1] [Citation(s) in RCA: 125] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Accepted: 01/18/2019] [Indexed: 01/11/2023]
Abstract
The retraction of >30 falsified studies by Anversa et al. has had a disheartening impact on the cardiac cell therapeutics field. The premise of heart muscle regeneration by the transdifferentiation of bone marrow cells or putative adult resident cardiac progenitors has been largely disproven. Over the past 18 years, a generation of physicians and scientists has lost years chasing these studies, and patients have been placed at risk with little scientific grounding. Funding agencies invested hundreds of millions of dollars in irreproducible work, and both academic institutions and the scientific community ignored troubling signals over a decade of questionable work. Our collective retrospective analysis identifies preventable problems at the level of the editorial and peer-review process, funding agencies and academic institutions. This Perspective provides a chronology of the forces that led to this scientific debacle, integrating direct knowledge of the process. We suggest a science-driven path forward that includes multiple novel approaches to the problem of heart muscle regeneration.
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