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1
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Mardi N, Khanicheragh P, Abbasi-Malati Z, Saghebasl S, Khosrowshahi ND, Chegeni SA, Javid F, Azari M, Salimi L, Rezabakhsh A, Milani SZ, Rahbarghazi R. Beneficial and challenges of exosome application in ischemic heart disease. Stem Cell Res Ther 2025; 16:247. [PMID: 40390086 PMCID: PMC12090443 DOI: 10.1186/s13287-025-04363-w] [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: 01/13/2025] [Accepted: 04/23/2025] [Indexed: 05/21/2025] Open
Abstract
Cardiovascular diseases are the main cause of death and disability in the clinical setting. Among several pathological conditions, myocardial infarction (MI) is a common clinical finding and happens due to the reduction or complete interruption of blood support. Stem cells and progenitors are valid cell sources with significant potential to alleviate several tissue injuries. Differentiation to mature and functional cells and the release of various growth factors, and cytokines are the main reparative mechanisms by which stem cells mediate their reparative tasks. Exosomes (Exos), a subset of extracellular vesicles (EVs), exhibit great theranostic potential in biomedicine. Along with whole-cell-based therapies, the pre-clinical and clinical application of Exos has been extended in animals and humans with ischemic heart diseases (IHD). Here, in this review article, we aimed to highlight the importance of Exos in IHD and address the mechanism of action by focusing on their regenerative potential.
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Affiliation(s)
- Narges Mardi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Parisa Khanicheragh
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Zahra Abbasi-Malati
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
- Tuberculosis and Lung Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Solmaz Saghebasl
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Nafiseh Didar Khosrowshahi
- Stem Cell and Tissue Engineering Research Laboratory, Sahand University of Technology, Tabriz, 51335-1996, Iran
| | | | - Farzin Javid
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mahdiyeh Azari
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Leila Salimi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Aysa Rezabakhsh
- Cardiovascular Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Soheil Zamen Milani
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Reza Rahbarghazi
- Tuberculosis and Lung Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
- Department of Applied Cell Sciences, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
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Báez-Díaz C, Torrescusa-Bermejo A, Sánchez-Margallo FM, Vázquez-López F, Pulido M, López E, Arenal Á, Crisóstomo V. Intracoronary-Cardiosphere-Derived Cell Secretome Therapy: Effects on Ventricular Tachycardia Inducibility and Cardiac Function in a Swine Model. Biomedicines 2025; 13:1043. [PMID: 40426870 PMCID: PMC12108644 DOI: 10.3390/biomedicines13051043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2025] [Revised: 04/22/2025] [Accepted: 04/23/2025] [Indexed: 05/29/2025] Open
Abstract
Background/Objectives: Ventricular tachycardia (VT) resulting in sudden cardiac death is common following a myocardial infarction (MI). Our objective was to evaluate the effects of an intracoronary (IC) administration of cardiosphere-derived cell secretome (S-CDCs) on VT inducibility and cardiac function in a swine model of MI. Methods: Fourteen pigs underwent endovascular MI model creation. At 4 weeks, saline (CON; 5 mL; n = 7) or S-CDCs (S-CDCs; 9.16 mg protein in 5 mL saline; n = 7) was blindly administered via the IC route. VT inducibility and magnetic resonance imaging (MRI) studies were performed both pre- and 4 months post-IC therapy, calculating left ventricular ejection fraction (LVEF), infarct size as a percentage of left ventricle (% MI), and left ventricular indexed end-diastolic and end-systolic volumes (LVEDVi, LVESVi). Results: While VT was inducible in 100% of the animals before IC therapy, at 4 months, the inducibility rate was lower in the S-CDCs group compared to the CON group (57% versus 100%, p = 0.05). Likewise, in the S-CDCs group, % MI was significantly lower than in the CON group (12 ± 3% versus 16 ± 3%, p = 0.03). LVEF (S-CDCs: 35 ± 10% versus CON: 29 ± 10%, p = NS), LVEDVi and LVESVi (S-CDCs: 83 ± 18 mL/m2 and 56 ± 20 mL/m2 versus CON: 88 ± 29 mL/m2 and 64 ± 20 mL/m2, p = NS) did not change. Conclusions: IC therapy with S-CDCs appears to reduce the development of post-MI VT. Furthermore, it suggests a beneficial effect on infarct size, reducing % MI in this experimental swine model.
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Affiliation(s)
- Claudia Báez-Díaz
- Fundación Centro de Cirugía de Mínima Invasión Jesús Usón, 10071 Cáceres, Spain; (A.T.-B.); (F.M.S.-M.); (F.V.-L.); (M.P.); (E.L.); (V.C.)
- Red Española de Terapias Avanzadas RICORS-TERAV, 28029 Madrid, Spain
| | - Axiel Torrescusa-Bermejo
- Fundación Centro de Cirugía de Mínima Invasión Jesús Usón, 10071 Cáceres, Spain; (A.T.-B.); (F.M.S.-M.); (F.V.-L.); (M.P.); (E.L.); (V.C.)
| | - Francisco Miguel Sánchez-Margallo
- Fundación Centro de Cirugía de Mínima Invasión Jesús Usón, 10071 Cáceres, Spain; (A.T.-B.); (F.M.S.-M.); (F.V.-L.); (M.P.); (E.L.); (V.C.)
- Red Española de Terapias Avanzadas RICORS-TERAV, 28029 Madrid, Spain
| | - Fátima Vázquez-López
- Fundación Centro de Cirugía de Mínima Invasión Jesús Usón, 10071 Cáceres, Spain; (A.T.-B.); (F.M.S.-M.); (F.V.-L.); (M.P.); (E.L.); (V.C.)
| | - María Pulido
- Fundación Centro de Cirugía de Mínima Invasión Jesús Usón, 10071 Cáceres, Spain; (A.T.-B.); (F.M.S.-M.); (F.V.-L.); (M.P.); (E.L.); (V.C.)
| | - Esther López
- Fundación Centro de Cirugía de Mínima Invasión Jesús Usón, 10071 Cáceres, Spain; (A.T.-B.); (F.M.S.-M.); (F.V.-L.); (M.P.); (E.L.); (V.C.)
- Red Española de Terapias Avanzadas RICORS-TERAV, 28029 Madrid, Spain
| | - Ángel Arenal
- Hospital General Universitario Gregorio Marañón, 28007 Madrid, Spain;
| | - Verónica Crisóstomo
- Fundación Centro de Cirugía de Mínima Invasión Jesús Usón, 10071 Cáceres, Spain; (A.T.-B.); (F.M.S.-M.); (F.V.-L.); (M.P.); (E.L.); (V.C.)
- Red Española de Terapias Avanzadas RICORS-TERAV, 28029 Madrid, Spain
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Tandon R, Srivastava N. Unravelling exosome paradigm: Therapeutic, diagnostic and theranostics application and regulatory consideration. Life Sci 2025; 366-367:123472. [PMID: 39956185 DOI: 10.1016/j.lfs.2025.123472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2024] [Revised: 01/13/2025] [Accepted: 02/13/2025] [Indexed: 02/18/2025]
Abstract
In the recent decade, extracellular vesicles (EVs) have been released from nearly all the kingdoms, modulating intercellular communication and maintaining the human body's homeostasis by regulating different cellular processes. Among EVs, exosomes are the emerging field in biopharmaceuticals. They have lipid bilayer ranging from 30 to 150 nm in size and encompass DNA, RNA, protein lipids, etc. Their sources are widespread, easy to acquire, and cost-effective in manufacturing. This review focuses on the detailed classification of exosomes existing in nature, knowledge and application of omics, therapeutic, diagnostic and theranostic application of exosomes. It covers diseases such as cancer, infectious diseases (viral, bacterial, fungal infections), neurodegenerative diseases, metabolic diseases, lifestyle diseases (diabetes, cardiovascular, gastric disorder (IBD)), autoimmune disorders and their biodistribution. This article unfolds the recent progress in the exosomes arena and covers all the regulatory considerations (FDA, EMA, and other nations) involved with it. Moreover, a detailed discussion about clinical trials and its manifestation with exosomes and challenges associated with their isolation procedures, reproducibility, and safety concerns.
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Affiliation(s)
- Reetika Tandon
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research-Raebareli, Lucknow 226002, India
| | - Nidhi Srivastava
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research-Raebareli, Lucknow 226002, India.
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Tariq H, Bukhari SZ, An R, Dong J, Ihsan A, Younis MR. Stem cell-derived exosome delivery systems for treating atherosclerosis: The new frontier of stem cell therapy. Mater Today Bio 2025; 30:101440. [PMID: 39866781 PMCID: PMC11758955 DOI: 10.1016/j.mtbio.2024.101440] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Revised: 12/14/2024] [Accepted: 12/30/2024] [Indexed: 01/28/2025] Open
Abstract
Cardiovascular diseases (CVDs) are a leading cause of mortality worldwide. As a chronic inflammatory disease with a complicated pathophysiology marked by abnormal lipid metabolism and arterial plaque formation, atherosclerosis is a major contributor to CVDs and can induce abrupt cardiac events. The discovery of exosomes' role in intercellular communication has sparked a great deal of interest in them recently. Exosomes are involved in strategic phases of the onset and development of atherosclerosis because they have been identified to control pathophysiologic pathways including inflammation, angiogenesis, or senescence. This review investigates the potential role of stem cell-derived exosomes in atherosclerosis management. We briefly introduced atherosclerosis and stem cell therapy including stem cell-derived exosomes. The biogenesis of exosomes along with their secretion and isolation have been elaborated. The design engineering of exosomes has been summarized to present how drug loading and surface modification with targeting ligands can improve the therapeutic and targeting capacity of exosomes, demonstrating atheroprotective action. Moreover, the mechanism of action (endothelial dysfunction, reduction of dyslipidemia, macrophage polarization, vascular calcification, and angiogenesis) of drug-loaded exosomes to treat atherosclerosis has been discussed in detail. In the end, a comparative and balanced viewpoint has been given regarding the current challenges and potential solutions to advance exosome engineering for cardiovascular therapeutic applications.
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Affiliation(s)
- Hassan Tariq
- Department of Molecular, Cell and Developmental Biology, University of California - Los Angeles, Los Angeles, CA, 90095, USA
| | - Syeda Zunaira Bukhari
- National Institute for Biotechnology and Genetic Engineering College, Pakistan Institute of Engineering and Applied Sciences (NIBGE-C, PIEAS), Faisalabad, Pakistan
| | - Ruibing An
- Institute of Optical Functional Materials for Biomedical Imaging, School of Chemistry and Pharmaceutical Engineering, Shandong First Medical University & Shandong Academy of Medical Science, Taian, Shandong, 271016, PR China
| | - Jian Dong
- Institute of Optical Functional Materials for Biomedical Imaging, School of Chemistry and Pharmaceutical Engineering, Shandong First Medical University & Shandong Academy of Medical Science, Taian, Shandong, 271016, PR China
| | - Ayesha Ihsan
- National Institute for Biotechnology and Genetic Engineering College, Pakistan Institute of Engineering and Applied Sciences (NIBGE-C, PIEAS), Faisalabad, Pakistan
| | - Muhammad Rizwan Younis
- Institute of Optical Functional Materials for Biomedical Imaging, School of Chemistry and Pharmaceutical Engineering, Shandong First Medical University & Shandong Academy of Medical Science, Taian, Shandong, 271016, PR China
- Department of Chemical and Biomolecular Engineering, University of California - Los Angeles, Los Angeles, CA, 90095, USA
- Department of Molecular, Cell and Developmental Biology, University of California - Los Angeles, Los Angeles, CA, 90095, USA
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5
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Schoettler FI, Fatehi Hassanabad A, Jadli AS, Patel VB, Fedak PWM. Exploring the role of pericardial miRNAs and exosomes in modulating cardiac fibrosis. Cardiovasc Pathol 2024; 73:107671. [PMID: 38906439 DOI: 10.1016/j.carpath.2024.107671] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2024] [Revised: 05/26/2024] [Accepted: 06/15/2024] [Indexed: 06/23/2024] Open
Abstract
The potential of the pericardial space as a therapeutic delivery tool for cardiac fibrosis and heart failure (HF) treatment has yet to be elucidated. Recently, miRNAs and exosomes have been discovered to be present in human pericardial fluid (PF). Novel studies have shown characteristic human PF miRNA compositions associated with cardiac diseases and higher miRNA expressions in PF compared to peripheral blood. Five key studies found differentially expressed miRNAs in HF, angina pectoris, aortic stenosis, ventricular tachycardia, and congenital heart diseases with either atrial fibrillation or sinus rhythm. As miRNA-based therapeutics for cardiac fibrosis and HF showed promising results in several in vivo studies for multiple miRNAs, we hypothesize a potential role of miRNA-based therapeutics delivered through the pericardial cavity. This is underlined by the favorable results of the first phase 1b clinical trial in this emerging field. Presenting the first human miRNA antisense drug trial, inhibition of miR-132 by intravenous administration of a novel antisense oligonucleotide, CDR132L, established efficacy in reducing miR-132 in plasma samples in a dose-dependent manner. We screened the literature, provided an overview of the miRNAs and exosomes present in PF, and drew a connection to those miRNAs previously elucidated in cardiac fibrosis and HF. Further, we speculate about clinical implications and potential delivery methods.
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Affiliation(s)
- Friederike I Schoettler
- Department of Cardiac Sciences, Libin Cardiovascular Institute, University of Calgary, Calgary, Alberta, Canada; Department of Cardiac Surgery, Medical Faculty, University Hospital Düsseldorf, Heinrich-Heine-University, Düsseldorf, Germany
| | - Ali Fatehi Hassanabad
- Department of Cardiac Sciences, Libin Cardiovascular Institute, University of Calgary, Calgary, Alberta, Canada; Department of Cardiac Sciences, Section of Cardiac Surgery, Libin Cardiovascular Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Anshul S Jadli
- Department of Cardiac Sciences, Libin Cardiovascular Institute, University of Calgary, Calgary, Alberta, Canada; Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Vaibhav B Patel
- Department of Cardiac Sciences, Libin Cardiovascular Institute, University of Calgary, Calgary, Alberta, Canada; Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Paul W M Fedak
- Department of Cardiac Sciences, Libin Cardiovascular Institute, University of Calgary, Calgary, Alberta, Canada; Department of Cardiac Sciences, Section of Cardiac Surgery, Libin Cardiovascular Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
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Liu C, Zhang D, Long K, Qi W, Pang L, Li J, Cheng KKY, Cai Y. From exosomes to mitochondria and myocardial infarction: Molecular insight and therapeutic challenge. Pharmacol Res 2024; 209:107468. [PMID: 39426469 DOI: 10.1016/j.phrs.2024.107468] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Revised: 09/21/2024] [Accepted: 10/14/2024] [Indexed: 10/21/2024]
Abstract
Myocardial infarction (MI) remains a leading cause of mortality worldwide. Despite patients with MI benefit from timely reperfusion therapies, the rates of mortality and morbidity remain substantial, suggesting an enduring need for the development of new approaches. Molecular mechanisms underlying myocardial ischemic injury are associated with both cardiomyocytes and non-cardiomyocytes. Exosomes are nano-sized extracellular vesicles released by almost all eukaryotic cells. They facilitate the communication between various cells by transferring information via their cargo and altering different biological activities in recipient cells. Studies have created great prospects for therapeutic applications of exosomes in MI, as demonstrated through their beneficial effect on heart function and reducing ventricular remodeling in association with fibrosis, angiogenesis, apoptosis, and inflammation. Of note, myocardial ischemic injury is primarily due to restricted blood flow, reducing oxygen availability, and causing inefficient utilization of energy substrates. However, the impact of exosomes on cardiac energy metabolism has not been adequately investigated. Although exosomes have been engineered for targeted delivery to enhance clinical efficacy, challenges must be overcome to utilize them reliably in the clinic. In this review, we summarize the research progress of exosomes for MI with a focus on the known and unknown regarding the role of exosomes in energy metabolism in cardiomyocytes and non-cardiomyocytes; as well as potential research avenues of exosome-mitochondrial energy regulation as well as therapeutic challenges. We aim to help identify more efficient molecular targets that may promote the clinical application of exosomes.
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Affiliation(s)
- Chang Liu
- Department of Anesthesiology, The First Hospital of Jilin University, Jilin, China; Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong SAR, China
| | - Dengwen Zhang
- Department of Anesthesiology, Heyuan People's Hospital, Guangdong, China; Department of Anesthesiology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangdong, China
| | - Kekao Long
- Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong SAR, China
| | - Wensheng Qi
- Department of Anesthesiology, The First Hospital of Jilin University, Jilin, China; Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong SAR, China
| | - Lei Pang
- Department of Anesthesiology, The First Hospital of Jilin University, Jilin, China
| | - Jia Li
- Department of Neurology, Wuhan No.1 Hospital, Hubei, China
| | - Kenneth King-Yip Cheng
- Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong SAR, China.
| | - Yin Cai
- Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong SAR, China; Research Center for Chinese Medicine Innovation, The Hong Kong Polytechnic University, Hong Kong SAR, China; Research Institute for Future Food, The Hong Kong Polytechnic University, Hong Kong SAR, China.
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7
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Feng Y, Wang Y, Li L, Yang Y, Tan X, Chen T. Exosomes Induce Crosstalk Between Multiple Types of Cells and Cardiac Fibroblasts: Therapeutic Potential for Remodeling After Myocardial Infarction. Int J Nanomedicine 2024; 19:10605-10621. [PMID: 39445157 PMCID: PMC11498042 DOI: 10.2147/ijn.s476995] [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] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Accepted: 10/09/2024] [Indexed: 10/25/2024] Open
Abstract
Recanalization therapy can significantly improve the prognosis of patients with acute myocardial infarction (AMI). However, infarction or reperfusion-induced cardiomyocyte death, immune cell infiltration, fibroblast proliferation, and scarring formation lead to cardiac remodeling and gradually progress to heart failure or arrhythmia, resulting in a high mortality rate. Due to the inability of cardiomyocytes to regenerate, the healing of infarcted myocardium mainly relies on the formation of scars. Cardiac fibroblasts, as the main effector cells involved in repair and scar formation, play a crucial role in maintaining the structural integrity of the heart after MI. Recent studies have revealed that exosome-mediated intercellular communication plays a huge role in myocardial repair and signaling transduction after myocardial infarction (MI). Exosomes can regulate the biological behavior of fibroblasts by activating or inhibiting the intracellular signaling pathways through their contents, which are derived from cardiomyocytes, immune cells, endothelial cells, mesenchymal cells, and others. Understanding the interactions between fibroblasts and other cell types during cardiac remodeling will be the key to breakthrough therapies. This review examines the role of exosomes from different sources in the repair process after MI injury, especially the impacts on fibroblasts during myocardial remodeling, and explores the use of exosomes in the treatment of myocardial remodeling after MI.
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Affiliation(s)
- Yijuan Feng
- Key Laboratory of Medical Electrophysiology of the Ministry of Education, Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, Sichuan, People’s Republic of China
| | - Yan Wang
- Key Laboratory of Medical Electrophysiology of the Ministry of Education, Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, Sichuan, People’s Republic of China
| | - Li Li
- Key Laboratory of Medical Electrophysiology of the Ministry of Education, Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, Sichuan, People’s Republic of China
| | - Yan Yang
- Key Laboratory of Medical Electrophysiology of the Ministry of Education, Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, Sichuan, People’s Republic of China
| | - Xiaoqiu Tan
- Key Laboratory of Medical Electrophysiology of the Ministry of Education, Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, Sichuan, People’s Republic of China
- Department of Cardiology, the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China
- Department of Physiology, School of Basic Medical Sciences, Southwest Medical University, Luzhou, Sichuan, People’s Republic of China
| | - Tangting Chen
- Key Laboratory of Medical Electrophysiology of the Ministry of Education, Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, Sichuan, People’s Republic of China
- Department of Cardiology, the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China
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Long M, Cheng M. Small extracellular vesicles associated miRNA in myocardial fibrosis. Biochem Biophys Res Commun 2024; 727:150336. [PMID: 38959731 DOI: 10.1016/j.bbrc.2024.150336] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Revised: 06/20/2024] [Accepted: 06/29/2024] [Indexed: 07/05/2024]
Abstract
Myocardial fibrosis involves the loss of cardiomyocytes, myocardial fibroblast proliferation, and a reduction in angiogenesis, ultimately leading to heart failure, Given its significant implications, it is crucial to explore novel therapies for myocardial fibrosis. Recently one emerging avenue has been the use of small extracellular vesicles (sEV)-carried miRNA. In this review, we summarize the regulatory role of sEV-carried miRNA in myocardial fibrosis. We explored not only the potential diagnostic value of circulating miRNA as biomarkers for heart disease but also the therapeutic implications of sEV-carried miRNA derived from various cellular sources and applications of modified sEV. This exploration is paramount for researchers striving to develop innovative, cell-free therapies as potential drug candidates for the management of myocardial fibrosis.
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Affiliation(s)
- Minwen Long
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Min Cheng
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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Mentkowski KI, Tarvirdizadeh T, Manzanero CA, Eagler LA, Lang JK. Surface engineering enhances the therapeutic potential of systemically delivered extracellular vesicles following acute myocardial infarction. FASEB J 2024; 38:e70070. [PMID: 39301939 PMCID: PMC11424026 DOI: 10.1096/fj.202400828r] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Revised: 08/21/2024] [Accepted: 09/10/2024] [Indexed: 09/22/2024]
Abstract
The objective of the study was to assess the therapeutic efficacy of targeting remote zone cardiomyocytes with cardiosphere-derived cell (CDC) extracellular vesicles (EVs) delivered via intramyocardial and intravenous routes following acute myocardial infarction (MI). Cardiomyocyte (CM) cell death plays a significant role in left ventricular (LV) remodeling and cardiac dysfunction following MI. While EVs secreted by CDCs have shown efficacy in promoting cardiac repair in preclinical models of MI, their translational potential is limited by their biodistribution and requirement for intramyocardial delivery. We hypothesized that engineering the surface of EVs to target cardiomyocytes would enhance their therapeutic efficacy following systemic delivery in a model of acute MI. CDC-derived EVs were engineered to express a CM-specific binding peptide (CMP) on their surface and characterized for size, morphology, and protein expression. Mice with acute MI underwent both intramyocardial and intravenous delivery of EVs, CMP-EVs and placebo in a double-blind study. LVEF was assessed by echo at 2- and 28-days post-MI and tissue samples processed for assessment of EV biodistribution and histological endpoints. CMP-EVs demonstrated superior cardiac targeting and retention when compared with unmodified EVs 24 h post-MI. Mice treated with IV delivered CMP-EVs demonstrated a significant improvement in LVEF and a significant reduction in remote zone cardiomyocyte apoptosis when compared with IV delivered non-targeted EVs at 28-day post-MI. Systemic administration of CMP-EVs improved cardiac function and reduced remote zone cardiomyocyte apoptosis compared with IV-administered unmodified EVs, demonstrating a strategy to optimize therapeutic EV delivery post-MI.
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Affiliation(s)
- Kyle I. Mentkowski
- Department of Medicine, Division of Cardiology, Jacobs School of Medicine and Biomedical Sciences, Buffalo, NY, 14203, USA
- Department of Biomedical Engineering, University at Buffalo, Buffalo, NY, 14260, USA
| | - Touba Tarvirdizadeh
- Department of Medicine, Division of Cardiology, Jacobs School of Medicine and Biomedical Sciences, Buffalo, NY, 14203, USA
| | - Cody A. Manzanero
- Department of Medicine, Division of Cardiology, Jacobs School of Medicine and Biomedical Sciences, Buffalo, NY, 14203, USA
| | - Lisa A. Eagler
- Department of Medicine, Division of Cardiology, Jacobs School of Medicine and Biomedical Sciences, Buffalo, NY, 14203, USA
- VA WNY Healthcare System, Buffalo, NY, 14215, USA
| | - Jennifer K. Lang
- Department of Medicine, Division of Cardiology, Jacobs School of Medicine and Biomedical Sciences, Buffalo, NY, 14203, USA
- Department of Biomedical Engineering, University at Buffalo, Buffalo, NY, 14260, USA
- VA WNY Healthcare System, Buffalo, NY, 14215, USA
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Đorđević DB, Koračević GP, Đorđević AD, Lović DB. Hypertension and left ventricular hypertrophy. J Hypertens 2024; 42:1505-1515. [PMID: 38747417 DOI: 10.1097/hjh.0000000000003774] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/03/2024]
Abstract
In the initial stage, left ventricular hypertrophy (LVH) is adaptive, but in time, it transforms to maladaptive LVH which is specific for the development of various phenotypes that cause heart failure, initially with preserved, but later with reduced left ventricular ejection fraction. Pathophysiological mechanisms, which are characteristic for remodeling procedure, are numerous and extremely complex, and should be subjected to further research with the aim of making a comprehensive overview of hypertensive heart disease (HHD) and discovering new options for preventing and treating HHD. The contemporary methods, such as cardiac magnetic resonance (CMR) and computed tomography (CT) provide very accurate morphological and functional information on HHD. The objective of this review article is to summarize the available scientific information in terms of prevalence, pathophysiology, diagnostics, prevention, contemporary therapeutic options, as well as to present potential therapeutic solutions based on the research of pathological mechanisms which are at the core of HHD.
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Affiliation(s)
- Dragan B Đorđević
- Faculty of Medicine, University of Nis
- Institute for Treatment and Rehabilitation Niska Banja
| | - Goran P Koračević
- Faculty of Medicine, University of Nis
- Department for Cardiovascular Diseases, Clinical Center Nis, Nis, Serbia
| | | | - Dragan B Lović
- Clinic for Internal Diseases Intermedica, Singidunum University Nis, Jovana Ristica, Nis, Serbia
- Veterans Affair Medical Centre, Washington DC, USA
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11
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Gu Y, Feng J, Shi J, Xiao G, Zhang W, Shao S, Liu B, Guo H. Global Research Trends on Exosome in Cardiovascular Diseases: A Bibliometric-Based Visual Analysis. Vasc Health Risk Manag 2024; 20:377-402. [PMID: 39188326 PMCID: PMC11346494 DOI: 10.2147/vhrm.s473520] [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: 05/09/2024] [Accepted: 08/10/2024] [Indexed: 08/28/2024] Open
Abstract
Background Exosomes in cardiovascular diseases (CVDs) have attracted huge attention with substantial value and potential. Our bibliometrics is based on literature from the field of cardiovascular exosomes over the past 30 years, which has been visualized to display the development process, research hotspots, and cutting-edge trends of clinical practices, mechanisms, and management strategies related to psych cardiology. Methods We selected articles and reviews on exosomes in CVDs from the core collection of Web of Science, and generated visual charts by using CiteSpace and VOSviewer software. Results Our research included 1613 publications. The number of exosome articles in CVD fluctuates slightly, but overall shows an increasing trend. The main research institutions were Tongji University and Nanjing Medical University. The International Journal of Molecular Sciences has the highest publication volume, while the Journal of Cellular and Molecular Medicine has the highest citation count. Among all the authors, Eduardo Marban ranks first in terms of publication volume and H-index. The most common keywords are exosome, extracellular vesicles, and angiogenesis. Conclusion This is a bibliometric study on the research hotspots and trends of exosomes in CVD. Exosome research in the field of cardiovascular medicine is on the rise. Some exosome treatment methods may become the focus of future research.
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Affiliation(s)
- Yunxiao Gu
- Department of Anatomy, School of Chinese Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
| | - Jiaming Feng
- Department of Anatomy, School of Chinese Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
| | - Jiayi Shi
- Department of Anatomy, School of Chinese Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
| | - Guanyi Xiao
- Department of Anatomy, School of Chinese Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
| | - Weiwei Zhang
- Department of Anatomy, School of Chinese Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
| | - Shuijin Shao
- Department of Anatomy, School of Chinese Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
| | - Baonian Liu
- Department of Anatomy, School of Chinese Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
| | - Haidong Guo
- Department of Anatomy, School of Chinese Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
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12
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Bhat OM, Mir RA, Nehvi IB, Wani NA, Dar AH, Zargar MA. Emerging role of sphingolipids and extracellular vesicles in development and therapeutics of cardiovascular diseases. IJC HEART & VASCULATURE 2024; 53:101469. [PMID: 39139609 PMCID: PMC11320467 DOI: 10.1016/j.ijcha.2024.101469] [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: 03/18/2024] [Revised: 07/08/2024] [Accepted: 07/12/2024] [Indexed: 08/15/2024]
Abstract
Sphingolipids are eighteen carbon alcohol lipids synthesized from non-sphingolipid precursors in the endoplasmic reticulum (ER). The sphingolipids serve as precursors for a vast range of moieties found in our cells that play a critical role in various cellular processes, including cell division, senescence, migration, differentiation, apoptosis, pyroptosis, autophagy, nutrition intake, metabolism, and protein synthesis. In CVDs, different subclasses of sphingolipids and other derived molecules such as sphingomyelin (SM), ceramides (CERs), and sphingosine-1-phosphate (S1P) are directly related to diabetic cardiomyopathy, dilated cardiomyopathy, myocarditis, ischemic heart disease (IHD), hypertension, and atherogenesis. Several genome-wide association studies showed an association between genetic variations in sphingolipid pathway genes and the risk of CVDs. The sphingolipid pathway plays an important role in the biogenesis and secretion of exosomes. Small extracellular vesicles (sEVs)/ exosomes have recently been found as possible indicators for the onset of CVDs, linking various cellular signaling pathways that contribute to the disease progression. Important features of EVs like biocompatibility, and crossing of biological barriers can improve the pharmacokinetics of drugs and will be exploited to develop next-generation drug delivery systems. In this review, we have comprehensively discussed the role of sphingolipids, and sphingolipid metabolites in the development of CVDs. In addition, concise deliberations were laid to discuss the role of sEVs/exosomes in regulating the pathophysiological processes of CVDs and the exosomes as therapeutic targets.
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Affiliation(s)
- Owais Mohmad Bhat
- Department of Biotechnology, School of Life Sciences, Central University of Kashmir, Ganderbal, India
| | - Rakeeb Ahmad Mir
- Department of Biotechnology, School of Life Sciences, Central University of Kashmir, Ganderbal, India
| | | | - Nissar Ahmad Wani
- Department of Biotechnology, School of Life Sciences, Central University of Kashmir, Ganderbal, India
| | - Abid Hamid Dar
- Department of Biotechnology, School of Life Sciences, Central University of Kashmir, Ganderbal, India
| | - M Afzal Zargar
- Department of Biotechnology, School of Life Sciences, Central University of Kashmir, Ganderbal, India
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13
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Nowicka G. Extracellular vesicles in the diagnosis and treatment of cardiovascular disease. What's behind? What do we need to implement them into clinical practice? Int J Biochem Cell Biol 2024; 172:106600. [PMID: 38806094 DOI: 10.1016/j.biocel.2024.106600] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Revised: 05/23/2024] [Accepted: 05/23/2024] [Indexed: 05/30/2024]
Abstract
Extracellular vesicles (EVs) represent a heterogeneous group of particles secreted by cells to transfer information from the cell of origin to recipient cells by carrying various bioactive molecules. Numerous PubMed records on EVs reveal a burgeoning interest in EV-research, with a notable subset focusing on the potential diagnostic and therapeutic applications of EVs for diverse diseases, including cardiovascular disease (CVD), currently a globally leading cause of mortality. However, this great diagnostic and clinical potential has not yet been translated into clinical practice. No EV-based biomarkers and EV-therapeutic products have been approved, and EV-based therapy for CVD has not yet been shown to be effective. Therefore, this paper aims to scrutinize available data and identify what is needed to translate the underlying potential of EVs into specific EV-biomarkers and EV-therapeutic tools applicable in clinical practice.
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Affiliation(s)
- Grażyna Nowicka
- Medical University of Warsaw, Department of Biochemistry and Pharmacogenomics, Banacha 1, Warszawa 02-091, Poland.
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14
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Lin Q, He P, Tao J, Peng J. Role of Exosomes in Cardiovascular Diseases. Rev Cardiovasc Med 2024; 25:222. [PMID: 39076309 PMCID: PMC11270122 DOI: 10.31083/j.rcm2506222] [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: 02/22/2024] [Revised: 03/29/2024] [Accepted: 04/11/2024] [Indexed: 07/31/2024] Open
Abstract
Exosomes (EXOs) are a subgroup of extracellular vesicles (EVs) that contain numerous biologically active molecules. They exhibit an essential mode of cell communication, primarily between distinct cell populations, for the maintenance of tissue homeostasis and coordination of adaptive responses to various stresses. These intercellular communications are vital for the complex, multicellular cardiovascular system. In the last ten years, their potential role as effective tissue-to-tissue communicators has received increasing attention in cardiovascular physiology and pathology. There is growing evidence that repair of the heart and regeneration can be promoted by EXOs derived from cardiomyocytes or stem/progenitor cells. However, the underlying mechanisms remain unclear. EVs derived from different stem/progenitor cell populations have been used as cell-free therapies in different preclinical models involving cardiovascular diseases and have shown promising results. In this review, we have summarized the recent developments in EXOs research, the impact of EXOs derived from different cells on the cardiovascular system, their potential therapeutic roles as well as new diagnostic biomarkers, and the possible clinical translational outcomes.
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Affiliation(s)
- Qiumei Lin
- Department of General Medicine, Chongqing University Central Hospital, Chongqing Emergency Medical Center, Chongqing Key Laboratory of Emergency Medicine, 400014 Chongqing, China
| | - Pingfeng He
- Department of General Medicine, Chongqing University Central Hospital, Chongqing Emergency Medical Center, Chongqing Key Laboratory of Emergency Medicine, 400014 Chongqing, China
| | - Jing Tao
- Department of General Medicine, Chongqing University Central Hospital, Chongqing Emergency Medical Center, Chongqing Key Laboratory of Emergency Medicine, 400014 Chongqing, China
| | - Jing Peng
- Department of General Medicine, Chongqing University Central Hospital, Chongqing Emergency Medical Center, Chongqing Key Laboratory of Emergency Medicine, 400014 Chongqing, China
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15
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Farahzadi R, Fathi E, Valipour B, Ghaffary S. Stem cells-derived exosomes as cardiac regenerative agents. IJC HEART & VASCULATURE 2024; 52:101399. [PMID: 38584674 PMCID: PMC10990901 DOI: 10.1016/j.ijcha.2024.101399] [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: 12/07/2023] [Revised: 03/03/2024] [Accepted: 03/28/2024] [Indexed: 04/09/2024]
Abstract
Heart failure is a root cause of morbidity and mortality worldwide. Due to the limited regenerative capacity of the heart following myocardial injury, stem cell-based therapies have been considered a hopeful approach for improving cardiac regeneration. In recent years, different kinds of cell products have been investigated regarding their potential to treat patients with heart failure. Despite special attention to cell therapy and its products, therapeutic efficacy has been disappointing, and clinical application is not affordable. In the past few years, a subset of small extracellular vehicles (EVs), commonly known as "exosomes," was reported to grant regenerative and cardioprotective signals at a value similar to their donor cells. The conceptual advantage is that they may be ideally used without evoking a relevant recipient immune response or other adverse effects associated with viable cells. The evidence related to their beneficial effects in animal models of heart failure is rapidly growing. However, there is remarkable heterogeneity regarding source cells, isolation process, effective dosage, and delivery mode. This brief review will focus on the latest research and debates on regenerative potential and cardiac repair of exosomes from different sources, such as cardiac/non-cardiac stem, somatic cells, and progenitor cells. Overall, the current state of research on exosomes as an experimental therapy for heart diseases will be discussed.
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Affiliation(s)
- Raheleh Farahzadi
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Medical Philosophy and History Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ezzatollah Fathi
- Department of Clinical Sciences, Faculty of Veterinary Medicine, University of Tabriz, Tabriz, Iran
| | - Behnaz Valipour
- Department of Anatomical Sciences, Sarab Faculty of Medical Sciences, Sarab, Iran
- Department of Anatomical Sciences, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Saba Ghaffary
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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16
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Gatto F, Benemei S, Piluso G, Bello L. The complex landscape of DMD mutations: moving towards personalized medicine. Front Genet 2024; 15:1360224. [PMID: 38596212 PMCID: PMC11002111 DOI: 10.3389/fgene.2024.1360224] [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: 12/22/2023] [Accepted: 02/26/2024] [Indexed: 04/11/2024] Open
Abstract
Duchenne muscular dystrophy (DMD) is a severe genetic disorder characterized by progressive muscle degeneration, with respiratory and cardiac complications, caused by mutations in the DMD gene, encoding the protein dystrophin. Various DMD mutations result in different phenotypes and disease severity. Understanding genotype/phenotype correlations is essential to optimize clinical care, as mutation-specific therapies and innovative therapeutic approaches are becoming available. Disease modifier genes, trans-active variants influencing disease severity and phenotypic expressivity, may modulate the response to therapy, and become new therapeutic targets. Uncovering more disease modifier genes via extensive genomic mapping studies offers the potential to fine-tune prognostic assessments for individuals with DMD. This review provides insights into genotype/phenotype correlations and the influence of modifier genes in DMD.
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Affiliation(s)
| | | | - Giulio Piluso
- Medical Genetics and Cardiomyology, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Napoli, Italy
| | - Luca Bello
- Department of Neurosciences DNS, University of Padova, Padova, Italy
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17
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Bryl R, Kulus M, Bryja A, Domagała D, Mozdziak P, Antosik P, Bukowska D, Zabel M, Dzięgiel P, Kempisty B. Cardiac progenitor cell therapy: mechanisms of action. Cell Biosci 2024; 14:30. [PMID: 38444042 PMCID: PMC10913616 DOI: 10.1186/s13578-024-01211-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2023] [Accepted: 02/17/2024] [Indexed: 03/07/2024] Open
Abstract
Heart failure (HF) is an end-stage of many cardiac diseases and one of the main causes of death worldwide. The current management of this disease remains suboptimal. The adult mammalian heart was considered a post-mitotic organ. However, several reports suggest that it may possess modest regenerative potential. Adult cardiac progenitor cells (CPCs), the main players in the cardiac regeneration, constitute, as it may seem, a heterogenous group of cells, which remain quiescent in physiological conditions and become activated after an injury, contributing to cardiomyocytes renewal. They can mediate their beneficial effects through direct differentiation into cardiac cells and activation of resident stem cells but majorly do so through paracrine release of factors. CPCs can secrete cytokines, chemokines, and growth factors as well as exosomes, rich in proteins, lipids and non-coding RNAs, such as miRNAs and YRNAs, which contribute to reparation of myocardium by promoting angiogenesis, cardioprotection, cardiomyogenesis, anti-fibrotic activity, and by immune modulation. Preclinical studies assessing cardiac progenitor cells and cardiac progenitor cells-derived exosomes on damaged myocardium show that administration of cardiac progenitor cells-derived exosomes can mimic effects of cell transplantation. Exosomes may become new promising therapeutic strategy for heart regeneration nevertheless there are still several limitations as to their use in the clinic. Key questions regarding their dosage, safety, specificity, pharmacokinetics, pharmacodynamics and route of administration remain outstanding. There are still gaps in the knowledge on basic biology of exosomes and filling them will bring as closer to translation into clinic.
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Affiliation(s)
- Rut Bryl
- Section of Regenerative Medicine and Cancer Research, Natural Sciences Club, Faculty of Biology, Adam Mickiewicz University, Poznań, Poznan, 61-614, Poland
| | - Magdalena Kulus
- Department of Veterinary Surgery, Institute of Veterinary Medicine, Nicolaus Copernicus University, Torun, 87-100, Poland
| | - Artur Bryja
- Department of Human Morphology and Embryology, Division of Anatomy, Wroclaw Medical University, Wroclaw, 50-367, Poland
| | - Dominika Domagała
- Department of Human Morphology and Embryology, Division of Anatomy, Wroclaw Medical University, Wroclaw, 50-367, Poland
| | - Paul Mozdziak
- Prestage Department of Poultry Science, North Carolina State University, Raleigh, NC, 27695, USA
- Physiology Graduate Faculty, North Carolina State University, Raleigh, NC, 27695, USA
| | - Paweł Antosik
- Department of Veterinary Surgery, Institute of Veterinary Medicine, Nicolaus Copernicus University, Torun, 87-100, Poland
| | - Dorota Bukowska
- Department of Diagnostics and Clinical Sciences, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, Torun, 87-100, Poland
| | - Maciej Zabel
- Division of Anatomy and Histology, University of Zielona Góra, Zielona Góra, 65-046, Poland
- Department of Human Morphology and Embryology, Division of Histology and Embryology, Wroclaw Medical University, Wroclaw, 50-368, Poland
| | - Piotr Dzięgiel
- Department of Human Morphology and Embryology, Division of Histology and Embryology, Wroclaw Medical University, Wroclaw, 50-368, Poland
| | - Bartosz Kempisty
- Department of Veterinary Surgery, Institute of Veterinary Medicine, Nicolaus Copernicus University, Torun, 87-100, Poland.
- Department of Human Morphology and Embryology, Division of Anatomy, Wroclaw Medical University, Wroclaw, 50-367, Poland.
- Physiology Graduate Faculty, North Carolina State University, Raleigh, NC, 27695, USA.
- Department of Obstetrics and Gynaecology, University Hospital and Masaryk University, Brno, 62500, Czech Republic.
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18
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Malhotra K, Van Remortel S, Ly V, Davis DR. Combinatorial Effect of Biomaterials and Extracellular Vesicle Therapy for Heart Failure with Reduced Ejection Fraction: A Systematic Review of Preclinical Studies. Adv Healthc Mater 2023; 12:e2301980. [PMID: 37811703 PMCID: PMC11468038 DOI: 10.1002/adhm.202301980] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Revised: 09/18/2023] [Indexed: 10/10/2023]
Abstract
Heart failure, a pervasive global health burden, necessitates innovative therapeutic strategies. Extracellular vesicles (EVs) have emerged as promising contenders for cardiac repair, owing to their profound influence on fibrosis and inflammation. Merging EVs with biomaterials holds the potential for a synergistic leap in therapeutic efficacy. In this review, the impact of combining EVs with biomaterials in preclinical heart failure models is scrutinized. Fifteen studies, predominantly employing mesenchymal stromal cell-derived EVs along with hyaluronic acid or peptides in coronary ligation models, meet these stringent criteria. The amalgamation of EVs and biomaterials consistently enhances cardiac ejection fraction (1.39; 95% CI: 0.68, 2.11; p = 0.0001) and fractional shortening (1.46, 95% CI: 0.70, 2.22; p = 0.0002) compared to EV monotherapy. Secondary outcomes similarly showcased improvement in the combined treatment group. Although the number of studies analyzed is modest, no indications of publication bias surface. In summary, combination therapy with EVs and biomaterials enhances therapeutic benefit in preclinical heart failure models. The consistent improvement observed across diverse EV sources, biomaterials, and animal models underscores the exciting potential of this synergistic approach.
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Affiliation(s)
- Kamal Malhotra
- University of Ottawa Heart InstituteDivision of CardiologyDepartment of MedicineUniversity of OttawaOttawaK1Y4W7Canada
- Department of Cellular and Molecular MedicineUniversity of OttawaOttawaK1H8M5Canada
| | - Sophie Van Remortel
- University of Ottawa Heart InstituteDivision of CardiologyDepartment of MedicineUniversity of OttawaOttawaK1Y4W7Canada
| | - Valentina Ly
- Health Sciences LibraryUniversity of OttawaOttawaK1H8M5Canada
| | - Darryl R. Davis
- University of Ottawa Heart InstituteDivision of CardiologyDepartment of MedicineUniversity of OttawaOttawaK1Y4W7Canada
- Department of Cellular and Molecular MedicineUniversity of OttawaOttawaK1H8M5Canada
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19
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Chepeleva EV. Cell Therapy in the Treatment of Coronary Heart Disease. Int J Mol Sci 2023; 24:16844. [PMID: 38069167 PMCID: PMC10706847 DOI: 10.3390/ijms242316844] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 11/24/2023] [Accepted: 11/27/2023] [Indexed: 12/18/2023] Open
Abstract
Heart failure is a leading cause of death in patients who have suffered a myocardial infarction. Despite the timely use of modern reperfusion therapies such as thrombolysis, surgical revascularization and balloon angioplasty, they are sometimes unable to prevent the development of significant areas of myocardial damage and subsequent heart failure. Research efforts have focused on developing strategies to improve the functional status of myocardial injury areas. Consequently, the restoration of cardiac function using cell therapy is an exciting prospect. This review describes the characteristics of various cell types relevant to cellular cardiomyoplasty and presents findings from experimental and clinical studies investigating cell therapy for coronary heart disease. Cell delivery methods, optimal dosage and potential treatment mechanisms are discussed.
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Affiliation(s)
- Elena V. Chepeleva
- Federal State Budgetary Institution National Medical Research Center Named after Academician E.N. Meshalkin of the Ministry of Health of the Russian Federation, 15, Rechkunovskaya Str., 630055 Novosibirsk, Russia;
- Research Institute of Clinical and Experimental Lymphology—Branch of the Institute of Cytology and Genetics Siberian Branch of Russian Academy of Sciences, 2, Timakova Str., 630060 Novosibirsk, Russia
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20
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Ranjan P, Colin K, Dutta RK, Verma SK. Challenges and future scope of exosomes in the treatment of cardiovascular diseases. J Physiol 2023; 601:4873-4893. [PMID: 36398654 PMCID: PMC10192497 DOI: 10.1113/jp282053] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Accepted: 10/21/2022] [Indexed: 07/28/2023] Open
Abstract
Exosomes are nanosized vesicles that carry biologically diverse molecules for intercellular communication. Researchers have been trying to engineer exosomes for therapeutic purposes by using different approaches to deliver biologically active molecules to the various target cells efficiently. Recent technological advances may allow the biodistribution and pharmacokinetics of exosomes to be modified to meet scientific needs with respect to specific diseases. However, it is essential to determine an exosome's optimal dosage and potential side effects before its clinical use. Significant breakthroughs have been made in recent decades concerning exosome labelling and imaging techniques. These tools provide in situ monitoring of exosome biodistribution and pharmacokinetics and pinpoint targetability. However, because exosomes are nanometres in size and vary significantly in contents, a deeper understanding is required to ensure accurate monitoring before they can be applied in clinical settings. Different research groups have established different approaches to elucidate the roles of exosomes and visualize their spatial properties. This review covers current and emerging strategies for in vivo and in vitro exosome imaging and tracking for potential studies.
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Affiliation(s)
- Prabhat Ranjan
- Department of Medicine, Division of Cardiovascular Disease, The University of Alabama at Birmingham, Birmingham, AL-35233
| | - Karen Colin
- Department of Medicine, Division of Cardiovascular Disease, The University of Alabama at Birmingham, Birmingham, AL-35233
- UAB School of Health Professions, The University of Alabama at Birmingham, Birmingham, AL
| | - Roshan Kumar Dutta
- Department of Medicine, Division of Cardiovascular Disease, The University of Alabama at Birmingham, Birmingham, AL-35233
| | - Suresh Kumar Verma
- Department of Medicine, Division of Cardiovascular Disease, The University of Alabama at Birmingham, Birmingham, AL-35233
- Department of Biomedical Engineering, The University of Alabama at Birmingham, Birmingham, Alabama
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21
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Bragança J, Pinto R, Silva B, Marques N, Leitão HS, Fernandes MT. Charting the Path: Navigating Embryonic Development to Potentially Safeguard against Congenital Heart Defects. J Pers Med 2023; 13:1263. [PMID: 37623513 PMCID: PMC10455635 DOI: 10.3390/jpm13081263] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Revised: 08/11/2023] [Accepted: 08/14/2023] [Indexed: 08/26/2023] Open
Abstract
Congenital heart diseases (CHDs) are structural or functional defects present at birth due to improper heart development. Current therapeutic approaches to treating severe CHDs are primarily palliative surgical interventions during the peri- or prenatal stages, when the heart has fully developed from faulty embryogenesis. However, earlier interventions during embryonic development have the potential for better outcomes, as demonstrated by fetal cardiac interventions performed in utero, which have shown improved neonatal and prenatal survival rates, as well as reduced lifelong morbidity. Extensive research on heart development has identified key steps, cellular players, and the intricate network of signaling pathways and transcription factors governing cardiogenesis. Additionally, some reports have indicated that certain adverse genetic and environmental conditions leading to heart malformations and embryonic death may be amendable through the activation of alternative mechanisms. This review first highlights key molecular and cellular processes involved in heart development. Subsequently, it explores the potential for future therapeutic strategies, targeting early embryonic stages, to prevent CHDs, through the delivery of biomolecules or exosomes to compensate for faulty cardiogenic mechanisms. Implementing such non-surgical interventions during early gestation may offer a prophylactic approach toward reducing the occurrence and severity of CHDs.
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Affiliation(s)
- José Bragança
- Algarve Biomedical Center-Research Institute (ABC-RI), University of Algarve Campus Gambelas, 8005-139 Faro, Portugal
- Algarve Biomedical Center (ABC), University of Algarve Campus Gambelas, 8005-139 Faro, Portugal
- Faculty of Medicine and Biomedical Sciences (FMCB), University of Algarve Campus Gambelas, 8005-139 Faro, Portugal
- Champalimaud Research Program, Champalimaud Centre for the Unknown, 1400-038 Lisbon, Portugal
| | - Rute Pinto
- Algarve Biomedical Center-Research Institute (ABC-RI), University of Algarve Campus Gambelas, 8005-139 Faro, Portugal
- Algarve Biomedical Center (ABC), University of Algarve Campus Gambelas, 8005-139 Faro, Portugal
| | - Bárbara Silva
- Algarve Biomedical Center-Research Institute (ABC-RI), University of Algarve Campus Gambelas, 8005-139 Faro, Portugal
- Algarve Biomedical Center (ABC), University of Algarve Campus Gambelas, 8005-139 Faro, Portugal
- Faculty of Medicine and Biomedical Sciences (FMCB), University of Algarve Campus Gambelas, 8005-139 Faro, Portugal
- PhD Program in Biomedical Sciences, Faculty of Medicine and Biomedical Sciences, Universidade do Algarve, 8005-139 Faro, Portugal
| | - Nuno Marques
- Algarve Biomedical Center-Research Institute (ABC-RI), University of Algarve Campus Gambelas, 8005-139 Faro, Portugal
- Algarve Biomedical Center (ABC), University of Algarve Campus Gambelas, 8005-139 Faro, Portugal
| | - Helena S. Leitão
- Algarve Biomedical Center-Research Institute (ABC-RI), University of Algarve Campus Gambelas, 8005-139 Faro, Portugal
- Algarve Biomedical Center (ABC), University of Algarve Campus Gambelas, 8005-139 Faro, Portugal
- Faculty of Medicine and Biomedical Sciences (FMCB), University of Algarve Campus Gambelas, 8005-139 Faro, Portugal
| | - Mónica T. Fernandes
- Algarve Biomedical Center-Research Institute (ABC-RI), University of Algarve Campus Gambelas, 8005-139 Faro, Portugal
- Algarve Biomedical Center (ABC), University of Algarve Campus Gambelas, 8005-139 Faro, Portugal
- School of Health, University of Algarve Campus Gambelas, 8005-139 Faro, Portugal
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22
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Gallet R, Su JB, Corboz D, Chiaroni PM, Bizé A, Dai J, Panel M, Boucher P, Pallot G, Brehat J, Sambin L, Thery G, Mouri N, de Pommereau A, Denormandie P, Germain S, Lacampagne A, Teiger E, Marbán E, Ghaleh B. Three-vessel coronary infusion of cardiosphere-derived cells for the treatment of heart failure with preserved ejection fraction in a pre-clinical pig model. Basic Res Cardiol 2023; 118:26. [PMID: 37400630 DOI: 10.1007/s00395-023-00995-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 06/06/2023] [Accepted: 06/07/2023] [Indexed: 07/05/2023]
Abstract
Heart failure with preserved ejection fraction (HFpEF) is a major public health concern. Its outcome is poor and, as of today, barely any treatments have been able to decrease its morbidity or mortality. Cardiosphere-derived cells (CDCs) are heart cell products with anti-fibrotic, anti-inflammatory and angiogenic properties. Here, we tested the efficacy of CDCs in improving left ventricular (LV) structure and function in pigs with HFpEF. Fourteen chronically instrumented pigs received continuous angiotensin II infusion for 5 weeks. LV function was investigated through hemodynamic measurements and echocardiography at baseline, after 3 weeks of angiotensin II infusion before three-vessel intra-coronary CDC (n = 6) or placebo (n = 8) administration and 2 weeks after treatment (i.e., at completion of the protocol). As expected, arterial pressure was significantly and similarly increased in both groups. This was accompanied by LV hypertrophy that was not affected by CDCs. LV systolic function remained similarly preserved during the whole protocol in both groups. In contrast, LV diastolic function was impaired (increases in Tau, LV end-diastolic pressure as well as E/A, E/E'septal and E/E'lateral ratios) but CDC treatment significantly improved all of these parameters. The beneficial effect of CDCs on LV diastolic function was not explained by reduced LV hypertrophy or increased arteriolar density; however, interstitial fibrosis was markedly reduced. Three-vessel intra-coronary administration of CDCs improves LV diastolic function and reduces LV fibrosis in this hypertensive model of HFpEF.
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Affiliation(s)
- Romain Gallet
- Inserm U955-IMRB, UPEC, Ecole Nationale Vétérinaire d'Alfort, Maisons-Alfort, France
- Assistance Publique-Hôpitaux de Paris, Hôpital Henri Mondor, Service de Cardiologie, Créteil, France
| | - Jin-Bo Su
- Inserm U955-IMRB, UPEC, Ecole Nationale Vétérinaire d'Alfort, Maisons-Alfort, France
| | - Daphné Corboz
- Inserm U955-IMRB, UPEC, Ecole Nationale Vétérinaire d'Alfort, Maisons-Alfort, France
| | - Paul-Matthieu Chiaroni
- Inserm U955-IMRB, UPEC, Ecole Nationale Vétérinaire d'Alfort, Maisons-Alfort, France
- Assistance Publique-Hôpitaux de Paris, Hôpital Henri Mondor, Service de Cardiologie, Créteil, France
| | - Alain Bizé
- Inserm U955-IMRB, UPEC, Ecole Nationale Vétérinaire d'Alfort, Maisons-Alfort, France
| | - Jianping Dai
- Inserm U955-IMRB, UPEC, Ecole Nationale Vétérinaire d'Alfort, Maisons-Alfort, France
| | - Mathieu Panel
- PhyMedExp, Université de Montpellier, INSERM U1046, CNRS UMR 9214, Montpellier, France
| | - Pierre Boucher
- Center for Interdisciplinary Research in Biology (CIRB), College de France, CNRS, INSERM, PSL Research University, Paris, France
| | - Gaëtan Pallot
- Center for Interdisciplinary Research in Biology (CIRB), College de France, CNRS, INSERM, PSL Research University, Paris, France
| | - Juliette Brehat
- Inserm U955-IMRB, UPEC, Ecole Nationale Vétérinaire d'Alfort, Maisons-Alfort, France
| | - Lucien Sambin
- Inserm U955-IMRB, UPEC, Ecole Nationale Vétérinaire d'Alfort, Maisons-Alfort, France
| | - Guillaume Thery
- Inserm U955-IMRB, UPEC, Ecole Nationale Vétérinaire d'Alfort, Maisons-Alfort, France
| | - Nadir Mouri
- Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Henri Mondor, Département de biochimie-pharmacologie-biologie moléculaire-génétique médicale, Créteil, France
| | - Aurélien de Pommereau
- Inserm U955-IMRB, UPEC, Ecole Nationale Vétérinaire d'Alfort, Maisons-Alfort, France
| | - Pierre Denormandie
- Inserm U955-IMRB, UPEC, Ecole Nationale Vétérinaire d'Alfort, Maisons-Alfort, France
| | - Stéphane Germain
- Center for Interdisciplinary Research in Biology (CIRB), College de France, CNRS, INSERM, PSL Research University, Paris, France
| | - Alain Lacampagne
- PhyMedExp, Université de Montpellier, INSERM U1046, CNRS UMR 9214, Montpellier, France
| | - Emmanuel Teiger
- Inserm U955-IMRB, UPEC, Ecole Nationale Vétérinaire d'Alfort, Maisons-Alfort, France
- Assistance Publique-Hôpitaux de Paris, Hôpital Henri Mondor, Service de Cardiologie, Créteil, France
| | - Eduardo Marbán
- Smidt Heart Institute, Cedars Sinai Medical Center, Los Angeles, CA, USA
| | - Bijan Ghaleh
- Inserm U955-IMRB, UPEC, Ecole Nationale Vétérinaire d'Alfort, Maisons-Alfort, France.
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23
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Shah MNA, Yokota T. Cardiac therapies for Duchenne muscular dystrophy. Ther Adv Neurol Disord 2023; 16:17562864231182934. [PMID: 37425427 PMCID: PMC10328182 DOI: 10.1177/17562864231182934] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Accepted: 06/02/2023] [Indexed: 07/11/2023] Open
Abstract
Duchenne muscular dystrophy (DMD) is a devastating disease that results in life-limiting complications such as loss of skeletal muscle function as well as respiratory and cardiac complications. Advanced therapeutics in pulmonary care have significantly reduced respiratory complication-related mortality, making cardiomyopathy the main determinant factor of survival. While there are multiple therapies such as the use of anti-inflammatory drugs, physical therapy, and ventilatory assistance targeted toward delaying the disease progression in DMD, a cure remains elusive. In the last decade, several therapeutic approaches have been developed to improve patient survival. These include small molecule-based therapy, micro-dystrophin gene delivery, CRISPR-mediated gene editing, nonsense readthrough, exon skipping, and cardiosphere-derived cell therapy. Associated with the specific benefits of each of these approaches are their individual risks and limitations. The variability in the genetic aberrations leading to DMD also limits the widespread use of these therapies. While numerous approaches have been explored to treat DMD pathophysiology, only a handful have successfully advanced through the preclinical stages. In this review, we summarize the currently approved as well as the most promising therapeutics undergoing clinical trials aimed toward treating DMD with a focus on its cardiac manifestations.
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Affiliation(s)
- Md Nur Ahad Shah
- Department of Medical Genetics, University of Alberta, Edmonton, AB, Canada
| | - Toshifumi Yokota
- Department of Medical Genetics, University of Alberta, Edmonton, AB T6G 2H7, Canada
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24
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Parent S, Vaka R, Risha Y, Ngo C, Kanda P, Nattel S, Khan S, Courtman D, Stewart DJ, Davis DR. Prevention of atrial fibrillation after open-chest surgery with extracellular vesicle therapy. JCI Insight 2023; 8:e163297. [PMID: 37384420 PMCID: PMC10481795 DOI: 10.1172/jci.insight.163297] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Accepted: 06/28/2023] [Indexed: 07/01/2023] Open
Abstract
Almost half of patients recovering from open-chest surgery experience atrial fibrillation (AF) that results principally from inflammation in the pericardial space surrounding the heart. Given that postoperative AF is associated with increased mortality, effective measures to prevent AF after open-chest surgery are highly desirable. In this study, we tested the concept that extracellular vesicles (EVs) isolated from human atrial explant-derived cells can prevent postoperative AF. Middle-aged female and male rats were randomized to undergo sham operation or induction of sterile pericarditis followed by trans-epicardial injection of human EVs or vehicle into the atrial tissue. Pericarditis increased the probability of inducing AF while EV treatment abrogated this effect in a sex-independent manner. EV treatment reduced infiltration of inflammatory cells and production of pro-inflammatory cytokines. Atrial fibrosis and hypertrophy seen after pericarditis were markedly attenuated by EV pretreatment, an effect attributable to suppression of fibroblast proliferation by EVs. Our study demonstrates that injection of EVs at the time of open-chest surgery shows prominent antiinflammatory effects and prevents AF due to sterile pericarditis. Translation of this finding to patients might provide an effective new strategy to prevent postoperative AF by reducing atrial inflammation and fibrosis.
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Affiliation(s)
- Sandrine Parent
- University of Ottawa Heart Institute, Division of Cardiology, Department of Medicine, and
- Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Ramana Vaka
- University of Ottawa Heart Institute, Division of Cardiology, Department of Medicine, and
| | - Yousef Risha
- University of Ottawa Heart Institute, Division of Cardiology, Department of Medicine, and
| | - Clarissa Ngo
- University of Ottawa Heart Institute, Division of Cardiology, Department of Medicine, and
| | - Pushpinder Kanda
- University of Ottawa Heart Institute, Division of Cardiology, Department of Medicine, and
- Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Stanley Nattel
- Research Center and Department of Medicine, Montreal Heart Institute, University of Montreal, Montreal, Quebec, Canada
- Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada
- Institute of Pharmacology, West German Heart and Vascular Center, Faculty of Medicine, University of Duisburg-Essen, Essen, Germany
| | - Saad Khan
- Ottawa Hospital Research Institute, Division of Regenerative Medicine, Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - David Courtman
- Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
- Ottawa Hospital Research Institute, Division of Regenerative Medicine, Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Duncan J. Stewart
- University of Ottawa Heart Institute, Division of Cardiology, Department of Medicine, and
- Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
- Ottawa Hospital Research Institute, Division of Regenerative Medicine, Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Darryl R. Davis
- University of Ottawa Heart Institute, Division of Cardiology, Department of Medicine, and
- Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
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25
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Zhu J, Wang S, Yang D, Xu W, Qian H. Extracellular vesicles: emerging roles, biomarkers and therapeutic strategies in fibrotic diseases. J Nanobiotechnology 2023; 21:164. [PMID: 37221595 DOI: 10.1186/s12951-023-01921-3] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Accepted: 05/06/2023] [Indexed: 05/25/2023] Open
Abstract
Extracellular vesicles (EVs), a cluster of cell-secreted lipid bilayer nanoscale particles, universally exist in body fluids, as well as cell and tissue culture supernatants. Over the past years, increasing attention have been paid to the important role of EVs as effective intercellular communicators in fibrotic diseases. Notably, EV cargos, including proteins, lipids, nucleic acids, and metabolites, are reported to be disease-specific and can even contribute to fibrosis pathology. Thus, EVs are considered as effective biomarkers for disease diagnosis and prognosis. Emerging evidence shows that EVs derived from stem/progenitor cells have great prospects for cell-free therapy in various preclinical models of fibrotic diseases and engineered EVs can improve the targeting and effectiveness of their treatment. In this review, we will focus on the biological functions and mechanisms of EVs in the fibrotic diseases, as well as their potential as novel biomarkers and therapeutic strategies.
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Affiliation(s)
- Junyan Zhu
- Jiangsu Province Key Laboratory of Medical Science and Laboratory Medicine, Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, 212013, China
| | - Sicong Wang
- Jiangsu Province Key Laboratory of Medical Science and Laboratory Medicine, Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, 212013, China
| | - Dakai Yang
- Jiangsu Province Key Laboratory of Medical Science and Laboratory Medicine, Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, 212013, China
| | - Wenrong Xu
- Jiangsu Province Key Laboratory of Medical Science and Laboratory Medicine, Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, 212013, China.
| | - Hui Qian
- Jiangsu Province Key Laboratory of Medical Science and Laboratory Medicine, Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, 212013, China.
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26
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Reiss AB, Ahmed S, Johnson M, Saeedullah U, De Leon J. Exosomes in Cardiovascular Disease: From Mechanism to Therapeutic Target. Metabolites 2023; 13:479. [PMID: 37110138 PMCID: PMC10142472 DOI: 10.3390/metabo13040479] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 03/22/2023] [Accepted: 03/24/2023] [Indexed: 03/29/2023] Open
Abstract
Cardiovascular disease (CVD) is the leading cause of morbidity and mortality globally. In recent decades, clinical research has made significant advances, resulting in improved survival and recovery rates for patients with CVD. Despite this progress, there is substantial residual CVD risk and an unmet need for better treatment. The complex and multifaceted pathophysiological mechanisms underlying the development of CVD pose a challenge for researchers seeking effective therapeutic interventions. Consequently, exosomes have emerged as a new focus for CVD research because their role as intercellular communicators gives them the potential to act as noninvasive diagnostic biomarkers and therapeutic nanocarriers. In the heart and vasculature, cell types such as cardiomyocytes, endothelial cells, vascular smooth muscle, cardiac fibroblasts, inflammatory cells, and resident stem cells are involved in cardiac homeostasis via the release of exosomes. Exosomes encapsulate cell-type specific miRNAs, and this miRNA content fluctuates in response to the pathophysiological setting of the heart, indicating that the pathways affected by these differentially expressed miRNAs may be targets for new treatments. This review discusses a number of miRNAs and the evidence that supports their clinical relevance in CVD. The latest technologies in applying exosomal vesicles as cargo delivery vehicles for gene therapy, tissue regeneration, and cell repair are described.
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Affiliation(s)
- Allison B. Reiss
- Department of Medicine and Biomedical Research Institute, NYU Long Island School of Medicine, Mineola, NY 11501, USA
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27
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Zhang R, Mesquita T, Cho JH, Li C, Sanchez L, Holm K, Akhmerov A, Liu W, Li Y, Ibrahim AG, Cingolani E. Systemic Delivery of Extracellular Vesicles Attenuates Atrial Fibrillation in Heart Failure With Preserved Ejection Fraction. JACC Clin Electrophysiol 2023; 9:147-158. [PMID: 36858679 PMCID: PMC11073791 DOI: 10.1016/j.jacep.2022.09.012] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 09/15/2022] [Accepted: 09/20/2022] [Indexed: 12/03/2022]
Abstract
BACKGROUND Atrial fibrillation (AF) is a common comorbidity in heart failure with preserved ejection fraction (HFpEF) patients. To date, treatments for HFpEF-related AF have been limited to anti-arrhythmic drugs and ablation. Here we examined the effects of immortalized cardiosphere-derived extracellular vesicles (imCDCevs) in rats with HFpEF. OBJECTIVES This study sought to investigate the mechanisms of AF in HFpEF and probe the potential therapeutic efficacy of imCDCevs in HFpEF-related AF. METHODS Dahl salt-sensitive rats were fed a high-salt diet for 7 weeks to induce HFpEF and randomized to receive imCDCevs (n = 18) or vehicle intravenously (n = 14). Rats fed a normal-salt diet were used as control animals (n = 26). A comprehensive characterization of atrial remodeling was conducted using functional and molecular techniques. RESULTS HFpEF-verified animals showed significantly higher AF inducibility (84%) compared with control animals (15%). These changes were associated with prolonged action potential duration, slowed conduction velocity (connexin 43 lateralization), and fibrotic remodeling in the left atrium of HFpEF compared with control animals. ImCDCevs reversed adverse electrical remodeling (restoration of action potential duration to control levels and reorganization of connexin 43) and reduced AF inducibility (33%). In addition, fibrosis, inflammation, and oxidative stress, which are major pathological AF drivers, were markedly attenuated in imCDCevs-treated animals. Importantly, these effects occurred without changes in blood pressure and diastolic function. CONCLUSIONS Thus, imCDCevs attenuated adverse remodeling, and prevented AF in a rat model of HFpEF.
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Affiliation(s)
- Rui Zhang
- Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA; Department of Cardiology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Thassio Mesquita
- Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Jae Hyung Cho
- Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Chang Li
- Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Lizbeth Sanchez
- Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Kevin Holm
- Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Akbarshakh Akhmerov
- Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Weixin Liu
- Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Yigang Li
- Department of Cardiology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Ahmed G Ibrahim
- Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Eugenio Cingolani
- Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
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28
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Tong X, Zhao X, Dang X, Kou Y, Kou J. circRNA, a novel diagnostic biomarker for coronary heart disease. Front Cardiovasc Med 2023; 10:1070616. [PMID: 36818340 PMCID: PMC9928865 DOI: 10.3389/fcvm.2023.1070616] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2022] [Accepted: 01/05/2023] [Indexed: 02/04/2023] Open
Abstract
Objective This study aimed to identify the potential diagnostic biomarkers of coronary heart disease (CHD) from exosome-derived circRNA. Methods The microarray data of circRNA derived from the exosomes of patients with CHD and mRNA in acute myocardial infarction was retrieved from exoRBase website and GEO database (GSE61144), respectively, to identify the differentially expressed genes (DEGs). Our findings detected the differentially expressed circRNAs and mRNAs and predicted their correlation with microRNAs using the microRNA target prediction website, thus ascertaining the corresponding circ-microRNA and micro-mRNAs. Then, we performed systematic Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis on the differentially expressed mRNA. Protein-Protein Interactions (PPI) of these DEGs were examined using STRING. The receiver operator characteristic (ROC) curve was used to validate the diagnostic efficacy of circRNA in patients with CHD. Finally, the RNAs identified in this study were verified by quantitative real-time polymerase chain reaction (qRT-PCR). Results A total of 85 differentially expressed circRNAs (4 up-regulated and 81 down-regulated) were identified by screening the circRNAs in exosome of CHD patients. Based on the prediction data of circRNA, mRNA, and the corresponding microRNA, a ceRNA network was constructed, including 7 circRNA nodes, 5 microRNA nodes, and 2 mRNA nodes. Finally, validated by qRT-PCR testing, we found circRNA0001785, circRNA0000973, circRNA0001741, and circRNA0003922 to be the promising candidate for the effective prediction of CHD. These potential diagnostic markers can provide insight for further research on the occurrence of CHD or even acute coronary syndrome (ACS).
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29
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Gao R, Li X. Extracellular Vesicles and Pathological Cardiac Hypertrophy. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1418:17-31. [PMID: 37603270 DOI: 10.1007/978-981-99-1443-2_2] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/22/2023]
Abstract
Pathological cardiac hypertrophy is a well-recognized risk factor for cardiovascular diseases (CVDs). Although lots of efforts have been made to illustrate the underlying molecular mechanisms, many issues remain undiscovered. Recently, intercellular communication by delivering small molecules between different cell types in the progression of cardiac hypertrophy has been reported, including bioactive nucleic acids or proteins. These extracellular vesicles (EVs) may act in an autocrine or paracrine manner between cardiomyocytes and noncardiomyocytes to provoke or inhibit cardiac remodeling and hypertrophy. Besides, EVs can be used as novel diagnostic or prognostic biomarkers in cardiac hypertrophy and also may serve as potential therapeutic targets due to its biocompatible nature and low immunogenicity. In this chapter, we will first summarize the current knowledge about EVs from different cells in pathological cardiac hypertrophy. Then, we will focus on the value of EVs as therapeutic agents and biomarkers for pathological myocardial hypertrophy.
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Affiliation(s)
- Rongrong Gao
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xinli Li
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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30
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Buntsma N, van der Pol E, Nieuwland R, Gąsecka A. Extracellular Vesicles in Coronary Artery Disease. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1418:81-103. [PMID: 37603274 DOI: 10.1007/978-981-99-1443-2_6] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/22/2023]
Abstract
Coronary artery disease (CAD) is the leading cause of death and disability worldwide. Despite recent progress in the diagnosis and treatment of CAD, evidence gaps remain, including pathogenesis, the most efficient diagnostic strategy, prognosis of individual patients, monitoring of therapy, and novel therapeutic strategies. These gaps could all be filled by developing novel, minimally invasive, blood-based biomarkers. Potentially, extracellular vesicles (EVs) could fill such gaps. EVs are lipid membrane particles released from cells into blood and other body fluids. Because the concentration, composition, and functions of EVs change during disease, and because all cell types involved in the development and progression of CAD release EVs, currently available guidelines potentially enable reliable and reproducible measurements of EVs in clinical trials, offering a wide range of opportunities. In this chapter, we provide an overview of the associations reported between EVs and CAD, including (1) the role of EVs in CAD pathogenesis, (2) EVs as biomarkers to diagnose CAD, predict prognosis, and monitor therapy in individual patients, and (3) EVs as new therapeutic targets and/or drug delivery vehicles. In addition, we summarize the challenges encountered in EV isolation and detection, and the lack of standardization, which has hampered real clinical applications of EVs. Since most conclusions are based on animal models and single-center studies, the knowledge and insights into the roles and opportunities of EVs as biomarkers in CAD are still changing, and therefore, the content of this chapter should be seen as a snapshot in time rather than a final and complete compendium of knowledge on EVs in CAD.
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Affiliation(s)
- Naomi Buntsma
- Department of Neurology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
- Biomedical Engineering and Physics, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
- Vesicle Observation Centre, and Laboratory of Experimental Clinical Chemistry, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Edwin van der Pol
- Biomedical Engineering and Physics, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
- Vesicle Observation Centre, and Laboratory of Experimental Clinical Chemistry, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Rienk Nieuwland
- Vesicle Observation Centre, and Laboratory of Experimental Clinical Chemistry, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Aleksandra Gąsecka
- Vesicle Observation Centre, and Laboratory of Experimental Clinical Chemistry, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
- 1st Chair and Department of Cardiology, Medical University of Warsaw, Warsaw, Poland.
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31
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Yedigaryan L, Sampaolesi M. Extracellular vesicles and Duchenne muscular dystrophy pathology: Modulators of disease progression. Front Physiol 2023; 14:1130063. [PMID: 36891137 PMCID: PMC9987248 DOI: 10.3389/fphys.2023.1130063] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Accepted: 01/31/2023] [Indexed: 02/16/2023] Open
Abstract
Duchenne muscular dystrophy (DMD) is a devastating disorder and is considered to be one of the worst forms of inherited muscular dystrophies. DMD occurs as a result of mutations in the dystrophin gene, leading to progressive muscle fiber degradation and weakness. Although DMD pathology has been studied for many years, there are aspects of disease pathogenesis and progression that have not been thoroughly explored yet. The underlying issue with this is that the development of further effective therapies becomes stalled. It is becoming more evident that extracellular vesicles (EVs) may contribute to DMD pathology. EVs are vesicles secreted by cells that exert a multitude of effects via their lipid, protein, and RNA cargo. EV cargo (especially microRNAs) is also said to be a good biomarker for identifying the status of specific pathological processes that occur in dystrophic muscle, such as fibrosis, degeneration, inflammation, adipogenic degeneration, and dilated cardiomyopathy. On the other hand, EVs are becoming more prominent vehicles for custom-engineered cargos. In this review, we will discuss the possible contribution of EVs to DMD pathology, their potential use as biomarkers, and the therapeutic efficacy of both, EV secretion inhibition and custom-engineered cargo delivery.
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Affiliation(s)
- Laura Yedigaryan
- Translational Cardiomyology Laboratory, Stem Cell and Developmental Biology, Department of Development and Regeneration, KU Leuven, Leuven, Belgium
| | - Maurilio Sampaolesi
- Translational Cardiomyology Laboratory, Stem Cell and Developmental Biology, Department of Development and Regeneration, KU Leuven, Leuven, Belgium.,Histology and Medical Embryology Unit, Department of Anatomy, Histology, Forensic Medicine and Orthopaedics, Sapienza University of Rome, Rome, Italy
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32
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Khan FB, Uddin S, Elderdery AY, Goh KW, Ming LC, Ardianto C, Palakot AR, Anwar I, Khan M, Owais M, Huang CY, Daddam JR, Khan MA, Shoaib S, Khursheed M, Reshadat S, Khayat Kashani HR, Mirza S, Khaleel AA, Ayoub MA. Illuminating the Molecular Intricacies of Exosomes and ncRNAs in Cardiovascular Diseases: Prospective Therapeutic and Biomarker Potential. Cells 2022; 11:3664. [PMID: 36429092 PMCID: PMC9688392 DOI: 10.3390/cells11223664] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2022] [Revised: 10/29/2022] [Accepted: 11/01/2022] [Indexed: 11/19/2022] Open
Abstract
Cardiovascular diseases (CVDs) are one of the leading causes of death worldwide. Accumulating evidences have highlighted the importance of exosomes and non-coding RNAs (ncRNAs) in cardiac physiology and pathology. It is in general consensus that exosomes and ncRNAs play a crucial role in the maintenance of normal cellular function; and interestingly it is envisaged that their potential as prospective therapeutic candidates and biomarkers are increasing rapidly. Considering all these aspects, this review provides a comprehensive overview of the recent understanding of exosomes and ncRNAs in CVDs. We provide a great deal of discussion regarding their role in the cardiovascular system, together with providing a glimpse of ideas regarding strategies exploited to harness their potential as a therapeutic intervention and prospective biomarker against CVDs. Thus, it could be envisaged that a thorough understanding of the intricacies related to exosomes and ncRNA would seemingly allow their full exploration and may lead clinical settings to become a reality in near future.
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Affiliation(s)
- Farheen Badrealam Khan
- Department of Biology, College of Science, The United Arab Emirates University, Al Ain 15551, United Arab Emirates
| | - Shahab Uddin
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar
- Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar
| | - Abozer Y. Elderdery
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Sakaka 72388, Saudi Arabia
| | - Khang Wen Goh
- Faculty of Data Sciences and Information Technology, INTI International University, Nilai 78100, Malaysia
| | - Long Chiau Ming
- PAPRSB Institute of Health Sciences, Universiti Brunei Darussalam, Gadong BE1410, Brunei
- Department of Pharmacy Practice, Faculty of Pharmacy, Universitas Airlangga, Surabaya 60115, Indonesia
| | - Chrismawan Ardianto
- Department of Pharmacy Practice, Faculty of Pharmacy, Universitas Airlangga, Surabaya 60115, Indonesia
| | - Abdul Rasheed Palakot
- Department of Biology, College of Science, The United Arab Emirates University, Al Ain 15551, United Arab Emirates
| | - Irfa Anwar
- Department of Biology, College of Science, The United Arab Emirates University, Al Ain 15551, United Arab Emirates
| | - Mohsina Khan
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Mohammad Owais
- Interdisciplinary Biotechnology Unit, Aligarh Muslim University, Aligarh 202002, UP, India
| | - Chih-Yang Huang
- Department of Biotechnology, Asia University, Taichung 404, Taiwan
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung 404, Taiwan
- Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970, Taiwan
- Centre of General Education, Buddhist Tzu Chi Medical Foundation, Tzu Chi University of Science and Technology, Hualien 970, Taiwan
- Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 404, Taiwan
| | - Jayasimha Rayalu Daddam
- Department of Ruminant Science, Institute of Animal Sciences, Agriculture Research Organization, Volcani Center, Rishon Lezion 7505101, Israel
| | - Meraj Alam Khan
- Program in Translational Medicine, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children & DigiBiomics Inc, Toronto, ON M51X8, Canada
| | - Shoaib Shoaib
- Department Biochemistry, Jawaharlal Nehru Medical College, Faculty of Medicine, Aligarh Muslim University, Aligarh 202002, UP, India
| | - Md Khursheed
- College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai 505055, United Arab Emirates
| | - Sara Reshadat
- Department of Internal Medicine, Semnan University of Medical Sciences, Semnan 3513119111, Iran
| | | | - Sameer Mirza
- Department of Chemistry, United Arab Emirates University, Al Ain 15551, United Arab Emirates
| | - Abbas A. Khaleel
- Department of Chemistry, United Arab Emirates University, Al Ain 15551, United Arab Emirates
| | - Mohammed Akli Ayoub
- Department of Biology, College of Science, The United Arab Emirates University, Al Ain 15551, United Arab Emirates
- Zayed Center for Health Sciences, United Arab Emirates University, Al Ain 15551, United Arab Emirates
- Department of Biology, College of Arts and Sciences, Khalifa University, Abu Dhabi 127788, United Arab Emirates
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Fang J, Zhang Y, Chen D, Zheng Y, Jiang J. Exosomes and Exosomal Cargos: A Promising World for Ventricular Remodeling Following Myocardial Infarction. Int J Nanomedicine 2022; 17:4699-4719. [PMID: 36217495 PMCID: PMC9547598 DOI: 10.2147/ijn.s377479] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2022] [Accepted: 09/21/2022] [Indexed: 11/23/2022] Open
Abstract
Exosomes are a pluripotent group of extracellular nanovesicles secreted by all cells that mediate intercellular communications. The effective information within exosomes is primarily reflected in exosomal cargos, including proteins, lipids, DNAs, and non-coding RNAs (ncRNAs), the most intensively studied molecules. Cardiac resident cells (cardiomyocytes, fibroblasts, and endothelial cells) and foreign cells (infiltrated immune cells, cardiac progenitor cells, cardiosphere-derived cells, and mesenchymal stem cells) are involved in the progress of ventricular remodeling (VR) following myocardial infarction (MI) via transferring exosomes into target cells. Here, we summarize the pathological mechanisms of VR following MI, including cardiac myocyte hypertrophy, cardiac fibrosis, inflammation, pyroptosis, apoptosis, autophagy, angiogenesis, and metabolic disorders, and the roles of exosomal cargos in these processes, with a focus on proteins and ncRNAs. Continued research in this field reveals a novel diagnostic and therapeutic strategy for VR.
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Affiliation(s)
- Jiacheng Fang
- Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009, People’s Republic of China
| | - Yuxuan Zhang
- Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009, People’s Republic of China
| | - Delong Chen
- Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009, People’s Republic of China
| | - Yiyue Zheng
- Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009, People’s Republic of China
| | - Jun Jiang
- Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009, People’s Republic of China,Correspondence: Jun Jiang, Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, No. 88 Jiefang Road, Hangzhou, Zhejiang, 310009, People’s Republic of China, Tel/Fax +86 135 8870 6891, Email
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You B, Yang Y, Zhou Z, Yan Y, Zhang L, Jin J, Qian H. Extracellular Vesicles: A New Frontier for Cardiac Repair. Pharmaceutics 2022; 14:pharmaceutics14091848. [PMID: 36145595 PMCID: PMC9503573 DOI: 10.3390/pharmaceutics14091848] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 08/26/2022] [Accepted: 08/30/2022] [Indexed: 11/16/2022] Open
Abstract
The ability of extracellular vesicles (EVs) to regulate a broad range of cellular processes has recently been used to treat diseases. Growing evidence indicates that EVs play a cardioprotective role in heart disease by activating beneficial signaling pathways. Multiple functional components of EVs and intracellular molecular mechanisms are involved in the process. To overcome the shortcomings of native EVs such as their heterogeneity and limited tropism, a series of engineering approaches has been developed to improve the therapeutic efficiency of EVs. In this review, we present an overview of the research and future directions for EVs-based cardiac therapies with an emphasis on EVs-mediated delivery of therapeutic agents. The advantages and limitations of various modification strategies are discussed, and possible opportunities for improvement are proposed. An in-depth understanding of the endogenous properties of EVs and EVs engineering strategies could lead to a promising cell-free therapy for cardiac repair.
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Affiliation(s)
- Benshuai You
- Wujin Institute of Molecular Diagnostics and Precision Cancer Medicine of Jiangsu University, Wujin Hospital Affiliated with Jiangsu University, Changzhou 213017, China
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang 212013, China
| | - Yang Yang
- Clinical Laboratory Center, The Affiliated Taizhou People’s Hospital of Nanjing Medical University, Taizhou 225317, China
| | - Zixuan Zhou
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang 212013, China
| | - Yongmin Yan
- Wujin Institute of Molecular Diagnostics and Precision Cancer Medicine of Jiangsu University, Wujin Hospital Affiliated with Jiangsu University, Changzhou 213017, China
| | - Leilei Zhang
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang 212013, China
| | - Jianhua Jin
- Wujin Institute of Molecular Diagnostics and Precision Cancer Medicine of Jiangsu University, Wujin Hospital Affiliated with Jiangsu University, Changzhou 213017, China
- Correspondence: (J.J.); (H.Q.)
| | - Hui Qian
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang 212013, China
- Correspondence: (J.J.); (H.Q.)
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35
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Gao H, Zhang L, Wang Z, Yan K, Zhao L, Xiao W. Research Progress on Transorgan Regulation of the Cardiovascular and Motor System through Cardiogenic Exosomes. Int J Mol Sci 2022; 23:ijms23105765. [PMID: 35628575 PMCID: PMC9146752 DOI: 10.3390/ijms23105765] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Revised: 05/17/2022] [Accepted: 05/19/2022] [Indexed: 02/01/2023] Open
Abstract
The heart is the core organ of the circulatory system. Through the blood circulation system, it has close contact with all tissues and cells in the body. An exosome is an extracellular vesicle enclosed by a phospholipid bilayer. A variety of heart tissue cells can secrete and release exosomes, which transfer RNAs, lipids, proteins, and other biomolecules to adjacent or remote cells, mediate intercellular communication, and regulate the physiological and pathological activities of target cells. Cardiogenic exosomes play an important role in regulating almost all pathological and physiological processes of the heart. In addition, they can also reach distant tissues and organs through the peripheral circulation, exerting profound influence on their functional status. In this paper, the composition and function of cardiogenic exosomes, the factors affecting cardiogenic exosomes and their roles in cardiovascular physiology and pathophysiology are discussed, and the close relationship between cardiovascular system and motor system is innovatively explored from the perspective of exosomes. This study provides a reference for the development and application of exosomes in regenerative medicine and sports health, and also provides a new idea for revealing the close relationship between the heart and other organ systems.
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36
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Janouskova O, Herma R, Semeradtova A, Poustka D, Liegertova M, Malinska HA, Maly J. Conventional and Nonconventional Sources of Exosomes-Isolation Methods and Influence on Their Downstream Biomedical Application. Front Mol Biosci 2022; 9:846650. [PMID: 35586196 PMCID: PMC9110031 DOI: 10.3389/fmolb.2022.846650] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Accepted: 03/28/2022] [Indexed: 11/13/2022] Open
Abstract
Despite extensive study of extracellular vesicles (EVs), specifically exosomes (EXs) as biomarkers, important modulators of physiological or pathological processes, or therapeutic agents, relatively little is known about nonconventional sources of EXs, such as invertebrate or plant EXs, and their uses. Likewise, there is no clear information on the overview of storage conditions and currently used isolation methods, including new ones, such as microfluidics, which fundamentally affect the characterization of EXs and their other biomedical applications. The purpose of this review is to briefly summarize conventional and nonconventional sources of EXs, storage conditions and typical isolation methods, widely used kits and new "smart" technologies with emphasis on the influence of isolation techniques on EX content, protein detection, RNA, mRNA and others. At the same time, attention is paid to a brief overview of the direction of biomedical application of EXs, especially in diagnostics, therapy, senescence and aging and, with regard to the current situation, in issues related to Covid-19.
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Affiliation(s)
- Olga Janouskova
- Centre of Nanomaterials and Biotechnology, Faculty of Science, Jan Evangelista University in Ústí Nad Labem, Ústí Nad Labem, Czech Republic
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George TA, Hsu CC, Meeson A, Lundy DJ. Nanocarrier-Based Targeted Therapies for Myocardial Infarction. Pharmaceutics 2022; 14:930. [PMID: 35631516 PMCID: PMC9143269 DOI: 10.3390/pharmaceutics14050930] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 04/22/2022] [Accepted: 04/22/2022] [Indexed: 12/30/2022] Open
Abstract
Myocardial infarction is a major cause of morbidity and mortality worldwide. Due to poor inherent regeneration of the adult mammalian myocardium and challenges with effective drug delivery, there has been little progress in regenerative therapies. Nanocarriers, including liposomes, nanoparticles, and exosomes, offer many potential advantages for the therapy of myocardial infarction, including improved delivery, retention, and prolonged activity of therapeutics. However, there are many challenges that have prevented the widespread clinical use of these technologies. This review aims to summarize significant principles and developments in the field, with a focus on nanocarriers using ligand-based or cell mimicry-based targeting. Lastly, a discussion of limitations and potential future direction is provided.
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Affiliation(s)
- Thomashire A. George
- International Ph.D. Program in Biomedical Engineering, Taipei Medical University, Taipei 110, Taiwan;
| | - Chuan-Chih Hsu
- Department of Cardiovascular Surgery, Taipei Medical University Hospital, Taipei 110, Taiwan;
| | - Annette Meeson
- Biosciences Institute, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK;
| | - David J. Lundy
- International Ph.D. Program in Biomedical Engineering, Taipei Medical University, Taipei 110, Taiwan;
- Graduate Institute of Biomedical Materials and Tissue Engineering, Taipei Medical University, Taipei 110, Taiwan
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38
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Chimenti I, Picchio V, Pagano F, Schirone L, Schiavon S, D'Ambrosio L, Valenti V, Forte M, di Nonno F, Rubattu S, Peruzzi M, Versaci F, Greco E, Calogero A, De Falco E, Frati G, Sciarretta S. The impact of autophagy modulation on phenotype and survival of cardiac stromal cells under metabolic stress. Cell Death Discov 2022; 8:149. [PMID: 35365624 PMCID: PMC8975847 DOI: 10.1038/s41420-022-00924-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 01/31/2022] [Accepted: 02/17/2022] [Indexed: 01/18/2023] Open
Abstract
Cardiac stromal cells (CSCs) embrace multiple phenotypes and are a contributory factor in tissue homeostasis and repair. They can be exploited as therapeutic mediators against cardiac fibrosis and remodeling, but their survival and cardioprotective properties can be decreased by microenvironmental cues. We evaluated the impact of autophagy modulation by different pharmacological/genetic approaches on the viability and phenotype of murine CSCs, which had been subjected to nutrient deprivation or hyperglycemia, in order to mimic relevant stress conditions and risk factors of cardiovascular diseases. Our results show that autophagy is activated in CSCs by nutrient deprivation, and that autophagy induction by trehalose or autophagy-related protein 7 (ATG7)-overexpression can significantly preserve CSC viability. Furthermore, autophagy induction is associated with a higher proportion of primitive, non-activated stem cell antigen 1 (Sca1)-positive cells, and with a reduced fibrotic fraction (positive for the discoidin domain-containing receptor 2, DDR2) in the CSC pool after nutrient deprivation. Hyperglycemia, on the other hand, is associated with reduced autophagic flux in CSCs, and with a significant reduction in primitive Sca1+ cells. Autophagy induction by adenoviral-mediated ATG7-overexpression maintains a cardioprotective, anti-inflammatory and pro-angiogenic paracrine profile of CSCs exposed to hyperglycemia for 1 week. Finally, autophagy induction by ATG7-overexpression during hyperglycemia can significantly preserve cell viability in CSCs, which were subsequently exposed to nutrient deprivation, reducing hyperglycemia-induced impairment of cell resistance to stress. In conclusion, our results show that autophagy stimulation preserves CSC viability and function in response to metabolic stressors, suggesting that it may boost the beneficial functions of CSCs in cardiac repair mechanisms.
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Affiliation(s)
- Isotta Chimenti
- Department of Medical Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy.
- Mediterranea Cardiocentro, Napoli, Italy.
| | - Vittorio Picchio
- Department of Medical Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy
| | - Francesca Pagano
- Biochemistry and Cellular Biology Istitute, CNR, Monterotondo, Italy
| | - Leonardo Schirone
- Department of Medical Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy
- Department of Clinical, Internal Medicine, Anaesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy
| | - Sonia Schiavon
- Department of Medical Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy
| | - Luca D'Ambrosio
- Department of Medical Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy
| | - Valentina Valenti
- Haemodynamic and Cardiology Unit, "Santa Maria Goretti" Hospital, Latina, Italy
| | | | | | - Speranza Rubattu
- IRCCS Neuromed, Pozzilli, Italy
- Department of Clinical and Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Mariangela Peruzzi
- Mediterranea Cardiocentro, Napoli, Italy
- Department of Clinical, Internal Medicine, Anaesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy
| | - Francesco Versaci
- Haemodynamic and Cardiology Unit, "Santa Maria Goretti" Hospital, Latina, Italy
- Department of System Medicine, "Tor Vergata" University, Rome, Italy
| | - Ernesto Greco
- Department of Clinical, Internal Medicine, Anaesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy
| | - Antonella Calogero
- Department of Medical Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy
| | - Elena De Falco
- Department of Medical Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy
- Mediterranea Cardiocentro, Napoli, Italy
| | - Giacomo Frati
- Department of Medical Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy
- IRCCS Neuromed, Pozzilli, Italy
| | - Sebastiano Sciarretta
- Department of Medical Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy
- IRCCS Neuromed, Pozzilli, Italy
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McDonald CM, Marbán E, Hendrix S, Hogan N, Ruckdeschel Smith R, Eagle M, Finkel RS, Tian C, Janas J, Harmelink MM, Varadhachary AS, Taylor MD, Hor KN, Mayer OH, Henricson EK, Furlong P, Ascheim DD, Rogy S, Williams P, Marbán L. Repeated intravenous cardiosphere-derived cell therapy in late-stage Duchenne muscular dystrophy (HOPE-2): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet 2022; 399:1049-1058. [PMID: 35279258 DOI: 10.1016/s0140-6736(22)00012-5] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 11/28/2021] [Accepted: 12/02/2021] [Indexed: 12/19/2022]
Abstract
BACKGROUND Cardiosphere-derived cells (CDCs) ameliorate skeletal and cardiac muscle deterioration in experimental models of Duchenne muscular dystrophy. The HOPE-2 trial examined the safety and efficacy of sequential intravenous infusions of human allogeneic CDCs in late-stage Duchenne muscular dystrophy. METHODS In this multicentre, randomised, double-blind, placebo-controlled, phase 2 trial, patients with Duchenne muscular dystrophy, aged 10 years or older with moderate upper limb impairment, were enrolled at seven centres in the USA. Patients were randomly assigned (1:1) using stratified permuted blocks to receive CAP-1002 (1·5 × 108 CDCs) or placebo intravenously every 3 months for a total of four infusions. Clinicians, caregivers, patients, and clinical operations personnel were fully masked to treatment groups. The primary outcome was the change in mid-level elbow Performance of Upper Limb version 1.2 (PUL 1.2) score at 12 months, assessed in the intention-to-treat population. Safety was assessed in all individuals who received an investigational product. This trial is registered with ClinicalTrials.gov, NCT03406780. FINDINGS Between March 1, 2018, and March 31, 2020, 26 male patients with Duchenne muscular dystrophy were enrolled, of whom eight were randomly assigned to the CAP-1002 group and 12 to the placebo group (six were not randomised due to screening failure). In patients who had a post-treatment PUL 1.2 assessment (eight in the CAP-1002 group and 11 in the placebo group), the mean 12-month change from baseline in mid-level elbow PUL1.2 favoured CAP-1002 over placebo (percentile difference 36·2, 95% CI 12·7-59·7; difference of 2·6 points; p=0·014). Infusion-related hypersensitivity reactions without long-term sequelae were observed in three patients, with one patient discontinuing therapy due to a severe allergic reaction. No other major adverse reactions were noted, and no deaths occurred. INTERPRETATION CAP-1002 cell therapy appears to be safe and effective in reducing deterioration of upper limb function in patients with late-stage Duchenne muscular dystrophy. Various measures of cardiac function and structure were also improved in the CAP-1002 group compared with the placebo group. Longer-term extension studies are needed to confirm the therapeutic durability and safety of CAP-1002 beyond 12 months for the treatment of skeletal myopathy and cardiomyopathy in Duchenne muscular dystrophy. FUNDING Capricor Therapeutics.
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Affiliation(s)
- Craig M McDonald
- University of California Davis School of Medicine, Sacramento, CA, USA.
| | - Eduardo Marbán
- Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | | | | | | | | | - Richard S Finkel
- Nemours Children's Hospital, Orlando, FL, USA; St Jude Children's Research Hospital, Memphis, TN, USA
| | - Cuixia Tian
- Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Joanne Janas
- University of Colorado, Children's Hospital Colorado, Denver, CO, USA
| | | | | | - Michael D Taylor
- Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Kan N Hor
- Nationwide Children's Hospital, Columbus, OH, USA
| | - Oscar H Mayer
- Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA, USA
| | - Erik K Henricson
- University of California Davis School of Medicine, Sacramento, CA, USA
| | - Pat Furlong
- Parent Project Muscular Dystrophy, Hackensack, NJ, USA
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40
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Marbán E, Liao K. On the cellular origin of cardiosphere-derived cells (CDCs). Basic Res Cardiol 2022; 117:12. [PMID: 35258685 DOI: 10.1007/s00395-022-00914-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2022] [Revised: 01/24/2022] [Accepted: 01/25/2022] [Indexed: 01/31/2023]
Affiliation(s)
- Eduardo Marbán
- Cedars-Sinai Medical Center, Smidt Heart Institute, 127 South San Vicente Boulevard, AHSP A3600, Los Angeles, CA, 90048, USA.
| | - Ke Liao
- Cedars-Sinai Medical Center, Smidt Heart Institute, 127 South San Vicente Boulevard, AHSP A3600, Los Angeles, CA, 90048, USA
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41
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Mehanna RA, Essawy MM, Barkat MA, Awaad AK, Thabet EH, Hamed HA, Elkafrawy H, Khalil NA, Sallam A, Kholief MA, Ibrahim SS, Mourad GM. Cardiac stem cells: Current knowledge and future prospects. World J Stem Cells 2022; 14:1-40. [PMID: 35126826 PMCID: PMC8788183 DOI: 10.4252/wjsc.v14.i1.1] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 07/02/2021] [Accepted: 01/06/2022] [Indexed: 02/06/2023] Open
Abstract
Regenerative medicine is the field concerned with the repair and restoration of the integrity of damaged human tissues as well as whole organs. Since the inception of the field several decades ago, regenerative medicine therapies, namely stem cells, have received significant attention in preclinical studies and clinical trials. Apart from their known potential for differentiation into the various body cells, stem cells enhance the organ's intrinsic regenerative capacity by altering its environment, whether by exogenous injection or introducing their products that modulate endogenous stem cell function and fate for the sake of regeneration. Recently, research in cardiology has highlighted the evidence for the existence of cardiac stem and progenitor cells (CSCs/CPCs). The global burden of cardiovascular diseases' morbidity and mortality has demanded an in-depth understanding of the biology of CSCs/CPCs aiming at improving the outcome for an innovative therapeutic strategy. This review will discuss the nature of each of the CSCs/CPCs, their environment, their interplay with other cells, and their metabolism. In addition, important issues are tackled concerning the potency of CSCs/CPCs in relation to their secretome for mediating the ability to influence other cells. Moreover, the review will throw the light on the clinical trials and the preclinical studies using CSCs/CPCs and combined therapy for cardiac regeneration. Finally, the novel role of nanotechnology in cardiac regeneration will be explored.
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Affiliation(s)
- Radwa A Mehanna
- Medical Physiology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Marwa M Essawy
- Oral Pathology Department, Faculty of Dentistry/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Mona A Barkat
- Human Anatomy and Embryology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Ashraf K Awaad
- Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Eman H Thabet
- Medical Physiology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Heba A Hamed
- Histology and Cell Biology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Hagar Elkafrawy
- Medical Biochemistry Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Nehal A Khalil
- Medical Biochemistry Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Abeer Sallam
- Medical Physiology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Marwa A Kholief
- Forensic Medicine and Clinical toxicology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Samar S Ibrahim
- Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Ghada M Mourad
- Histology and Cell Biology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt.
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Mehanna RA, Essawy MM, Barkat MA, Awaad AK, Thabet EH, Hamed HA, Elkafrawy H, Khalil NA, Sallam A, Kholief MA, Ibrahim SS, Mourad GM. Cardiac stem cells: Current knowledge and future prospects. World J Stem Cells 2022. [PMID: 35126826 DOI: 10.4252/wjsc.v14.i1.1]] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Regenerative medicine is the field concerned with the repair and restoration of the integrity of damaged human tissues as well as whole organs. Since the inception of the field several decades ago, regenerative medicine therapies, namely stem cells, have received significant attention in preclinical studies and clinical trials. Apart from their known potential for differentiation into the various body cells, stem cells enhance the organ's intrinsic regenerative capacity by altering its environment, whether by exogenous injection or introducing their products that modulate endogenous stem cell function and fate for the sake of regeneration. Recently, research in cardiology has highlighted the evidence for the existence of cardiac stem and progenitor cells (CSCs/CPCs). The global burden of cardiovascular diseases' morbidity and mortality has demanded an in-depth understanding of the biology of CSCs/CPCs aiming at improving the outcome for an innovative therapeutic strategy. This review will discuss the nature of each of the CSCs/CPCs, their environment, their interplay with other cells, and their metabolism. In addition, important issues are tackled concerning the potency of CSCs/CPCs in relation to their secretome for mediating the ability to influence other cells. Moreover, the review will throw the light on the clinical trials and the preclinical studies using CSCs/CPCs and combined therapy for cardiac regeneration. Finally, the novel role of nanotechnology in cardiac regeneration will be explored.
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Affiliation(s)
- Radwa A Mehanna
- Medical Physiology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Marwa M Essawy
- Oral Pathology Department, Faculty of Dentistry/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Mona A Barkat
- Human Anatomy and Embryology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Ashraf K Awaad
- Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Eman H Thabet
- Medical Physiology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Heba A Hamed
- Histology and Cell Biology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Hagar Elkafrawy
- Medical Biochemistry Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Nehal A Khalil
- Medical Biochemistry Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Abeer Sallam
- Medical Physiology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Marwa A Kholief
- Forensic Medicine and Clinical toxicology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Samar S Ibrahim
- Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Ghada M Mourad
- Histology and Cell Biology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt.
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Saludas L, Garbayo E, Ruiz-Villalba A, Hernández S, Vader P, Prósper F, Blanco-Prieto MJ. Isolation methods of large and small extracellular vesicles derived from cardiovascular progenitors: A comparative study. Eur J Pharm Biopharm 2022; 170:187-196. [PMID: 34968647 DOI: 10.1016/j.ejpb.2021.12.012] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Revised: 12/20/2021] [Accepted: 12/23/2021] [Indexed: 12/18/2022]
Abstract
Since the discovery of the beneficial therapeutical effects of extracellular vesicles (EVs), these agents have been attracting great interest as next-generation therapies. EVs are nanosized membrane bodies secreted by all types of cells that mediate cell-cell communication. Although the classification of different subpopulations of EVs can be complex, they are broadly divided into microvesicles and exosomes based on their biogenesis and in large and small EVs based on their size. As this is an emerging field, current investigations are focused on basic aspects such as the more convenient method for EV isolation. In the present paper, we used cardiac progenitor cells (CPCs) to study and compare different cell culture conditions for EV isolation as well as two of the most commonly employed purification methods: ultracentrifugation (UC) and size-exclusion chromatography (SEC). Large and small EVs were separately analysed. We found that serum starvation of cells during the EV collecting period led to a dramatic decrease in EV secretion and major cell death. Regarding the isolation method, our findings suggest that UC and SEC gave similar EV recovery rates. Separation of large and small EV-enriched subpopulations was efficiently achieved with both purification protocols although certain difference in sample heterogeneity was observed. Noteworthy, while calnexin was abundant in large EVs, ALIX and CD63 were mainly found in small EVs. Finally, when the functionality of EVs was assessed on primary culture of adult murine cardiac fibroblasts, we found that EVs were taken up by these cells, which resulted in a pronounced reduction in the proliferative and migratory capacity of the cells. Specifically, a tendency towards a larger effect of SEC-related EVs was observed. No differences could be found between large and small EVs. Altogether, these results contribute to establish the basis for the use of EVs as therapeutic platforms, in particular in regenerative fields.
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Affiliation(s)
- Laura Saludas
- Department of Pharmaceutical Technology and Chemistry, School of Pharmacy and Nutrition, University of Navarra, Pamplona, Spain; Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain
| | - Elisa Garbayo
- Department of Pharmaceutical Technology and Chemistry, School of Pharmacy and Nutrition, University of Navarra, Pamplona, Spain; Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain
| | - Adrián Ruiz-Villalba
- Hematology Service and Area of Cell Therapy, Clinic Universidad de Navarra, Foundation for Applied Medical Research, University of Navarra, Pamplona, Spain; Department of Animal Biology, Institute of Biomedicine of Málaga (IBIMA), Faculty of Science, University of Málaga, Málaga, Spain. Andalusian Centre for Nanomedicine and Biotechnology (BIONAND), Málaga, Spain
| | - Silvia Hernández
- Hematology Service and Area of Cell Therapy, Clinic Universidad de Navarra, Foundation for Applied Medical Research, University of Navarra, Pamplona, Spain
| | - Pieter Vader
- Department of Clinical Chemistry and Hematology, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Felipe Prósper
- Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain; Hematology Service and Area of Cell Therapy, Clinic Universidad de Navarra, Foundation for Applied Medical Research, University of Navarra, Pamplona, Spain; Hematology Department, Clínica Universidad de Navarra and Foundation for Applied Medical Research (CIMA), Pamplona, Spain; Centro de Investigacion en Red de Oncologia (CIBERONC), Spain.
| | - María J Blanco-Prieto
- Department of Pharmaceutical Technology and Chemistry, School of Pharmacy and Nutrition, University of Navarra, Pamplona, Spain; Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain.
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Kogan PS, Wirth F, Tomar A, Darr J, Teperino R, Lahm H, Dreßen M, Puluca N, Zhang Z, Neb I, Beck N, Luzius T, de la Osa de la Rosa L, Gärtner K, Hüls C, Zeidler R, Ramanujam D, Engelhardt S, Wenk C, Holdt LM, Mononen M, Sahara M, Cleuziou J, Hörer J, Lange R, Krane M, Doppler SA. Uncovering the molecular identity of cardiosphere-derived cells (CDCs) by single-cell RNA sequencing. Basic Res Cardiol 2022; 117:11. [PMID: 35258704 PMCID: PMC8902493 DOI: 10.1007/s00395-022-00913-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Revised: 01/11/2022] [Accepted: 01/11/2022] [Indexed: 01/31/2023]
Abstract
Cardiosphere-derived cells (CDCs) generated from human cardiac biopsies have been shown to have disease-modifying bioactivity in clinical trials. Paradoxically, CDCs' cellular origin in the heart remains elusive. We studied the molecular identity of CDCs using single-cell RNA sequencing (sc-RNAseq) in comparison to cardiac non-myocyte and non-hematopoietic cells (cardiac fibroblasts/CFs, smooth muscle cells/SMCs and endothelial cells/ECs). We identified CDCs as a distinct and mitochondria-rich cell type that shared biological similarities with non-myocyte cells but not with cardiac progenitor cells derived from human-induced pluripotent stem cells. CXCL6 emerged as a new specific marker for CDCs. By analysis of sc-RNAseq data from human right atrial biopsies in comparison with CDCs we uncovered transcriptomic similarities between CDCs and CFs. By direct comparison of infant and adult CDC sc-RNAseq data, infant CDCs revealed GO-terms associated with cardiac development. To analyze the beneficial effects of CDCs (pro-angiogenic, anti-fibrotic, anti-apoptotic), we performed functional in vitro assays with CDC-derived extracellular vesicles (EVs). CDC EVs augmented in vitro angiogenesis and did not stimulate scarring. They also reduced the expression of pro-apoptotic Bax in NRCMs. In conclusion, CDCs were disclosed as mitochondria-rich cells with unique properties but also with similarities to right atrial CFs. CDCs displayed highly proliferative, secretory and immunomodulatory properties, characteristics that can also be found in activated or inflammatory cell types. By special culture conditions, CDCs earn some bioactivities, including angiogenic potential, which might modify disease in certain disorders.
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Affiliation(s)
- Palgit-S. Kogan
- School of Medicine and Health, Department of Cardiovascular Surgery, Institute Insure, Technical University of Munich, German Heart Center Munich, Lazarettstrasse 36, 80636 Munich, Germany
| | - Felix Wirth
- School of Medicine and Health, Department of Cardiovascular Surgery, Institute Insure, Technical University of Munich, German Heart Center Munich, Lazarettstrasse 36, 80636 Munich, Germany
| | - Archana Tomar
- Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany ,German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Jonatan Darr
- Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany ,German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Raffaele Teperino
- Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany ,German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Harald Lahm
- School of Medicine and Health, Department of Cardiovascular Surgery, Institute Insure, Technical University of Munich, German Heart Center Munich, Lazarettstrasse 36, 80636 Munich, Germany
| | - Martina Dreßen
- School of Medicine and Health, Department of Cardiovascular Surgery, Institute Insure, Technical University of Munich, German Heart Center Munich, Lazarettstrasse 36, 80636 Munich, Germany
| | - Nazan Puluca
- School of Medicine and Health, Department of Cardiovascular Surgery, Institute Insure, Technical University of Munich, German Heart Center Munich, Lazarettstrasse 36, 80636 Munich, Germany
| | - Zhong Zhang
- School of Medicine and Health, Department of Cardiovascular Surgery, Institute Insure, Technical University of Munich, German Heart Center Munich, Lazarettstrasse 36, 80636 Munich, Germany
| | - Irina Neb
- School of Medicine and Health, Department of Cardiovascular Surgery, Institute Insure, Technical University of Munich, German Heart Center Munich, Lazarettstrasse 36, 80636 Munich, Germany
| | - Nicole Beck
- School of Medicine and Health, Department of Cardiovascular Surgery, Institute Insure, Technical University of Munich, German Heart Center Munich, Lazarettstrasse 36, 80636 Munich, Germany
| | - Tatjana Luzius
- School of Medicine and Health, Department of Cardiovascular Surgery, Institute Insure, Technical University of Munich, German Heart Center Munich, Lazarettstrasse 36, 80636 Munich, Germany
| | - Luis de la Osa de la Rosa
- School of Medicine and Health, Department of Cardiovascular Surgery, Institute Insure, Technical University of Munich, German Heart Center Munich, Lazarettstrasse 36, 80636 Munich, Germany
| | - Kathrin Gärtner
- Research Unit Gene Vectors, Helmholtz Center Munich German Research Center for Environmental Health, Munich, Germany
| | - Corinna Hüls
- Research Unit Gene Vectors, Helmholtz Center Munich German Research Center for Environmental Health, Munich, Germany
| | - Reinhard Zeidler
- Research Unit Gene Vectors, Helmholtz Center Munich German Research Center for Environmental Health, Munich, Germany ,Department of Otorhinolaryngology, Klinikum der Universität (KUM), Munich, Germany
| | - Deepak Ramanujam
- DZHK (German Center for Cardiovascular Research)-Partner Site Munich Heart Alliance, Biedersteiner Straße 29, 80802 Munich, Germany ,Institute of Pharmacology and Toxicology, Technische Universität München, Biedersteiner Str. 29, 80802 Munich, Germany
| | - Stefan Engelhardt
- DZHK (German Center for Cardiovascular Research)-Partner Site Munich Heart Alliance, Biedersteiner Straße 29, 80802 Munich, Germany ,Institute of Pharmacology and Toxicology, Technische Universität München, Biedersteiner Str. 29, 80802 Munich, Germany
| | - Catharina Wenk
- Institute of Laboratory Medicine, University Hospital, Ludwig Maximilians University Munich, Munich, Germany
| | - Lesca M. Holdt
- Institute of Laboratory Medicine, University Hospital, Ludwig Maximilians University Munich, Munich, Germany
| | - Mimmi Mononen
- Department of Cell and Molecular Biology, Karolinska Institutet, 171 77 Stockholm, Sweden
| | - Makoto Sahara
- Department of Cell and Molecular Biology, Karolinska Institutet, 171 77 Stockholm, Sweden ,Department of Surgery, Yale University School of Medicine, CN06510 New Haven, CT USA
| | - Julie Cleuziou
- School of Medicine and Health, Department of Pediatric and Congenital Heart Surgery, Institute Insure, Technical University of Munich, Lazarettstraße 36, 80636 Munich, Germany
| | - Jürgen Hörer
- School of Medicine and Health, Department of Pediatric and Congenital Heart Surgery, Technical University of Munich, German Heart Center Munich, Lazarettstraße 36, 80636 Munich, Germany ,Division of Congenital and Pediatric Heart Surgery, University Hospital of Munich, Ludwig-Maximilians-Universität, Munich, Germany
| | - Rüdiger Lange
- School of Medicine and Health, Department of Cardiovascular Surgery, Institute Insure, Technical University of Munich, German Heart Center Munich, Lazarettstrasse 36, 80636 Munich, Germany ,DZHK (German Center for Cardiovascular Research)-Partner Site Munich Heart Alliance, Biedersteiner Straße 29, 80802 Munich, Germany
| | - Markus Krane
- School of Medicine and Health, Department of Cardiovascular Surgery, Institute Insure, Technical University of Munich, German Heart Center Munich, Lazarettstrasse 36, 80636 Munich, Germany ,DZHK (German Center for Cardiovascular Research)-Partner Site Munich Heart Alliance, Biedersteiner Straße 29, 80802 Munich, Germany ,Division of Cardiac Surgery, Department of Surgery, Yale University School of Medicine, New Haven, CT USA
| | - Stefanie A. Doppler
- School of Medicine and Health, Department of Cardiovascular Surgery, Institute Insure, Technical University of Munich, German Heart Center Munich, Lazarettstrasse 36, 80636 Munich, Germany
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Jadli AS, Parasor A, Gomes KP, Shandilya R, Patel VB. Exosomes in Cardiovascular Diseases: Pathological Potential of Nano-Messenger. Front Cardiovasc Med 2021; 8:767488. [PMID: 34869682 PMCID: PMC8632805 DOI: 10.3389/fcvm.2021.767488] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Accepted: 10/06/2021] [Indexed: 12/15/2022] Open
Abstract
Cardiovascular diseases (CVDs) represent a major global health problem, due to their continued high incidences and mortality. The last few decades have witnessed new advances in clinical research which led to increased survival and recovery in CVD patients. Nevertheless, elusive and multifactorial pathophysiological mechanisms of CVD development perplexed researchers in identifying efficacious therapeutic interventions. Search for novel and effective strategies for diagnosis, prevention, and intervention for CVD has shifted research focus on extracellular vesicles (EVs) in recent years. By transporting molecular cargo from donor to recipient cells, EVs modulate gene expression and influence the phenotype of recipient cells, thus EVs prove to be an imperative component of intercellular signaling. Elucidation of the role of EVs in intercellular communications under physiological conditions implied the enormous potential of EVs in monitoring and treatment of CVD. The EVs secreted from the myriad of cells in the cardiovascular system such as cardiomyocytes, cardiac fibroblasts, cardiac progenitor cells, endothelial cells, inflammatory cells may facilitate the communication in physiological and pathological conditions. Understanding EVs-mediated cellular communication may delineate the mechanism of origin and progression of cardiovascular diseases. The current review summarizes exosome-mediated paracrine signaling leading to cardiovascular disease. The mechanistic role of exosomes in cardiovascular disease will provide novel avenues in designing diagnosis and therapeutic interventions.
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Affiliation(s)
- Anshul S Jadli
- Department of Physiology and Pharmacology, Cumming School of Medicine, Calgary, AB, Canada.,Libin Cardiovascular Institute, University of Calgary, Calgary, AB, Canada
| | - Ananya Parasor
- Department of Physiology and Pharmacology, Cumming School of Medicine, Calgary, AB, Canada.,Libin Cardiovascular Institute, University of Calgary, Calgary, AB, Canada
| | - Karina P Gomes
- Department of Physiology and Pharmacology, Cumming School of Medicine, Calgary, AB, Canada.,Libin Cardiovascular Institute, University of Calgary, Calgary, AB, Canada
| | - Ruchita Shandilya
- Department of Physiology and Pharmacology, Cumming School of Medicine, Calgary, AB, Canada.,Libin Cardiovascular Institute, University of Calgary, Calgary, AB, Canada
| | - Vaibhav B Patel
- Department of Physiology and Pharmacology, Cumming School of Medicine, Calgary, AB, Canada.,Libin Cardiovascular Institute, University of Calgary, Calgary, AB, Canada
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46
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Han C, Yang J, Sun J, Qin G. Extracellular vesicles in cardiovascular disease: Biological functions and therapeutic implications. Pharmacol Ther 2021; 233:108025. [PMID: 34687770 PMCID: PMC9018895 DOI: 10.1016/j.pharmthera.2021.108025] [Citation(s) in RCA: 97] [Impact Index Per Article: 24.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 09/15/2021] [Accepted: 10/14/2021] [Indexed: 02/07/2023]
Abstract
Extracellular vesicles (EVs), including exosomes and microvesicles, are lipid bilayer particles naturally released from the cell. While exosomes are formed as intraluminal vesicles (ILVs) of the multivesicular endosomes (MVEs) and released to extracellular space upon MVE-plasma membrane fusion, microvesicles are generated through direct outward budding of the plasma membrane. Exosomes and microvesicles have same membrane orientation, different yet overlapping sizes; their cargo contents are selectively packed and dependent on the source cell type and functional state. Both exosomes and microvesicles can transfer bioactive RNAs, proteins, lipids, and metabolites from donor to recipient cells and influence the biological properties of the latter. Over the last decade, their potential roles as effective inter-tissue communicators in cardiovascular physiology and pathology have been increasingly appreciated. In addition, EVs are attractive sources of biomarkers for the diagnosis and prognosis of diseases, because they acquire their complex cargoes through cellular processes intimately linked to disease pathogenesis. Furthermore, EVs obtained from various stem/progenitor cell populations have been tested as cell-free therapy in various preclinical models of cardiovascular diseases and demonstrate unequivocally encouraging benefits. Here we summarize the findings from recent research on the biological functions of EVs in the ischemic heart disease and heart failure, and their potential as novel diagnostic biomarkers and therapeutic opportunities.
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Affiliation(s)
- Chaoshan Han
- Department of Biomedical Engineering, University of Alabama at Birmingham, School of Medicine and School of Engineering, Birmingham, AL 35294, USA
| | - Junjie Yang
- Department of Biomedical Engineering, University of Alabama at Birmingham, School of Medicine and School of Engineering, Birmingham, AL 35294, USA
| | - Jiacheng Sun
- Department of Biomedical Engineering, University of Alabama at Birmingham, School of Medicine and School of Engineering, Birmingham, AL 35294, USA
| | - Gangjian Qin
- Department of Biomedical Engineering, University of Alabama at Birmingham, School of Medicine and School of Engineering, Birmingham, AL 35294, USA.
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The Essential Need for a Validated Potency Assay for Cell-Based Therapies in Cardiac Regenerative and Reparative Medicine. A Practical Approach to Test Development. Stem Cell Rev Rep 2021; 17:2235-2244. [PMID: 34463902 PMCID: PMC8599250 DOI: 10.1007/s12015-021-10244-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/12/2021] [Indexed: 01/04/2023]
Abstract
Biological treatments are one of the medical breakthroughs in the twenty-first century. The initial enthusiasm pushed the field towards indiscriminatory use of cell therapy regardless of the pathophysiological particularities of underlying conditions. In the reparative and regenerative cardiovascular field, the results of the over two decades of research in cell-based therapies, although promising still could not be translated into clinical scenario. Now, when we identified possible deficiencies and try to rebuild its foundations rigorously on scientific evidence, development of potency assays for the potential therapeutic product is one of the steps which will bring our goal of clinical translation closer. Although, highly challenging, the potency tests for cell products are considered as a priority by the regulatory agencies. In this paper we describe the main characteristics and challenges for a cell therapy potency test focusing on the cardiovascular field. Moreover, we discuss different steps and types of assays that should be taken into consideration for an eventual potency test development by tying together two fundamental concepts: target disease and expected mechanism of action.
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48
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Jayaraman S, Gnanasampanthapandian D, Rajasingh J, Palaniyandi K. Stem Cell-Derived Exosomes Potential Therapeutic Roles in Cardiovascular Diseases. Front Cardiovasc Med 2021; 8:723236. [PMID: 34447796 PMCID: PMC8382889 DOI: 10.3389/fcvm.2021.723236] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Accepted: 07/12/2021] [Indexed: 12/12/2022] Open
Abstract
Owing to myocardial abnormalities, cardiac ailments are considered to be the major cause of morbidity and mortality worldwide. According to a recent study, membranous vesicles that are produced naturally, termed as "exosomes", have emerged as the potential candidate in the field of cardiac regenerative medicine. A wide spectrum of stem cells has also been investigated in the treatment of cardiovascular diseases (CVD). Exosomes obtained from the stem cells are found to be cardioprotective and offer great hope in the treatment of CVD. The basic nature of exosomes is to deal with the intracellular delivery of both proteins and nucleic acids. This activity of exosomes helps us to rely on them as the attractive pharmaceutical delivery agents. Most importantly, exosomes derived from microRNAs (miRNAs) hold great promise in assessing the risk of CVD, as they serve as notable biomarkers of the disease. Exosomes are small, less immunogenic, and lack toxicity. These nanovesicles harbor immense potential as a therapeutic entity and would provide fruitful benefits if consequential research were focused on their upbringing and development as a useful diagnostic and therapeutic tool in the field of medicine.
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Affiliation(s)
- Selvaraj Jayaraman
- Department of Biochemistry, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India
| | - Dhanavathy Gnanasampanthapandian
- Cancer Science Laboratory, Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Chennai, India
| | - Johnson Rajasingh
- Department of Bioscience Research & Medicine-Cardiology, The University of Tennessee Health Science Center, Memphis, TN, United States
| | - Kanagaraj Palaniyandi
- Cancer Science Laboratory, Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Chennai, India
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49
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Ghafouri-Fard S, Niazi V, Hussen BM, Omrani MD, Taheri M, Basiri A. The Emerging Role of Exosomes in the Treatment of Human Disorders With a Special Focus on Mesenchymal Stem Cells-Derived Exosomes. Front Cell Dev Biol 2021; 9:653296. [PMID: 34307345 PMCID: PMC8293617 DOI: 10.3389/fcell.2021.653296] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Accepted: 06/10/2021] [Indexed: 12/14/2022] Open
Abstract
Extracellular vesicles (EVs) are produced by diverse eukaryotic and prokaryotic cells. They have prominent roles in the modulation of cell-cell communication, inflammation versus immunomodulation, carcinogenic processes, cell proliferation and differentiation, and tissue regeneration. These acellular vesicles are more promising than cellular methods because of the lower risk of tumor formation, autoimmune responses and toxic effects compared with cell therapy. Moreover, the small size and lower complexity of these vesicles compared with cells have made their production and storage easier than cellular methods. Exosomes originated from mesenchymal stem cells has also been introduced as therapeutic option for a number of human diseases. The current review aims at summarization of the role of EVs in the regenerative medicine with a focus on their therapeutic impacts in liver fibrosis, lung disorders, osteoarthritis, colitis, myocardial injury, spinal cord injury and retinal injury.
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Affiliation(s)
- Soudeh Ghafouri-Fard
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Vahid Niazi
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Bashdar Mahmud Hussen
- Department of Pharmacognosy, College of Pharmacy, Hawler Medical University, Erbil, Iraq
| | - Mir Davood Omrani
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Taheri
- Skull Base Research Center, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Abbas Basiri
- Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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50
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Extracellular Vesicles in Organ Fibrosis: Mechanisms, Therapies, and Diagnostics. Cells 2021; 10:cells10071596. [PMID: 34202136 PMCID: PMC8305303 DOI: 10.3390/cells10071596] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 06/16/2021] [Accepted: 06/21/2021] [Indexed: 02/06/2023] Open
Abstract
Fibrosis is the unrelenting deposition of excessively large amounts of insoluble interstitial collagen due to profound matrigenic activities of wound-associated myofibroblasts during chronic injury in diverse tissues and organs. It is a highly debilitating pathology that affects millions of people globally and leads to decreased function of vital organs and increased risk of cancer and end-stage organ disease. Extracellular vesicles (EVs) produced within the chronic wound environment have emerged as important vehicles for conveying pro-fibrotic signals between many of the cell types involved in driving the fibrotic response. On the other hand, EVs from sources such as stem cells, uninjured parenchymal cells, and circulation have in vitro and in vivo anti-fibrotic activities that have provided novel and much-needed therapeutic options. Finally, EVs in body fluids of fibrotic individuals contain cargo components that may have utility as fibrosis biomarkers, which could circumvent current obstacles to fibrosis measurement in the clinic, allowing fibrosis stage, progression, or regression to be determined in a manner that is accurate, safe, minimally-invasive, and conducive to repetitive testing. This review highlights the rapid and recent progress in our understanding of EV-mediated fibrotic pathogenesis, anti-fibrotic therapy, and fibrosis staging in the lung, kidney, heart, liver, pancreas, and skin.
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