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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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2
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Saadh MJ, Muhammad FA, Albadr RJ, Sanghvi G, Ballal S, Pathak PK, Bareja L, Aminov Z, Taher WM, Alwan M, Jawad MJ, Al-Nuaimi AMA. Exosomal non-coding RNAs: key regulators of inflammation-related cardiovascular disorders. Eur J Med Res 2025; 30:395. [PMID: 40390035 PMCID: PMC12087048 DOI: 10.1186/s40001-025-02649-6] [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: 02/02/2025] [Accepted: 04/30/2025] [Indexed: 05/21/2025] Open
Abstract
Inflammation is a complex, tightly regulated process involving biochemical and cellular reactions to harmful stimuli. Often termed "the internal fire", it is crucial for protecting the body and facilitating tissue healing. While inflammation is essential for survival, chronic inflammation can be detrimental, leading to tissue damage and reduced survival. The innate immune system triggers inflammation, closely linked to the development of heart diseases, with significant consequences for individuals. Inflammation in arterial walls or the body substantially contributes to atherosclerotic disease progression, affecting the cardiovascular system. Altered lipoproteins increase the risk of excessive blood clotting, a hallmark of atherosclerotic cardiovascular disease and its complications. Integrating inflammatory biomarkers with established risk assessment techniques can enhance our ability to identify at-risk individuals, assess their risk severity, and recommend appropriate CVD prevention strategies. Exosomes, a type of extracellular vesicle, are released by various cells and mediate cell communication locally and systemically. In the past decade, exosomes have been increasingly studied for their vital roles in health maintenance and disease processes. They can transport substances like non-coding RNAs, lipids, and proteins between cells, influencing immune responses and inflammation to elicit harmful or healing effects. This study focuses on the critical role of inflammation in heart disease progression and how non-coding RNAs in exosomes modulate the inflammatory process, either exacerbating or alleviating inflammation-related damage in the cardiovascular system.
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Affiliation(s)
- Mohamed J Saadh
- Faculty of Pharmacy, Middle East University, Amman, 11831, Jordan
| | | | | | - Gaurav Sanghvi
- Marwadi University Research Center, Department of Microbiology, Faculty of Science, Marwadi University, Rajkot, Gujarat, 360003, India
| | - Suhas Ballal
- Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to Be University), Bangalore, Karnataka, India
| | - Piyus Kumar Pathak
- Department of Applied Sciences-Chemistry, NIMS Institute of Engineering & Technology, NIMS University Rajasthan, Jaipur, India
| | - Lakshay Bareja
- Centre for Research Impact & Outcome, Chitkara University Institute of Engineering and Technology, Chitkara University, Rajpura, Punjab, 140401, India
| | - Zafar Aminov
- Department of Public Health and Healthcare Management, Samarkand State Medical University, 18 Amir Temur Street, Samarkand, Uzbekistan
| | - Waam Mohammed Taher
- College of Nursing, National University of Science and Technology, Dhi Qar, Iraq
| | - Mariem Alwan
- Pharmacy College, Al-Farahidi University, Baghdad, Iraq
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İnci A, Dökmeci S. Extracellular chaperones in lysosomal storage diseases. Mol Genet Metab 2025; 145:109086. [PMID: 40106871 DOI: 10.1016/j.ymgme.2025.109086] [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: 11/27/2024] [Revised: 02/23/2025] [Accepted: 03/11/2025] [Indexed: 03/22/2025]
Abstract
Lysosomal storage disorders (LSDs) are a diverse group of inherited metabolic disorders characterized by the accumulation of undegraded substrates within lysosomes due to defective lysosomal function. Recent research has highlighted the pivotal role of extracellular chaperones in the pathophysiology of LSDs, revealing their crucial involvement in modulating disease progression. These chaperones aid in stabilizing and refolding misfolded lysosomal enzymes, enhancing their proper trafficking and function, which in turn reduces substrate accumulation. Furthermore, extracellular chaperones have emerged as promising biomarkers, with their levels in bodily fluids offering potential for disease diagnosis and monitoring. This review explores the current understanding of extracellular chaperones in the context of LSDs, examining their mechanisms of action, biomarker and therapeutic potential, and future directions in clinical application of LSDs.
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Affiliation(s)
- Aslı İnci
- Gazi University School of Medicine, Department of Pediatric Metabolism, Ankara, Turkey; Hacettepe University School of Medicine, Department of Medical Biology, Ankara, Turkey.
| | - Serap Dökmeci
- Hacettepe University School of Medicine, Department of Medical Biology, Ankara, Turkey
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4
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Wu L, Li Z, Song W, Zhang L, Li K, Wang H. Cardiac shock wave therapy-induced exosome derived from OGD/R-treated H9c2 cells carrying miR-98-5p promote HUVECs angiogenesis. Sci Rep 2025; 15:15213. [PMID: 40307279 PMCID: PMC12044020 DOI: 10.1038/s41598-025-00104-4] [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: 04/18/2024] [Accepted: 04/24/2025] [Indexed: 05/02/2025] Open
Abstract
Cardiac shock wave therapy (CSWT) as an effectual therapy can activate the function of exosomes to a certain extent. Here, we attempted to examine the role of CSWT in exosome released from ischemic cardiomyocytes and its function in myocardial ischemia recovery. The exosomes derived from OGD/R-treated H9c2 (H9c2-OGD/R-Exo) and CSWT-treated OGD/R-stimulated H9c2 (CSWT-H9c2-OGD/R-Exo) were performed with small RNA sequencing to determine miRNAs that differentially expressed. After miR-98-5p inhibitor transfection, H9c2 were subjected to OGD/R and co-cultured with CSWT-H9c2-OGD/R-Exo, the cell viability, LDH and cell apoptosis were assessed. The transfected HUVECs were co-cultured with CSWT-H9c2-OGD/R-Exo, then HUVECs viability, angiogenesis, migration and invasion were assessed. The luciferase reporter gene assay was conducted to prove the targeting relation between miR-98-5p and FOXN3. miR-98-5p was highly enriched in CSWT-H9c2-OGD/R-Exo in compared with H9c2-OGD/R-Exo. CSWT-H9c2-OGD/R-Exo could improve cell viability, inhibit LDH and cell apoptosis. And miR-98-5p released by CSWT-H9c2-OGD/R-Exo promoted HUVECs viability, angiogenesis, migration and invasion. Further FOXN3 was defined as the downstream target gene of miR-98-5p, and miR-98-5p overexpression decreased FOXN3 expression in HUVECs. Besides, the suppression effects of miR-98-5p inhibitor on HUVECs proliferation, angiogenesis and metastasis was partly blunted by FOXN3 silencing. miR-98-5p released from CSWT-H9c2-OGD/R-Exo promoted HUVECs proliferation, angiogenesis and metastasis through directly targeting and suppressing FOXN3 expression.
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Affiliation(s)
- Lizhou Wu
- Department of Medical Ultrasound, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, 250014, China
| | - Zhan Li
- Department of Cardiology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, 250014, China
| | - Wenhui Song
- Department of Medical Ultrasound, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, 250014, China
| | - Li Zhang
- The Department of Immunology, School of Basic Medicine, Qingdao University, Qingdao, 266000, China
| | - Kuan Li
- Clinical Medical Institute, Xinjiang Medical University, Urumqi, China
| | - Haiyan Wang
- Department of Medical Ultrasound, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, 250014, China.
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Sen MG, Chooi R, McMullen JR. Heart-derived factors and organ cross-talk in settings of health and disease: new knowledge and clinical opportunities for multimorbidity. J Physiol 2025. [PMID: 39888058 DOI: 10.1113/jp287400] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Accepted: 01/13/2025] [Indexed: 02/01/2025] Open
Abstract
Cardiovascular disease affects millions of people worldwide and often presents with other conditions including metabolic, renal and neurological disorders. A variety of secreted factors from multiple organs/tissues (proteins, nucleic acids and lipids) have been implicated in facilitating organ cross-talk that may contribute to the development of multimorbidity. Secreted proteins have received the most attention, with the greatest body of research related to factors released from adipose tissue (adipokines), followed by skeletal muscle (myokines). To date, there have been fewer studies on proteins released from the heart (cardiokines) implicated with organ cross-talk. Early evidence for the secretion of cardiac-specific factors facilitating organ cross-talk came in the form of natriuretic peptides which are secreted via the classical endoplasmic reticulum-Golgi pathway. More recently, studies in cardiomyocyte-specific genetic mouse models have revealed cardiac-initiated organ cross-talk. Cardiomyocyte-specific modulation of microRNAs (miR-208a and miR-23-27-24 cluster) and proteins such as the mediator complex subunit 13 (MED13), G-protein-coupled receptor kinase 2 (GRK2), mutant α-myosin heavy-chain (αMHC), ubiquitin-like modifier-activating enzyme (ATG7), oestrogen receptor alpha (ERα) and fibroblast growth factor 21 (FGF21) have resulted in metabolic and renal phenotypes. These studies have implicated a variety of factors which can be secreted via the classical pathway or via non-classical mechanisms including the release of extracellular vesicles. Cross-talk between the heart and the brain has also been described (e.g. via miR-1 and an emerging concept, interoception: detection of internal neural signals). Here we summarize these studies taking into consideration that factors may be secreted in both settings of health and in disease.
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Affiliation(s)
- Melodi G Sen
- Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
| | - Roger Chooi
- Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
| | - Julie R McMullen
- Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
- Heart Research Institute, Newtown, New South Wales, Australia
- Monash Alfred Baker Centre for Cardiovascular Research, Faculty of Medicine Nursing and Health Sciences, Monash University, Melbourne, Victoria, Australia
- Baker Department of Cardiometabolic Health, The University of Melbourne, Parkville, Victoria, Australia
- Baker Department of Cardiovascular Research, Translation and Implementation, La Trobe University, Bundoora, Victoria, Australia
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Hu H, Wang X, Yu H, Wang Z. Extracellular vesicular microRNAs and cardiac hypertrophy. Front Endocrinol (Lausanne) 2025; 15:1444940. [PMID: 39850481 PMCID: PMC11753959 DOI: 10.3389/fendo.2024.1444940] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Accepted: 12/23/2024] [Indexed: 01/25/2025] Open
Abstract
Cardiac hypertrophy is an adaptive response to pressure or volume overload such as hypertension and ischemic heart diseases. Sustained cardiac hypertrophy eventually leads to heart failure. The pathophysiological alterations of hypertrophy are complex, involving both cellular and molecular systems. Understanding the molecular events that inhibit or repress cardiac hypertrophy may help identify novel therapeutic strategies. Increasing evidence has indicated that extracellular vesicle (EV)-derived microRNAs (miRNAs) play a significant role in the development and progression of cardiac hypertrophy. In this review, we briefly review recent advancements in EV research, especially on biogenesis, cargoes and its role in cardiac hypertrophy. We then describe the latest findings regarding EV-derived miRNAs, highlighting their functions and regulatory mechanisms in cardiac hypertrophy. Finally, the potential role of EV-derived miRNAs as targets in the diagnosis and treatment of cardiac hypertrophy will be discussed.
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Affiliation(s)
- Hai Hu
- Inner Mongolia Key Laboratory of Disease-Related Biomarkers, The Second Affiliated Hospital, Baotou Medical College, Baotou, China
- School of Basic Medicine, Baotou Medical College, Baotou, China
| | - Xiulian Wang
- Inner Mongolia Key Laboratory of Disease-Related Biomarkers, The Second Affiliated Hospital, Baotou Medical College, Baotou, China
| | - Hui Yu
- Inner Mongolia Key Laboratory of Disease-Related Biomarkers, The Second Affiliated Hospital, Baotou Medical College, Baotou, China
- School of Basic Medicine, Baotou Medical College, Baotou, China
| | - Zhanli Wang
- Inner Mongolia Key Laboratory of Disease-Related Biomarkers, The Second Affiliated Hospital, Baotou Medical College, Baotou, China
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Bader J, Brigger F, Leroux JC. Extracellular vesicles versus lipid nanoparticles for the delivery of nucleic acids. Adv Drug Deliv Rev 2024; 215:115461. [PMID: 39490384 DOI: 10.1016/j.addr.2024.115461] [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: 08/26/2024] [Revised: 10/21/2024] [Accepted: 10/23/2024] [Indexed: 11/05/2024]
Abstract
Extracellular vesicles (EVs) are increasingly investigated for delivering nucleic acid (NA) therapeutics, leveraging their natural role in transporting NA and protein-based cargo in cell-to-cell signaling. Their synthetic counterparts, lipid nanoparticles (LNPs), have been developed over the past decades as NA carriers, culminating in the approval of several marketed formulations such as patisiran/Onpattro® and the mRNA-1273/BNT162 COVID-19 vaccines. The success of LNPs has sparked efforts to develop innovative technologies to target extrahepatic organs, and to deliver novel therapeutic modalities, such as tools for in vivo gene editing. Fueled by the recent advancements in both fields, this review aims to provide a comprehensive overview of the basic characteristics of EV and LNP-based NA delivery systems, from EV biogenesis to structural properties of LNPs. It addresses the primary challenges encountered in utilizing these nanocarriers from a drug formulation and delivery perspective. Additionally, biodistribution profiles, in vitro and in vivo transfection outcomes, as well as their status in clinical trials are compared. Overall, this review provides insights into promising research avenues and potential dead ends for EV and LNP-based NA delivery systems.
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Affiliation(s)
- Johannes Bader
- Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, 8093 Zurich, Switzerland
| | - Finn Brigger
- Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, 8093 Zurich, Switzerland
| | - Jean-Christophe Leroux
- Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, 8093 Zurich, Switzerland.
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8
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Verwilt J, Vromman M. Current Understandings and Open Hypotheses on Extracellular Circular RNAs. WILEY INTERDISCIPLINARY REVIEWS. RNA 2024; 15:e1872. [PMID: 39506237 DOI: 10.1002/wrna.1872] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Revised: 09/21/2024] [Accepted: 09/23/2024] [Indexed: 11/08/2024]
Abstract
Circular RNAs (circRNAs) are closed RNA loops present in humans and other organisms. Various circRNAs have an essential role in diseases, including cancer. Cells can release circRNAs into the extracellular space of adjacent biofluids and can be present in extracellular vesicles. Due to their circular nature, extracellular circRNAs (excircRNAs) are more stable than their linear counterparts and are abundant in many biofluids, such as blood plasma and urine. circRNAs' link with disease suggests their extracellular counterparts have high biomarker potential. However, circRNAs and the extracellular space are challenging research domains, as they consist of complex biological systems plagued with nomenclature issues and a wide variety of protocols with different advantages and disadvantages. Here, we summarize what is known about excircRNAs, the current challenges in the field, and what is needed to improve extracellular circRNA research.
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Affiliation(s)
- Jasper Verwilt
- Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium
- Complex Genetics of Alzheimer's Disease Group, VIB Center for Molecular Neurology, Antwerp, Belgium
| | - Marieke Vromman
- CNRS UMR3244 (Dynamics of Genetic Information), Sorbonne University, PSL University, Institut Curie, Centre de Recherche, Paris, France
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Liu Y, Chen J, Xiong J, Hu JQ, Yang LY, Sun YX, Wei Y, Zhao Y, Li X, Zheng QH, Qi WC, Liang FR. Potential cardiac-derived exosomal miRNAs involved in cardiac healing and remodeling after myocardial ischemia-reperfusion injury. Sci Rep 2024; 14:24275. [PMID: 39414956 PMCID: PMC11484883 DOI: 10.1038/s41598-024-75517-8] [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: 01/09/2024] [Accepted: 10/07/2024] [Indexed: 10/18/2024] Open
Abstract
Migratory cells exist in the heart, such as immune cells, fibroblasts, endothelial cells, etc. During myocardium injury, such as ischemia-reperfusion (MIRI), cells migrate to the site of injury to perform repair functions. However, excessive aggregation of these cells may exacerbate damage to the structure and function of the heart, such as acute myocarditis and myocardial fibrosis. Myocardial injury releases exosomes, which are a type of vesicle with signal transduction function and the miRNA carried by exosomes can control cell migration function. Therefore, regulating this migratory cell population through cardiac-derived exosomal miRNA is crucial for protecting and maintaining cardiac function. Through whole transcriptome RNA sequencing, exosomal miRNA sequencing and single-cell dataset analysis, we (1) determined the potential molecular regulatory role of the lncRNA‒miRNA‒mRNA axis in MIRI, (2) screened four important exosomal miRNAs that could be released by cardiac tissue, and (3) screened seven genes related to cell locomotion that are regulated by four miRNAs, among which Tradd and Ephb6 may be specific for promoting migration of different cells of myocardial tissue in myocardial infarct. We generated a core miRNA‒mRNA network based on the functions of the target genes, which may be not only a target for cardiac repair but also a potential diagnostic marker for interactions between the heart and other tissues or organs. In conclusion, we elucidated the potential mechanism of MIRI in cardiac remodeling from the perspective of cell migration, and inhibition of cellular overmigration based on this network may provide new therapeutic targets for MIRI and to prevent MIRI from developing into other diseases.
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Affiliation(s)
- Yu Liu
- School of Acupuncture-Moxibustion and Tuina, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China
| | - Jiao Chen
- School of Acupuncture-Moxibustion and Tuina, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China
| | - Jian Xiong
- School of Acupuncture-Moxibustion and Tuina, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China
| | - Jin-Qun Hu
- School of Acupuncture-Moxibustion and Tuina, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China
| | - Li-Yuan Yang
- School of Acupuncture-Moxibustion and Tuina, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China
| | - Yu-Xin Sun
- School of Acupuncture-Moxibustion and Tuina, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China
| | - Ying Wei
- School of Acupuncture-Moxibustion and Tuina, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China
| | - Yi Zhao
- School of Acupuncture-Moxibustion and Tuina, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China
| | - Xiao Li
- School of Acupuncture-Moxibustion and Tuina, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China
| | - Qian-Hua Zheng
- School of Acupuncture-Moxibustion and Tuina, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China
| | - Wen-Chuan Qi
- School of Acupuncture-Moxibustion and Tuina, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China.
| | - Fan-Rong Liang
- School of Acupuncture-Moxibustion and Tuina, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China.
- Sichuan Clinical Medicine Research Center of Acupuncture-Moxibustion, Chengdu, 610075, China.
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Liu CJ, Chen JJ, Wu JH, Chung YT, Chen JW, Liu MT, Chiu CH, Chang YC, Chang SN, Lin JW, Hwang JJ. Association of exosomes in patients with compromised myocardial perfusion on functional imaging. J Formos Med Assoc 2024; 123:968-974. [PMID: 38307800 DOI: 10.1016/j.jfma.2024.01.019] [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: 08/19/2023] [Revised: 12/19/2023] [Accepted: 01/17/2024] [Indexed: 02/04/2024] Open
Abstract
BACKGROUND Exosomes are membrane vesicles that are actively secreted in response to microenvironmental stimuli. In this study, we quantified the amount of exosomes in patients with significant coronary artery disease (CAD) and evaluated its relationship with myocardial perfusion imaging (MPI) results. METHODS Patients who underwent both MPI and coronary angiography were recruited. Plasma was collected during angiography, and exosomes were extracted via the precipitation method. The summed stress scores (SSS), summed difference scores, and ventricular functional parameters were calculated from the MPI and compared with the amounts of exosomes and extracted miRNAs. RESULTS In total, 115 patients were enrolled (males: 78 %; mean age: 66.6 ± 10.6 years). Those with abnormal SSS according to the MPI had significantly fewer exosomes (p = 0.032). After multivariate analysis, the SSS remained significantly related to the amount of exosomes (p = 0.035). In forty randomly selected samples, miRNA-432-5p and miRNA-382-3p were upregulated in patients with abnormal SSS. CONCLUSION Patients with compromised poststress myocardial perfusion on MPI tended to have fewer exosomes in association with CAD-related miRNAs. This is the first study to clarify the fundamental and pathophysiological causes of CAD using radiographic examinations.
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Affiliation(s)
- Chia-Ju Liu
- Department of Nuclear Medicine, National Taiwan University Hospital, Taipei City, Taiwan
| | - Jien-Jiun Chen
- Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital Yun-Lin Branch, Dou-Liu City, Taiwan
| | - Jo-Hsuan Wu
- Shiley Eye Institute and Viterbi Family Department of Ophthalmology, University of California, San Diego, CA, USA
| | - Yao-Te Chung
- Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital Yun-Lin Branch, Dou-Liu City, Taiwan
| | - Jin-Wun Chen
- Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital Yun-Lin Branch, Dou-Liu City, Taiwan
| | - Meng-Tsun Liu
- Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital Yun-Lin Branch, Dou-Liu City, Taiwan
| | - Chu-Hsuan Chiu
- Graduate Institute of Medical Genomics and Proteomics, Taipei, Taiwan; Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Yi-Cheng Chang
- Graduate Institute of Medical Genomics and Proteomics, Taipei, Taiwan; Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Sheng-Nan Chang
- Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital Yun-Lin Branch, Dou-Liu City, Taiwan.
| | - Jou-Wei Lin
- Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital Yun-Lin Branch, Dou-Liu City, Taiwan
| | - Juey-Jen Hwang
- Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital Yun-Lin Branch, Dou-Liu City, Taiwan; Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
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Asok A, Bhandary R, Shetty MS, Ramesh A, Venugopalan G, Sreeja SS. Comparative evaluation of serum heat shock protein 60 in chronic periodontitis patients with and without coronary heart disease - A case-control study. J Indian Soc Periodontol 2024; 28:557-562. [PMID: 40134401 PMCID: PMC11932562 DOI: 10.4103/jisp.jisp_309_23] [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: 06/14/2023] [Revised: 01/14/2025] [Accepted: 01/16/2025] [Indexed: 03/27/2025] Open
Abstract
Background Heat shock proteins (HSPs) are a group of stress proteins that participate in physiological processes such as cellular folding, assembly, translocation of polypeptides across membranes, and protein repair after cell damage. HSP60 has been implicated in the pathogenesis of both chronic periodontitis (CP) and coronary heart disease (CHD). Aim The aim was to assess the possible link between CP and CHD by estimating and comparing the serum HSP60 levels in patients with CP with and without CHD. Settings and Design Ninety patients in the age group of 30-60 years were involved in this study. The patients were categorized as CP (control group) and CP with CHD (case group). Materials and Methods Gingival index (GI) and periodontal parameters such as probing pocket depth and clinical attachment levels were documented. Enzyme-linked immunosorbent assay was used to determine the HSP60 levels in serum samples obtained from the patients. Statistical Analysis Results were statistically analyzed using the SPSS version 16.0 software to estimate the mean and standard deviation using independent t-test and Mann-Whitney U-test. Results The findings of the research indicated that patients with CP with CHD exhibited elevated serum HSP60 levels compared to CP without CHD (P < 0.05). In addition, a statistically significant rise in GI was noted in the case group. However, the periodontal measurements did not reveal any significant differences. Conclusion As a result, HSP60 levels were observed to be elevated in the case group compared to the control group. Consequently, there is a connection between periodontal disease and CHD that contributes to the overall inflammatory burden.
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Affiliation(s)
- Anjhana Asok
- Dr Kaushik’s Dental Speciality Center, Cochin, Kerala, India
| | - Rahul Bhandary
- Department of Periodontology, A B Shetty Memorial Institute of Dental Sciences, Nitte University, Mangalore, Karnataka, India
| | - Mamatha Shekar Shetty
- Department of Periodontology, A B Shetty Memorial Institute of Dental Sciences, Nitte University, Mangalore, Karnataka, India
| | - Amitha Ramesh
- Department of Periodontology, A B Shetty Memorial Institute of Dental Sciences, Nitte University, Mangalore, Karnataka, India
| | - Geethu Venugopalan
- Department of Periodontology, A B Shetty Memorial Institute of Dental Sciences, Nitte University, Mangalore, Karnataka, India
| | - S Sai Sreeja
- Department of Periodontology, A B Shetty Memorial Institute of Dental Sciences, Nitte University, Mangalore, Karnataka, India
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12
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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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13
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Yahyazadeh R, Baradaran Rahimi V, Askari VR. Stem cell and exosome therapies for regenerating damaged myocardium in heart failure. Life Sci 2024; 351:122858. [PMID: 38909681 DOI: 10.1016/j.lfs.2024.122858] [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: 05/09/2024] [Revised: 06/13/2024] [Accepted: 06/18/2024] [Indexed: 06/25/2024]
Abstract
Finding novel treatments for cardiovascular diseases (CVDs) is a hot topic in medicine; cell-based therapies have reported promising news for controlling dangerous complications of heart disease such as myocardial infarction (MI) and heart failure (HF). Various progenitor/stem cells were tested in various in-vivo, in-vitro, and clinical studies for regeneration or repairing the injured tissue in the myocardial to accelerate the healing. Fetal, adult, embryonic, and induced pluripotent stem cells (iPSC) have revealed the proper potency for cardiac tissue repair. As an essential communicator among cells, exosomes with specific contacts (proteins, lncRNAs, and miRNAs) greatly promote cardiac rehabilitation. Interestingly, stem cell-derived exosomes have more efficiency than stem cell transplantation. Therefore, stem cells induced pluripotent stem cells (iPSCs), embryonic stem cells (ESCs), cardiac stem cells (CDC), and skeletal myoblasts) and their-derived exosomes will probably be considered an alternative therapy for CVDs remedy. In addition, stem cell-derived exosomes have been used in the diagnosis/prognosis of heart diseases. In this review, we explained the advances of stem cells/exosome-based treatment, their beneficial effects, and underlying mechanisms, which will present new insights in the clinical field in the future.
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Affiliation(s)
- Roghayeh Yahyazadeh
- Pharmacological Research Center of Medicinal Plants, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Vafa Baradaran Rahimi
- Department of Cardiovascular Diseases, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Vahid Reza Askari
- Pharmacological Research Center of Medicinal Plants, Mashhad University of Medical Sciences, Mashhad, Iran.
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14
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Cui Z, Zhang L, Hu G, Zhang F. Extracellular Vesicles in Cardiovascular Pathophysiology: Communications, Biomarkers, and Therapeutic Potential. Cardiovasc Toxicol 2024; 24:711-726. [PMID: 38844744 DOI: 10.1007/s12012-024-09875-0] [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: 12/21/2023] [Accepted: 05/25/2024] [Indexed: 08/07/2024]
Abstract
Extracellular vesicles (EVs) are diverse, membrane-bound vesicles released from cells into the extracellular environment. They originate from either endosomes or the cell membrane and typically include exosomes and microvesicles. These EVs serve as crucial mediators of intercellular communication, carrying a variety of contents such as nucleic acids, proteins, and lipids, which regulate the physiological and pathological processes of target cells. Moreover, the molecular cargo of EVs can reflect critical information about the originating cells, making them potential biomarkers for the diagnosis and prognosis of diseases. Over the past decade, the role of EVs as key communicators between cell types in cardiovascular physiology and pathology has gained increasing recognition. EVs from different cellular sources, or from the same source under different cellular conditions, can have distinct impacts on the management, diagnosis, and prognosis of cardiovascular diseases. Furthermore, it is essential to consider the influence of cardiovascular-derived EVs on the metabolism of peripheral organs. This review aims to summarize recent advancements in the field of cardiovascular research with respect to the roles and implications of EVs. Our goal is to provide new insights and directions for the early prevention and treatment of cardiovascular diseases, with an emphasis on the therapeutic potential and diagnostic value of EVs.
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Affiliation(s)
- Zhe Cui
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, 127 Changle West Road, Xi'an, 710032, China
| | - Ling Zhang
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, 127 Changle West Road, Xi'an, 710032, China
| | - Guangyu Hu
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, 127 Changle West Road, Xi'an, 710032, China
| | - Fuyang Zhang
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, 127 Changle West Road, Xi'an, 710032, China.
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15
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Li H, Zhang J, Tan M, Yin Y, Song Y, Zhao Y, Yan L, Li N, Zhang X, Bai J, Jiang T, Li H. Exosomes based strategies for cardiovascular diseases: Opportunities and challenges. Biomaterials 2024; 308:122544. [PMID: 38579591 DOI: 10.1016/j.biomaterials.2024.122544] [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: 11/29/2023] [Revised: 03/11/2024] [Accepted: 03/19/2024] [Indexed: 04/07/2024]
Abstract
Exosomes, as nanoscale extracellular vesicles (EVs), are secreted by all types of cells to facilitate intercellular communication in living organisms. After being taken up by neighboring or distant cells, exosomes can alter the expression levels of target genes in recipient cells and thereby affect their pathophysiological outcomes depending on payloads encapsulated therein. The functions and mechanisms of exosomes in cardiovascular diseases have attracted much attention in recent years and are thought to have cardioprotective and regenerative potential. This review summarizes the biogenesis and molecular contents of exosomes and details the roles played by exosomes released from various cells in the progression and recovery of cardiovascular disease. The review also discusses the current status of traditional exosomes in cardiovascular tissue engineering and regenerative medicine, pointing out several limitations in their application. It emphasizes that some of the existing emerging industrial or bioengineering technologies are promising to compensate for these shortcomings, and the combined application of exosomes and biomaterials provides an opportunity for mutual enhancement of their performance. The integration of exosome-based cell-free diagnostic and therapeutic options will contribute to the further development of cardiovascular regenerative medicine.
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Affiliation(s)
- Hang Li
- Department of Cardiology, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu, 215006, PR China
| | - Jun Zhang
- Department of Cardiology, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu, 215006, PR China
| | - Mingyue Tan
- Department of Cardiology, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu, 215006, PR China; Department of Geriatrics, Cardiovascular Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, PR China
| | - Yunfei Yin
- Department of Cardiology, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu, 215006, PR China
| | - Yiyi Song
- Suzhou Medical College of Soochow University, Suzhou, Jiangsu, 215000, PR China
| | - Yongjian Zhao
- Department of Cardiology, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu, 215006, PR China
| | - Lin Yan
- Department of Cardiology, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu, 215006, PR China
| | - Ning Li
- Department of Orthopedics, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230022, PR China
| | - Xianzuo Zhang
- Department of Orthopedics, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230022, PR China
| | - Jiaxiang Bai
- Department of Orthopedics, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230022, PR China; National Center for Translational Medicine (Shanghai) SHU Branch, Shanghai University, Shanghai, 200444, PR China.
| | - Tingbo Jiang
- Department of Cardiology, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu, 215006, PR China.
| | - Hongxia Li
- Department of Cardiology, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu, 215006, PR China.
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Mao L, Liu S, Chen Y, Huang H, Ding F, Deng L. Engineered exosomes: a potential therapeutic strategy for septic cardiomyopathy. Front Cardiovasc Med 2024; 11:1399738. [PMID: 39006168 PMCID: PMC11239395 DOI: 10.3389/fcvm.2024.1399738] [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: 03/13/2024] [Accepted: 06/14/2024] [Indexed: 07/16/2024] Open
Abstract
Septic cardiomyopathy, a life-threatening complication of sepsis, can cause acute heart failure and carry a high mortality risk. Current treatments have limitations. Fortunately, engineered exosomes, created through bioengineering technology, may represent a potential new treatment method. These exosomes can both diagnose and treat septic cardiomyopathy, playing a crucial role in its development and progression. This article examines the strategies for using engineered exosomes to protect cardiac function and treat septic cardiomyopathy. It covers three innovative aspects: exosome surface modification technology, the use of exosomes as a multifunctional drug delivery platform, and plant exosome-like nanoparticle carriers. The article highlights the ability of exosomes to deliver small molecules, proteins, and drugs, summarizing several RNA molecules, proteins, and drugs beneficial for treating septic cardiomyopathy. Although engineered exosomes are a promising biotherapeutic carrier, they face challenges in clinical application, such as understanding the interaction mechanism with host cells, distribution within the body, metabolism, and long-term safety. Further research is essential, but engineered exosomes hold promise as an effective treatment for septic cardiomyopathy.
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Affiliation(s)
- Lixia Mao
- Department of Critical Care Medicine, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Songtao Liu
- Department of Critical Care Medicine, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Yongxia Chen
- Department of Critical Care Medicine, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Huiyi Huang
- Department of Critical Care Medicine, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Fenghua Ding
- Outpatient Appointment Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Liehua Deng
- Department of Critical Care Medicine, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
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17
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Thangavel H, Dhanyalayam D, Kim M, Lizardo K, Sidrat T, Lopez JG, Wang X, Bansal S, Nagajyothi JF. Adipocyte-released adipomes in Chagas cardiomyopathy: Impact on cardiac metabolic and immune regulation. iScience 2024; 27:109672. [PMID: 38660407 PMCID: PMC11039351 DOI: 10.1016/j.isci.2024.109672] [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: 08/14/2023] [Revised: 03/14/2024] [Accepted: 04/03/2024] [Indexed: 04/26/2024] Open
Abstract
Chronic Trypanosoma cruzi infection leads to Chagas cardiomyopathy (CCM), with varying manifestations such as inflammatory hypertrophic cardiomyopathy, arrhythmias, and dilated cardiomyopathy. The factors responsible for the increasing risk of progression to CCM are not fully understood. Previous studies link adipocyte loss to CCM progression, but the mechanism triggering CCM pathogenesis remains unexplored. Our study uncovers that T. cruzi infection triggers adipocyte apoptosis, leading to the release of extracellular vesicles named "adipomes". We developed an innovative method to isolate intact adipomes from infected mice's adipose tissue and plasma, showing they carry unique lipid cargoes. Large and Small adipomes, particularly plasma-derived infection-associated L-adipomes (P-ILA), regulate immunometabolic signaling and induce cardiomyopathy. P-ILA treatment induces hypertrophic cardiomyopathy in wild-type mice and worsens cardiomyopathy severity in post-acute-infected mice by regulating adipogenic/lipogenic and mitochondrial functions. These findings highlight adipomes' pivotal role in promoting inflammation and impairing myocardial function during cardiac remodeling in CD.
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Affiliation(s)
- Hariprasad Thangavel
- Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ 07110, USA
| | - Dhanya Dhanyalayam
- Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ 07110, USA
| | - Michelle Kim
- Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ 07110, USA
| | - Kezia Lizardo
- Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ 07110, USA
| | - Tabinda Sidrat
- Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ 07110, USA
| | | | - Xiang Wang
- Rutgers University Molecular Imaging Core (RUMIC), Rutgers Translational Sciences, Piscataway, NJ 08854, USA
| | - Shivani Bansal
- Departnment of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA
| | - Jyothi F. Nagajyothi
- Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ 07110, USA
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18
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Jeon G, Hwang AR, Park DY, Kim JH, Kim YH, Cho BK, Min J. miRNA profiling of B16F10 melanoma cell exosomes reveals melanin synthesis-related genes. Heliyon 2024; 10:e30474. [PMID: 38711645 PMCID: PMC11070906 DOI: 10.1016/j.heliyon.2024.e30474] [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: 10/02/2023] [Revised: 04/26/2024] [Accepted: 04/27/2024] [Indexed: 05/08/2024] Open
Abstract
This study investigates the communication between skin cells, specifically melanocytes, keratinocytes, and fibroblasts, which is crucial for the process of melanin production known as melanogenesis. We aimed to understand the role of melanocyte exosomes in regulating melanogenesis and to uncover the microRNAs influencing this process. We isolated exosomes and characterized them using advanced microscopy and protein analysis to achieve this. We conducted experiments on melanoma cells to study melanin production regulation and examined how exosomes influenced gene expression related to melanogenesis. The results revealed that melanocyte exosomes increased certain types of tyrosinases, thereby enhancing melanin production. Furthermore, we acquired the miRNA profile of exosomes and hypothesized that specific siRNAs, such as miR-21a-5p, could potentially facilitate melanin synthesis. Our findings shed light on the importance of exosomes in skin health and provide valuable insights into intercellular communication mechanisms. Understanding these processes can pave the way for innovative therapies to treat melanin-related disorders and maintain healthy skin.
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Affiliation(s)
- Gyeongchan Jeon
- Graduate School of Semiconductor and Chemical Engineering, Jeonbuk National University, 567 Baekje-daero, Deokjin-gu, Jeonju-si, Jeollabuk-do, 54896, Republic of Korea
| | - Ae Rim Hwang
- Graduate School of Semiconductor and Chemical Engineering, Jeonbuk National University, 567 Baekje-daero, Deokjin-gu, Jeonju-si, Jeollabuk-do, 54896, Republic of Korea
| | - Dae-Young Park
- Department of Microbiology, Chungbuk National University, Chungdae-Ro, Seowon-Gu, Cheongju, 28644, Republic of Korea
| | - Ji-Hun Kim
- Department of Biological Sciences, Korea Advanced Institute of Science and Technology, 291 Daehak-ro, Yuseong-Gu, Daejeon, 34141, Republic of Korea
| | - Yang-Hoon Kim
- Department of Microbiology, Chungbuk National University, Chungdae-Ro, Seowon-Gu, Cheongju, 28644, Republic of Korea
| | - Byung-Kwan Cho
- Department of Biological Sciences, Korea Advanced Institute of Science and Technology, 291 Daehak-ro, Yuseong-Gu, Daejeon, 34141, Republic of Korea
| | - Jiho Min
- Graduate School of Semiconductor and Chemical Engineering, Jeonbuk National University, 567 Baekje-daero, Deokjin-gu, Jeonju-si, Jeollabuk-do, 54896, Republic of Korea
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19
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Wang X, Han S, Liang J, Xu C, Cao R, Liu S, Luan Y, Gu Y, Han P. Essential role of Alix in regulating cardiomyocyte exosome biogenesis under physiological and stress conditions. J Mol Cell Cardiol 2024; 190:35-47. [PMID: 38593639 DOI: 10.1016/j.yjmcc.2024.04.001] [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: 10/25/2023] [Revised: 03/04/2024] [Accepted: 04/02/2024] [Indexed: 04/11/2024]
Abstract
BACKGROUND Exosomes released by cardiomyocytes are essential mediators of intercellular communications within the heart, and various exosomal proteins and miRNAs are associated with cardiovascular diseases. However, whether the endosomal sorting complex required for transport (ESCRT) and its key component Alix is required for exosome biogenesis within cardiomyocyte remains poorly understood. METHODS Super-resolution imaging was performed to investigate the subcellular location of Alix and multivesicular body (MVB) in primary cardiomyocytes. Cardiomyocyte-specific Alix-knockout mice were generated using AAV9/CRISPR/Cas9-mediated in vivo gene editing. A stable Alix-knockdown H9c2 cardiomyocyte line was constructed through lentiviral-mediated delivery of short hairpin RNA. In order to determine the role of Alix in controlling exosome biogenesis, exosomes from cardiomyocyte-specific Alix-knockout mice plasma and Alix-knockdown H9c2 culture medium were isolated and examined by western blot, NTA analysis and transmission electron microscopy. Biochemical and immunofluorescence analysis were performed to determine the role of ESCRT machinery in regulating MVB formation. Lastly, transverse aortic constriction (TAC)-induced cardiac pressure overload model was established to further explore the role of Alix-mediated exosome biogenesis under stress conditions. RESULTS A significant proportion of Alix localized to the MVB membrane within cardiomyocytes. Genetic deletion of Alix in murine heart resulted in a reduction of plasma exosome content without affecting cardiac structure or contractile function. Consistently, the downregulation of Alix in H9c2 cardiomyocyte line also suppressed the biogenesis of exosomes. We found the defective ESCRT machinery and suppressed MVB formation upon Alix depletion caused compromised exosome biogenesis. Remarkably, TAC-induced cardiac pressure overload led to increased Alix, MVB levels, and elevated plasma exosome content, which could be totally abolished by Alix deletion. CONCLUSION These results establish Alix as an essential and stress-sensitive regulator of cardiac exosome biogenesis and the findings may yield valuable therapeutic implications.
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Affiliation(s)
- Xinjian Wang
- Center for Genetic Medicine, the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; Institute of Genetics, Zhejiang University International School of Medicine, Hangzhou, Zhejiang, China; Division of Medical Genetics and Genomics, The Children's Hospital, Zhejiang University School of Medicine and National Clinical Research Center for Child Health, Hangzhou, Zhejiang, China; Zhejiang Provincial Key Laboratory of Genetic & Developmental Disorders, Hangzhou, Zhejiang, China
| | - Shuxian Han
- Center for Genetic Medicine, the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; Institute of Genetics, Zhejiang University International School of Medicine, Hangzhou, Zhejiang, China; Division of Medical Genetics and Genomics, The Children's Hospital, Zhejiang University School of Medicine and National Clinical Research Center for Child Health, Hangzhou, Zhejiang, China; Zhejiang Provincial Key Laboratory of Genetic & Developmental Disorders, Hangzhou, Zhejiang, China
| | - Jinxiu Liang
- Center for Genetic Medicine, the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; Institute of Genetics, Zhejiang University International School of Medicine, Hangzhou, Zhejiang, China; Division of Medical Genetics and Genomics, The Children's Hospital, Zhejiang University School of Medicine and National Clinical Research Center for Child Health, Hangzhou, Zhejiang, China; Zhejiang Provincial Key Laboratory of Genetic & Developmental Disorders, Hangzhou, Zhejiang, China
| | - Chen Xu
- Center for Genetic Medicine, the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; Institute of Genetics, Zhejiang University International School of Medicine, Hangzhou, Zhejiang, China; Division of Medical Genetics and Genomics, The Children's Hospital, Zhejiang University School of Medicine and National Clinical Research Center for Child Health, Hangzhou, Zhejiang, China; Zhejiang Provincial Key Laboratory of Genetic & Developmental Disorders, Hangzhou, Zhejiang, China
| | - Ranran Cao
- Center for Genetic Medicine, the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; Institute of Genetics, Zhejiang University International School of Medicine, Hangzhou, Zhejiang, China; Division of Medical Genetics and Genomics, The Children's Hospital, Zhejiang University School of Medicine and National Clinical Research Center for Child Health, Hangzhou, Zhejiang, China; Zhejiang Provincial Key Laboratory of Genetic & Developmental Disorders, Hangzhou, Zhejiang, China
| | - Shuoyang Liu
- Center for Genetic Medicine, the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; Institute of Genetics, Zhejiang University International School of Medicine, Hangzhou, Zhejiang, China; Division of Medical Genetics and Genomics, The Children's Hospital, Zhejiang University School of Medicine and National Clinical Research Center for Child Health, Hangzhou, Zhejiang, China; Zhejiang Provincial Key Laboratory of Genetic & Developmental Disorders, Hangzhou, Zhejiang, China
| | - Yi Luan
- Department of Cardiology, Key Laboratory of Cardiovascular Intervention and Regenerative Medicine of Zhejiang Province, Sir Run Run Shaw Hospital, Zhejiang University, School of Medicine, Hangzhou, Zhejiang 310016, China
| | - Ying Gu
- Center for Genetic Medicine, the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; Institute of Genetics, Zhejiang University International School of Medicine, Hangzhou, Zhejiang, China; Division of Medical Genetics and Genomics, The Children's Hospital, Zhejiang University School of Medicine and National Clinical Research Center for Child Health, Hangzhou, Zhejiang, China; Zhejiang Provincial Key Laboratory of Genetic & Developmental Disorders, Hangzhou, Zhejiang, China
| | - Peidong Han
- Center for Genetic Medicine, the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; Institute of Genetics, Zhejiang University International School of Medicine, Hangzhou, Zhejiang, China; Division of Medical Genetics and Genomics, The Children's Hospital, Zhejiang University School of Medicine and National Clinical Research Center for Child Health, Hangzhou, Zhejiang, China; Zhejiang Provincial Key Laboratory of Genetic & Developmental Disorders, Hangzhou, Zhejiang, China.
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20
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Yu T, Xu Q, Chen X, Deng X, Chen N, Kou MT, Huang Y, Guo J, Xiao Z, Wang J. Biomimetic nanomaterials in myocardial infarction treatment: Harnessing bionic strategies for advanced therapeutics. Mater Today Bio 2024; 25:100957. [PMID: 38322664 PMCID: PMC10844134 DOI: 10.1016/j.mtbio.2024.100957] [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: 10/20/2023] [Revised: 01/11/2024] [Accepted: 01/15/2024] [Indexed: 02/08/2024] Open
Abstract
Myocardial infarction (MI) and its associated poor prognosis pose significant risks to human health. Nanomaterials hold great potential for the treatment of MI due to their targeted and controlled release properties, particularly biomimetic nanomaterials. The utilization of biomimetic strategies based on extracellular vesicles (EVs) and cell membranes will serve as the guiding principle for the development of nanomaterial therapy in the future. In this review, we present an overview of research progress on various exosomes derived from mesenchymal stem cells, cardiomyocytes, or induced pluripotent stem cells in the context of myocardial infarction (MI) therapy. These exosomes, utilized as cell-free therapies, have demonstrated the ability to enhance the efficacy of reducing the size of the infarcted area and preventing ischaemic reperfusion through mechanisms such as oxidative stress reduction, polarization modulation, fibrosis inhibition, and angiogenesis promotion. Moreover, EVs can exert cardioprotective effects by encapsulating therapeutic agents and can be engineered to specifically target the infarcted myocardium. Furthermore, we discuss the use of cell membranes derived from erythrocytes, stem cells, immune cells and platelets to encapsulate nanomaterials. This approach allows the nanomaterials to camouflage themselves as endogenous substances targeting the region affected by MI, thereby minimizing toxicity and improving biocompatibility. In conclusion, biomimetic nano-delivery systems hold promise as a potentially beneficial technology for MI treatment. This review serves as a valuable reference for the application of biomimetic nanomaterials in MI therapy and aims to expedite the translation of NPs-based MI therapeutic strategies into practical clinical applications.
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Affiliation(s)
- Tingting Yu
- Department of Pharmacy, The First Affiliated Hospital of Jinan University, Guangzhou, 510630, China
- The Guangzhou Key Laboratory of Basic and Translational Research on Chronic Diseases, Jinan University, Guangzhou, 510630, China
| | - Qiaxin Xu
- Department of Pharmacy, The First Affiliated Hospital of Jinan University, Guangzhou, 510630, China
- The Guangzhou Key Laboratory of Basic and Translational Research on Chronic Diseases, Jinan University, Guangzhou, 510630, China
| | - Xu Chen
- Department of Clinical Pharmacy, Daqing Oilfield General Hospital, Daqing, 163000, China
| | - Xiujiao Deng
- Department of Pharmacy, The First Affiliated Hospital of Jinan University, Guangzhou, 510630, China
- The Guangzhou Key Laboratory of Basic and Translational Research on Chronic Diseases, Jinan University, Guangzhou, 510630, China
| | - Nenghua Chen
- Department of Pharmacy, The First Affiliated Hospital of Jinan University, Guangzhou, 510630, China
- The Guangzhou Key Laboratory of Basic and Translational Research on Chronic Diseases, Jinan University, Guangzhou, 510630, China
| | - Man Teng Kou
- Department of Pharmacy, The First Affiliated Hospital of Jinan University, Guangzhou, 510630, China
- The Guangzhou Key Laboratory of Basic and Translational Research on Chronic Diseases, Jinan University, Guangzhou, 510630, China
| | - Yanyu Huang
- Department of Biochemistry and Molecular Medicine, University of California Davis, Sacramento, CA, 95817, USA
| | - Jun Guo
- The Guangzhou Key Laboratory of Basic and Translational Research on Chronic Diseases, Jinan University, Guangzhou, 510630, China
- Department of Cardiology, The First Affiliated Hospital of Jinan University, Guangzhou, 510630, China
| | - Zeyu Xiao
- The Guangzhou Key Laboratory of Basic and Translational Research on Chronic Diseases, Jinan University, Guangzhou, 510630, China
- The Guangzhou Key Laboratory of Molecular and Functional Imaging for Clinical Translation, Jinan University, Guangzhou, 510630, China
| | - Jinghao Wang
- Department of Pharmacy, The First Affiliated Hospital of Jinan University, Guangzhou, 510630, China
- The Guangzhou Key Laboratory of Basic and Translational Research on Chronic Diseases, Jinan University, Guangzhou, 510630, China
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21
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Pantaleão LC, Loche E, Fernandez-Twinn DS, Dearden L, Córdova-Casanova A, Osmond C, Salonen MK, Kajantie E, Niu Y, de Almeida-Faria J, Thackray BD, Mikkola TM, Giussani DA, Murray AJ, Bushell M, Eriksson JG, Ozanne SE. Programming of cardiac metabolism by miR-15b-5p, a miRNA released in cardiac extracellular vesicles following ischemia-reperfusion injury. Mol Metab 2024; 80:101875. [PMID: 38218535 PMCID: PMC10832484 DOI: 10.1016/j.molmet.2024.101875] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Revised: 12/22/2023] [Accepted: 01/08/2024] [Indexed: 01/15/2024] Open
Abstract
OBJECTIVE We investigated the potential involvement of miRNAs in the developmental programming of cardiovascular diseases (CVD) by maternal obesity. METHODS Serum miRNAs were measured in individuals from the Helsinki Birth Cohort (with known maternal body mass index), and a mouse model was used to determine causative effects of maternal obesity during pregnancy and ischemia-reperfusion on offspring cardiac miRNA expression and release. RESULTS miR-15b-5p levels were increased in the sera of males born to mothers with higher BMI and in the hearts of adult mice born to obese dams. In an ex-vivo model of perfused mouse hearts, we demonstrated that cardiac tissue releases miR-15b-5p, and that some of the released miR-15b-5p was contained within small extracellular vesicles (EVs). We also demonstrated that release was higher from hearts exposed to maternal obesity following ischaemia/reperfusion. Over-expression of miR-15b-5p in vitro led to loss of outer mitochondrial membrane stability and to repressed fatty acid oxidation in cardiomyocytes. CONCLUSIONS These findings suggest that miR-15-b could play a mechanistic role in the dysregulation of cardiac metabolism following exposure to an in utero obesogenic environment and that its release in cardiac EVs following ischaemic damage may be a novel factor contributing to inter-organ communication between the programmed heart and peripheral tissues.
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Affiliation(s)
- Lucas C Pantaleão
- Wellcome-MRC Institute of Metabolic Science and Medical Research Council Metabolic Diseases Unit, University of Cambridge, Cambridge, UK
| | - Elena Loche
- Wellcome-MRC Institute of Metabolic Science and Medical Research Council Metabolic Diseases Unit, University of Cambridge, Cambridge, UK
| | - Denise S Fernandez-Twinn
- Wellcome-MRC Institute of Metabolic Science and Medical Research Council Metabolic Diseases Unit, University of Cambridge, Cambridge, UK
| | - Laura Dearden
- Wellcome-MRC Institute of Metabolic Science and Medical Research Council Metabolic Diseases Unit, University of Cambridge, Cambridge, UK
| | - Adriana Córdova-Casanova
- Wellcome-MRC Institute of Metabolic Science and Medical Research Council Metabolic Diseases Unit, University of Cambridge, Cambridge, UK
| | - Clive Osmond
- MRC Lifecourse Epidemiology Unit, University of Southampton, UK
| | - Minna K Salonen
- Finnish Institute for Health and Welfare, Public Health Unit, Finland
| | - Eero Kajantie
- Finnish Institute for Health and Welfare, Public Health Unit, Finland; Clinical Medicine Research Unit, MRC Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland; Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
| | - Youguo Niu
- Department of Physiology, Development, and Neuroscience, University of Cambridge, Cambridge, UK
| | - Juliana de Almeida-Faria
- Wellcome-MRC Institute of Metabolic Science and Medical Research Council Metabolic Diseases Unit, University of Cambridge, Cambridge, UK
| | - Benjamin D Thackray
- Wellcome-MRC Institute of Metabolic Science and Medical Research Council Metabolic Diseases Unit, University of Cambridge, Cambridge, UK; Department of Physiology, Development, and Neuroscience, University of Cambridge, Cambridge, UK
| | - Tuija M Mikkola
- Finnish Institute for Health and Welfare, Public Health Unit, Finland; Folkhalsan Research Center, Helsinki, Finland; Faculty of Medicine, University of Helsinki, Finland
| | - Dino A Giussani
- Department of Physiology, Development, and Neuroscience, University of Cambridge, Cambridge, UK
| | - Andrew J Murray
- Department of Physiology, Development, and Neuroscience, University of Cambridge, Cambridge, UK
| | - Martin Bushell
- CRUK Beatson Institute, Garscube Estate, Switchback Road, Bearsden, Glasgow, G61 1BD, UK
| | - Johan G Eriksson
- Folkhalsan Research Center, Helsinki, Finland; Department of General Practice and Primary Health Care, University of Helsinki and Helsinki University Hospital, Finland; Singapore Institute for Clinical Sciences, Agency for Science Technology and Research, Singapore, Singapore; Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Susan E Ozanne
- Wellcome-MRC Institute of Metabolic Science and Medical Research Council Metabolic Diseases Unit, University of Cambridge, Cambridge, UK.
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22
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Yamaga S, Aziz M, Murao A, Brenner M, Wang P. DAMPs and radiation injury. Front Immunol 2024; 15:1353990. [PMID: 38333215 PMCID: PMC10850293 DOI: 10.3389/fimmu.2024.1353990] [Citation(s) in RCA: 16] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Accepted: 01/15/2024] [Indexed: 02/10/2024] Open
Abstract
The heightened risk of ionizing radiation exposure, stemming from radiation accidents and potential acts of terrorism, has spurred growing interests in devising effective countermeasures against radiation injury. High-dose ionizing radiation exposure triggers acute radiation syndrome (ARS), manifesting as hematopoietic, gastrointestinal, and neurovascular ARS. Hematopoietic ARS typically presents with neutropenia and thrombocytopenia, while gastrointestinal ARS results in intestinal mucosal injury, often culminating in lethal sepsis and gastrointestinal bleeding. This deleterious impact can be attributed to radiation-induced DNA damage and oxidative stress, leading to various forms of cell death, such as apoptosis, necrosis and ferroptosis. Damage-associated molecular patterns (DAMPs) are intrinsic molecules released by cells undergoing injury or in the process of dying, either through passive or active pathways. These molecules then interact with pattern recognition receptors, triggering inflammatory responses. Such a cascade of events ultimately results in further tissue and organ damage, contributing to the elevated mortality rate. Notably, infection and sepsis often develop in ARS cases, further increasing the release of DAMPs. Given that lethal sepsis stands as a major contributor to the mortality in ARS, DAMPs hold the potential to function as mediators, exacerbating radiation-induced organ injury and consequently worsening overall survival. This review describes the intricate mechanisms underlying radiation-induced release of DAMPs. Furthermore, it discusses the detrimental effects of DAMPs on the immune system and explores potential DAMP-targeting therapeutic strategies to alleviate radiation-induced injury.
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Affiliation(s)
- Satoshi Yamaga
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY, United States
| | - Monowar Aziz
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY, United States
- Departments of Surgery and Molecular Medicine, Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, United States
| | - Atsushi Murao
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY, United States
| | - Max Brenner
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY, United States
- Departments of Surgery and Molecular Medicine, Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, United States
| | - Ping Wang
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY, United States
- Departments of Surgery and Molecular Medicine, Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, United States
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23
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Hánělová K, Raudenská M, Masařík M, Balvan J. Protein cargo in extracellular vesicles as the key mediator in the progression of cancer. Cell Commun Signal 2024; 22:25. [PMID: 38200509 PMCID: PMC10777590 DOI: 10.1186/s12964-023-01408-6] [Citation(s) in RCA: 15] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Accepted: 11/24/2023] [Indexed: 01/12/2024] Open
Abstract
Exosomes are small vesicles of endosomal origin that are released by almost all cell types, even those that are pathologically altered. Exosomes widely participate in cell-to-cell communication via transferring cargo, including nucleic acids, proteins, and other metabolites, into recipient cells. Tumour-derived exosomes (TDEs) participate in many important molecular pathways and affect various hallmarks of cancer, including fibroblasts activation, modification of the tumour microenvironment (TME), modulation of immune responses, angiogenesis promotion, setting the pre-metastatic niche, enhancing metastatic potential, and affecting therapy sensitivity and resistance. The unique exosome biogenesis, composition, nontoxicity, and ability to target specific tumour cells bring up their use as promising drug carriers and cancer biomarkers. In this review, we focus on the role of exosomes, with an emphasis on their protein cargo, in the key mechanisms promoting cancer progression. We also briefly summarise the mechanism of exosome biogenesis, its structure, protein composition, and potential as a signalling hub in both normal and pathological conditions. Video Abstract.
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Affiliation(s)
- Klára Hánělová
- Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, Brno, CZ-625 00, Czech Republic
| | - Martina Raudenská
- Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, Brno, CZ-625 00, Czech Republic
- Department of Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, Brno, CZ-625 00, Czech Republic
| | - Michal Masařík
- Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, Brno, CZ-625 00, Czech Republic
- Department of Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, Brno, CZ-625 00, Czech Republic
- BIOCEV, First Faculty of Medicine, Charles University, Prumyslova 595, Vestec, CZ-252 50, Czech Republic
| | - Jan Balvan
- Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, Brno, CZ-625 00, Czech Republic.
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24
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Pedrosa MA, Labandeira CM, Lago-Baameiro N, Valenzuela R, Pardo M, Labandeira-Garcia JL, Rodriguez-Perez AI. Extracellular Vesicles and Their Renin-Angiotensin Cargo as a Link between Metabolic Syndrome and Parkinson's Disease. Antioxidants (Basel) 2023; 12:2045. [PMID: 38136165 PMCID: PMC10741149 DOI: 10.3390/antiox12122045] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Revised: 11/20/2023] [Accepted: 11/23/2023] [Indexed: 12/24/2023] Open
Abstract
Several studies showed an association between metabolic syndrome (MetS) and Parkinson's disease (PD). The linking mechanisms remain unclear. MetS promotes low-grade peripheral oxidative stress and inflammation and dysregulation of the adipose renin-angiotensin system (RAS). Interestingly, brain RAS dysregulation is involved in the progression of dopaminergic degeneration and PD. Circulating extracellular vesicles (EVs) from MetS fat tissue can cross the brain-blood barrier and may act as linking signals. We isolated and characterized EVs from MetS and control rats and analyzed their mRNA and protein cargo using RT-PCR and the ExoView R200 platform, respectively. Furthermore, cultures of the N27 dopaminergic cell line and the C6 astrocytic cell line were treated with EVs from MetS rats. EVs were highly increased in MetS rat serum, which was inhibited by treatment of the rats with the angiotensin type-1-receptor blocker candesartan. Furthermore, EVs from MetS rats showed increased pro-oxidative/pro-inflammatory and decreased anti-oxidative/anti-inflammatory RAS components, which were inhibited in candesartan-treated MetS rats. In cultures, EVs from MetS rats increased N27 cell death and modulated C6 cell function, upregulating markers of neuroinflammation and oxidative stress, which were inhibited by the pre-treatment of cultures with candesartan. The results from rat models suggest EVs and their RAS cargo as a mechanism linking Mets and PD.
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Affiliation(s)
- Maria A. Pedrosa
- Cellular and Molecular Neurobiology of Parkinson’s Disease, Research Center for Molecular Medicine and Chronic Diseases (CIMUS), Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), University of Santiago de Compostela, 15782 Santiago de Compostela, Spain; (M.A.P.); (R.V.)
- Networking Research Center on Neurodegenerative Diseases (CIBERNED), 28029 Madrid, Spain
| | | | - Nerea Lago-Baameiro
- Grupo Obesidómica, Área de Endocrinología, Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Complexo Hospitalario Universitario de Santiago de Compostela/SERGAS, 15706 Santiago de Compostela, Spain; (N.L.-B.); (M.P.)
| | - Rita Valenzuela
- Cellular and Molecular Neurobiology of Parkinson’s Disease, Research Center for Molecular Medicine and Chronic Diseases (CIMUS), Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), University of Santiago de Compostela, 15782 Santiago de Compostela, Spain; (M.A.P.); (R.V.)
- Networking Research Center on Neurodegenerative Diseases (CIBERNED), 28029 Madrid, Spain
| | - Maria Pardo
- Grupo Obesidómica, Área de Endocrinología, Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Complexo Hospitalario Universitario de Santiago de Compostela/SERGAS, 15706 Santiago de Compostela, Spain; (N.L.-B.); (M.P.)
- CIBER Fisiopatología Obesidad y Nutrición, Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Jose Luis Labandeira-Garcia
- Cellular and Molecular Neurobiology of Parkinson’s Disease, Research Center for Molecular Medicine and Chronic Diseases (CIMUS), Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), University of Santiago de Compostela, 15782 Santiago de Compostela, Spain; (M.A.P.); (R.V.)
- Networking Research Center on Neurodegenerative Diseases (CIBERNED), 28029 Madrid, Spain
| | - Ana I. Rodriguez-Perez
- Cellular and Molecular Neurobiology of Parkinson’s Disease, Research Center for Molecular Medicine and Chronic Diseases (CIMUS), Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), University of Santiago de Compostela, 15782 Santiago de Compostela, Spain; (M.A.P.); (R.V.)
- Networking Research Center on Neurodegenerative Diseases (CIBERNED), 28029 Madrid, Spain
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25
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Wojtasińska A, Kućmierz J, Tokarek J, Dybiec J, Rodzeń A, Młynarska E, Rysz J, Franczyk B. New Insights into Cardiovascular Diseases Treatment Based on Molecular Targets. Int J Mol Sci 2023; 24:16735. [PMID: 38069058 PMCID: PMC10706703 DOI: 10.3390/ijms242316735] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2023] [Revised: 11/07/2023] [Accepted: 11/13/2023] [Indexed: 12/18/2023] Open
Abstract
Cardiovascular diseases (CVDs) which consist of ischemic heart disease, stroke, heart failure, peripheral arterial disease, and several other cardiac and vascular conditions are one of the most common causes of death worldwide and often co-occur with diabetes mellitus and lipid disorders which worsens the prognosis and becomes a therapeutic challenge. Due to the increasing number of patients with CVDs, we need to search for new risk factors and pathophysiological changes to create new strategies for preventing, diagnosing, and treating not only CVDs but also comorbidities like diabetes mellitus and lipid disorders. As increasing amount of patients suffering from CVDs, there are many therapies which focus on new molecular targets like proprotein convertase subtilisin/kexin type 9 (PCSK9), angiopoietin-like protein 3, ATP-citrate lyase, or new technologies such as siRNA in treatment of dyslipidemia or sodium-glucose co-transporter-2 and glucagon-like peptide-1 in treatment of diabetes mellitus. Both SGLT-2 inhibitors and GLP-1 receptor agonists are used in the treatment of diabetes, however, they proved to have a beneficial effect in CVDs as well. Moreover, a significant amount of evidence has shown that exosomes seem to be associated with myocardial ischaemia and that exosome levels correlate with the severity of myocardial injury. In our work, we would like to focus on the above mechanisms. The knowledge of them allows for the appearance of new strategies of treatment among patients with CVDs.
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Affiliation(s)
- Armanda Wojtasińska
- Department of Nephrocardiology, Medical University of Lodz, ul. Zeromskiego 113, 90-549 Lodz, Poland
| | - Joanna Kućmierz
- Department of Nephrocardiology, Medical University of Lodz, ul. Zeromskiego 113, 90-549 Lodz, Poland
| | - Julita Tokarek
- Department of Nephrocardiology, Medical University of Lodz, ul. Zeromskiego 113, 90-549 Lodz, Poland
| | - Jill Dybiec
- Department of Nephrocardiology, Medical University of Lodz, ul. Zeromskiego 113, 90-549 Lodz, Poland
| | - Anna Rodzeń
- Department of Nephrocardiology, Medical University of Lodz, ul. Zeromskiego 113, 90-549 Lodz, Poland
| | - Ewelina Młynarska
- Department of Nephrocardiology, Medical University of Lodz, ul. Zeromskiego 113, 90-549 Lodz, Poland
| | - Jacek Rysz
- Department of Nephrology, Hypertension and Family Medicine, Medical University of Lodz, ul. Zeromskiego 113, 90-549 Lodz, Poland
| | - Beata Franczyk
- Department of Nephrocardiology, Medical University of Lodz, ul. Zeromskiego 113, 90-549 Lodz, Poland
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26
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Zimbone S, Di Rosa MC, Chiechio S, Giuffrida ML. Exploring the Role of Hsp60 in Alzheimer's Disease and Type 2 Diabetes: Suggestion for Common Drug Targeting. Int J Mol Sci 2023; 24:12456. [PMID: 37569831 PMCID: PMC10419248 DOI: 10.3390/ijms241512456] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 08/01/2023] [Accepted: 08/02/2023] [Indexed: 08/13/2023] Open
Abstract
Heat shock protein 60 (Hsp60) is a member of the chaperonin family of heat shock proteins (HSPs), primarily found in the mitochondrial matrix. As a molecular chaperone, Hsp60 plays an essential role in mediating protein folding and assembly, and together with the co-chaperon Hsp10, it is thought to maintain protein homeostasis. Recently, it has been found to localize in non-canonical, extra-mitochondrial sites such as cell membranes or extracellular fluids, particularly in pathological conditions. Starting from its biological function, this review aims to provide a comprehensive understanding of the potential involvement of Hsp60 in Alzheimer's disease (AD) and Type II Diabetes Mellitus (T2DM), which are known to share impaired key pathways and molecular dysfunctions. Fragmentary data reported in the literature reveal interesting links between the altered expression level or localization of this chaperonin and several disease conditions. The present work offers an overview of the past and more recent knowledge about Hsp60 and its role in the most important cellular processes to shed light on neuronal Hsp60 as a potential common target for both pathologies. The absence of any effective cure for AD patients makes the identification of a new molecular target a promising path by which to move forward in the development of new drugs and/or repositioning of therapies already used for T2DM.
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Affiliation(s)
- Stefania Zimbone
- Institute of Crystallography, National Research Council (CNR-IC), 95126 Catania, Italy; (S.Z.); (M.C.D.R.)
| | - Maria Carmela Di Rosa
- Institute of Crystallography, National Research Council (CNR-IC), 95126 Catania, Italy; (S.Z.); (M.C.D.R.)
- Cogentech Società Benefit srl Actual Position, 95121 Catania, Italy
| | - Santina Chiechio
- Department of Drug and Health Sciences, University of Catania, 95125 Catania, Italy;
- Oasi Research Institute—IRCCS, 94018 Troina, Italy
| | - Maria Laura Giuffrida
- Institute of Crystallography, National Research Council (CNR-IC), 95126 Catania, Italy; (S.Z.); (M.C.D.R.)
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27
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Schöler D, Loosen SH, Wirtz TH, Brozat JF, dos Santos Ferreira Grani LA, Luedde T, Heinrichs L, Frank D, Koch A, Roderburg C, Spehlmann ME. Low extracellular vesicle concentrations predict survival in patients with heart failure. Front Cardiovasc Med 2023; 10:1163525. [PMID: 37293281 PMCID: PMC10244507 DOI: 10.3389/fcvm.2023.1163525] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Accepted: 05/11/2023] [Indexed: 06/10/2023] Open
Abstract
Background Heart disease is of worldwide importance due to high morbidity and mortality. Extracellular vesicle (EV) concentration and size represent novel diagnostic and prognostic biomarkers, e.g. in patients with liver cancer, but data on their prognostic relevance in heart disease are lacking. Here, we investigated the role of EV concentration, size and zeta potential in patients with heart disease. Methods Vesicle size distribution, concentration and zeta potential were measured by nanoparticle tracking analysis (NTA) in 28 intensive care unit (ICU) and 20 standard care (SC) patients and 20 healthy controls. Results Patients with any disease had a lower zeta potential compared to the healthy controls. Vesicle size (X50) was significantly higher in ICU patients (245 nm) with heart disease as compared to those patients with heart disease receiving standard care (195 nm), or healthy controls (215 nm) (p = 0.001). Notably, EV concentration was lower in ICU patients with heart disease (4.68 × 1010 particles/ml) compared to SC patients with heart disease (7,62 × 1010 particles/ml) and healthy controls (1.50 × 1011 particles/ml) (p = 0.002). Extracellular vesicle concentration is prognostic for overall survival in patients with heart disease. Overall survival is significantly reduced when the vesicle concentration is below 5.55 × 1010 particles/ml. Median overall survival was only 140 days in patients with vesicle concentrations below 5.55 × 1010 particles/ml compared to 211 days in patients with vesicle concentrations above 5.55 × 1010 particles/ml (p = 0.032). Summary Concentration of EVs is a novel prognostic marker in ICU and SC patients with heart disease.
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Affiliation(s)
- David Schöler
- Clinic for Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Sven H. Loosen
- Clinic for Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Theresa H. Wirtz
- Department of Gastroenterology, Digestive Diseases and Intensive Care Medicine, RWTH Aachen University Hospital, Aachen, Germany
| | - Jonathan F. Brozat
- Department of Gastroenterology, Digestive Diseases and Intensive Care Medicine, RWTH Aachen University Hospital, Aachen, Germany
- Department of Hepatology and Gastroenterology, Charite—Universitätsmedizin Berlin Campus Virchow-Klinikum (CVK) and Campus Charite Mitte (CCM), Berlin, Germany
| | - Lauredana A. dos Santos Ferreira Grani
- Clinic for Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Tom Luedde
- Clinic for Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Lisa Heinrichs
- Clinic for Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Derk Frank
- Internal Medicine III, University Hospital of Schleswig Holstein, Campus Kiel, Kiel, Germany
| | - Alexander Koch
- Department of Gastroenterology, Digestive Diseases and Intensive Care Medicine, RWTH Aachen University Hospital, Aachen, Germany
| | - Christoph Roderburg
- Clinic for Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Martina E. Spehlmann
- Internal Medicine III, University Hospital of Schleswig Holstein, Campus Kiel, Kiel, Germany
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28
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Koncz A, Turiák L, Németh K, Lenzinger D, Bárkai T, Lőrincz P, Zelenyánszki H, Vukman KV, Buzás EI, Visnovitz T. Endoplasmin Is a Hypoxia-Inducible Endoplasmic Reticulum-Derived Cargo of Extracellular Vesicles Released by Cardiac Cell Lines. MEMBRANES 2023; 13:431. [PMID: 37103858 PMCID: PMC10142439 DOI: 10.3390/membranes13040431] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 04/06/2023] [Accepted: 04/11/2023] [Indexed: 06/19/2023]
Abstract
Cardiomyopathies are leading causes of human mortality. Recent data indicate that the cardiomyocyte-derived extracellular vesicles (EVs) released upon cardiac injury are present in circulation. This paper aimed to analyze EVs released under normal and hypoxic conditions by H9c2 (rat), AC16 (human) and HL1 (mouse) cardiac cell lines. Small (sEVs), medium (mEVs) and large EVs (lEVs) were separated from a conditioned medium by a combination of gravity filtration, differential centrifugation and tangential flow filtration. The EVs were characterized by microBCA, SPV lipid assay, nanoparticle tracking analysis, transmission and immunogold electron microscopy, flow cytometry and Western blotting. Proteomic profiles of the EVs were determined. Surprisingly, an endoplasmic reticulum chaperone, endoplasmin (ENPL, grp94 or gp96), was identified in the EV samples, and its association with EVs was validated. The secretion and uptake of ENPL was followed by confocal microscopy using GFP-ENPL fusion protein expressing HL1 cells. We identified ENPL as an internal cargo of cardiomyocyte-derived mEVs and sEVs. Based on our proteomic analysis, its presence in EVs was linked to hypoxia in HL1 and H9c2 cells, and we hypothesize that EV-associated ENPL may have a cardioprotective role by reducing cardiomyocyte ER stress.
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Affiliation(s)
- Anna Koncz
- Department of Genetics, Cell and Immunobiology, Semmelweis University, Üllői út 26, 1085 Budapest, Hungary
| | - Lilla Turiák
- Research Centre for Natural Sciences, Institute of Organic Chemistry, Magyar Tudósok Körútja 2, 1117 Budapest, Hungary
| | - Krisztina Németh
- Department of Genetics, Cell and Immunobiology, Semmelweis University, Üllői út 26, 1085 Budapest, Hungary
- ELKH-SE Translational Extracellular Vesicle Research Group, Nagyvárad tér 4, 1085 Budapest, Hungary
| | - Dorina Lenzinger
- Department of Genetics, Cell and Immunobiology, Semmelweis University, Üllői út 26, 1085 Budapest, Hungary
| | - Tünde Bárkai
- Department of Genetics, Cell and Immunobiology, Semmelweis University, Üllői út 26, 1085 Budapest, Hungary
| | - Péter Lőrincz
- Department of Anatomy, Cell and Developmental Biology, ELTE Eötvös Loránd University, Pázmány Péter sétány 1/c, 1117 Budapest, Hungary
| | - Helga Zelenyánszki
- Department of Plant Physiology and Molecular Plant Biology, ELTE Eötvös Loránd University, Pázmány Péter sétány 1/c, 1117 Budapest, Hungary
| | - Krisztina V. Vukman
- Department of Genetics, Cell and Immunobiology, Semmelweis University, Üllői út 26, 1085 Budapest, Hungary
| | - Edit I. Buzás
- Department of Genetics, Cell and Immunobiology, Semmelweis University, Üllői út 26, 1085 Budapest, Hungary
- ELKH-SE Translational Extracellular Vesicle Research Group, Nagyvárad tér 4, 1085 Budapest, Hungary
- HCEMM-SU Extracellular Vesicle Research Group, Nagyvárad tér 4, 1085 Budapest, Hungary
| | - Tamás Visnovitz
- Department of Genetics, Cell and Immunobiology, Semmelweis University, Üllői út 26, 1085 Budapest, Hungary
- Department of Plant Physiology and Molecular Plant Biology, ELTE Eötvös Loránd University, Pázmány Péter sétány 1/c, 1117 Budapest, Hungary
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Yang Y, Huang C, Hui L, Song Y, Fu Y, Li M, Yang H, Wu J, Sun J, Xu W, Wei L. Cathelicidins Target HSP60 To Restrict CVB3 Transmission via Disrupting the Exosome and Reducing Cardiomyocyte Apoptosis. J Virol 2023; 97:e0143322. [PMID: 36916989 PMCID: PMC10062171 DOI: 10.1128/jvi.01433-22] [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: 10/28/2022] [Accepted: 02/17/2023] [Indexed: 03/16/2023] Open
Abstract
Cathelicidin antimicrobial peptides (mouse, CRAMP; human, LL-37) have broad-spectrum antiviral activities against enveloped viruses, but their mechanisms of action against nonenveloped viruses remain to be elucidated. Coxsackievirus B3 (CVB3), a member of nonenveloped virus belonging to the Enterovirus genus of Picornaviridae, is an important pathogen of viral myocarditis and dilated cardiomyopathy. Here, we observed that cardiac CRAMP expression was significantly upregulated in mice after CVB3 infection. The administration of CRAMP or LL-37 markedly suppressed CVB3 infection in mice, and CRAMP deficiency increased the susceptibility of mice to CVB3. CRAMP and LL-37 inhibited CVB3 replication in primary cardiomyocytes. However, they did not inactivate CVB3 particles and did not regulate the response of cardiomyocytes against CVB3 infection. Intriguingly, they inhibited CVB3 transmission through the exosome, but not virus receptor. In detail, CRAMP and LL-37 directly induced the lysis of exosomes by interfering with exosomal heat shock protein 60 (HSP60) and then blocked the diffusion of exosomes to recipient cells and inhibited the establishment of productive infection by exosomes. In addition, the interaction of CRAMP and LL-37 with HSP60 simultaneously inhibited HSP60-induced apoptosis in cardiomyocytes and reduced HSP60-enhanced CVB3 replication. Our findings reveal a novel mechanism of cathelicidins against viral infection and provide a new therapeutic strategy for CVB3-induced viral myocarditis. IMPORTANCE The relative mechanisms that cathelicidin antimicrobial peptides use to influence nonenveloped virus infection are unclear. We show here that cathelicidin antimicrobial peptides (CRAMP and LL-37) directly target exosomal HSP60 to destroy exosomes, which in turn block the diffusion of exosomes to recipient cardiomyocytes and reduced HSP60-induced apoptosis, thus restricting coxsackievirus B3 infection. Our results provide new insights into the mechanisms cathelicidin antimicrobial peptides use against viral infection.
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Affiliation(s)
- Yang Yang
- Jiangsu Provincial Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, Jiangsu, China
| | - Chunjing Huang
- Jiangsu Provincial Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, Jiangsu, China
| | - Li Hui
- The Affiliated Guangji Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Yahui Song
- Jiangsu Provincial Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, Jiangsu, China
| | - Yuxuan Fu
- Jiangsu Provincial Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, Jiangsu, China
| | - Min Li
- Jiangsu Provincial Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, Jiangsu, China
| | - Hailong Yang
- School of Basic Medical Sciences, Kunming Medical University, Kunming, Yunnan, China
| | - Jing Wu
- School of Basic Medical Sciences, Kunming Medical University, Kunming, Yunnan, China
| | - Jia Sun
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, China
| | - Wei Xu
- Jiangsu Provincial Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, Jiangsu, China
| | - Lin Wei
- Jiangsu Provincial Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, Jiangsu, China
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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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Zhang H, Shen Y, Kim IM, Liu Y, Cai J, Berman AE, Nilsson KR, Weintraub NL, Tang Y. Electrical Stimulation Increases the Secretion of Cardioprotective Extracellular Vesicles from Cardiac Mesenchymal Stem Cells. Cells 2023; 12:cells12060875. [PMID: 36980214 PMCID: PMC10047597 DOI: 10.3390/cells12060875] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 03/06/2023] [Accepted: 03/08/2023] [Indexed: 03/16/2023] Open
Abstract
Clinical trials have shown that electric stimulation (ELSM) using either cardiac resynchronization therapy (CRT) or cardiac contractility modulation (CCM) approaches is an effective treatment for patients with moderate to severe heart failure, but the mechanisms are incompletely understood. Extracellular vesicles (EV) produced by cardiac mesenchymal stem cells (C-MSC) have been reported to be cardioprotective through cell-to-cell communication. In this study, we investigated the effects of ELSM stimulation on EV secretion from C-MSCs (C-MSCELSM). We observed enhanced EV-dependent cardioprotection conferred by conditioned medium (CM) from C-MSCELSM compared to that from non-stimulated control C-MSC (C-MSCCtrl). To investigate the mechanisms of ELSM-stimulated EV secretion, we examined the protein levels of neutral sphingomyelinase 2 (nSMase2), a key enzyme of the endosomal sorting complex required for EV biosynthesis. We detected a time-dependent increase in nSMase2 protein levels in C-MSCELSM compared to C-MSCCtrl. Knockdown of nSMase2 in C-MSC by siRNA significantly reduced EV secretion in C-MSCELSM and attenuated the cardioprotective effect of CM from C-MSCELSM in HL-1 cells. Taken together, our results suggest that ELSM-mediated increases in EV secretion from C-MSC enhance the cardioprotective effects of C-MSC through an EV-dependent mechanism involving nSMase2.
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Affiliation(s)
- Haitao Zhang
- Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
| | - Yan Shen
- Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
| | - Il-man Kim
- Cell Biology and Physiology, School of Medicine, Indiana University, Indianapolis, IN 47405, USA
| | - Yutao Liu
- Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
| | - Jingwen Cai
- Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
| | - Adam E. Berman
- Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
| | - Kent R. Nilsson
- Medical College of Georgia, Augusta University/University of Georgia Partnership, Athens, GA 30602, USA
| | - Neal L. Weintraub
- Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
| | - Yaoliang Tang
- Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
- Correspondence:
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Graça AL, Domingues RMA, Gomez-Florit M, Gomes ME. Platelet-Derived Extracellular Vesicles Promote Tenogenic Differentiation of Stem Cells on Bioengineered Living Fibers. Int J Mol Sci 2023; 24:ijms24043516. [PMID: 36834925 PMCID: PMC9959969 DOI: 10.3390/ijms24043516] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 02/06/2023] [Accepted: 02/07/2023] [Indexed: 02/12/2023] Open
Abstract
Tendon mimetic scaffolds that recreate the tendon hierarchical structure and niche have increasing potential to fully restore tendon functionality. However, most scaffolds lack biofunctionality to boost the tenogenic differentiation of stem cells. In this study, we assessed the role of platelet-derived extracellular vesicles (EVs) in stem cells' tenogenic commitment using a 3D bioengineered in vitro tendon model. First, we relied on fibrous scaffolds coated with collagen hydrogels encapsulating human adipose-derived stem cells (hASCs) to bioengineer our composite living fibers. We found that the hASCs in our fibers showed high elongation and cytoskeleton anisotropic organization, typical of tenocytes. Moreover, acting as biological cues, platelet-derived EVs boosted the hASCs' tenogenic commitment, prevented phenotypic drift, enhanced the deposition of the tendon-like extracellular matrix, and induced lower collagen matrix contraction. In conclusion, our living fibers provided an in vitro system for tendon tissue engineering, allowing us to study not only the tendon microenvironment but also the influence of biochemical cues on stem cell behavior. More importantly, we showed that platelet-derived EVs are a promising biochemical tool for tissue engineering and regenerative medicine applications that are worthy of further exploration, as paracrine signaling might potentiate tendon repair and regeneration.
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Affiliation(s)
- Ana L. Graça
- 3B’s Research Group, I3Bs—Research Institute on Biomaterials, Biodegradables and Biomimetics, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, University of Minho, AvePark, Parque de Ciência e Tecnologia, Zona Industrial da Gandra, Barco, 4805-017 Guimarães, Portugal
- ICVS/3B’s–PT Government Associate Laboratory, 4805-017 Guimarães, Portugal
| | - Rui M. A. Domingues
- 3B’s Research Group, I3Bs—Research Institute on Biomaterials, Biodegradables and Biomimetics, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, University of Minho, AvePark, Parque de Ciência e Tecnologia, Zona Industrial da Gandra, Barco, 4805-017 Guimarães, Portugal
- ICVS/3B’s–PT Government Associate Laboratory, 4805-017 Guimarães, Portugal
| | - Manuel Gomez-Florit
- Health Research Institute of the Balearic Islands (IdISBa), 07010 Palma, Spain
- Correspondence: (M.G.-F.); (M.E.G.)
| | - Manuela E. Gomes
- 3B’s Research Group, I3Bs—Research Institute on Biomaterials, Biodegradables and Biomimetics, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, University of Minho, AvePark, Parque de Ciência e Tecnologia, Zona Industrial da Gandra, Barco, 4805-017 Guimarães, Portugal
- ICVS/3B’s–PT Government Associate Laboratory, 4805-017 Guimarães, Portugal
- Correspondence: (M.G.-F.); (M.E.G.)
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The Roles of Exosomal Proteins: Classification, Function, and Applications. Int J Mol Sci 2023; 24:ijms24043061. [PMID: 36834471 PMCID: PMC9961790 DOI: 10.3390/ijms24043061] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 01/24/2023] [Accepted: 01/26/2023] [Indexed: 02/09/2023] Open
Abstract
Exosome, a subpopulation of extracellular vesicles, plays diverse roles in various biological processes. As one of the most abundant components of exosomes, exosomal proteins have been revealed to participate in the development of many diseases, such as carcinoma, sarcoma, melanoma, neurological disorders, immune responses, cardiovascular diseases, and infection. Thus, understanding the functions and mechanisms of exosomal proteins potentially assists clinical diagnosis and targeted delivery of therapies. However, current knowledge about the function and application of exosomal proteins is still limited. In this review, we summarize the classification of exosomal proteins, and the roles of exosomal proteins in exosome biogenesis and disease development, as well as in the clinical applications.
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Popov SV, Mukhomedzyanov AV, Voronkov NS, Derkachev IA, Boshchenko AA, Fu F, Sufianova GZ, Khlestkina MS, Maslov LN. Regulation of autophagy of the heart in ischemia and reperfusion. Apoptosis 2023; 28:55-80. [PMID: 36369366 DOI: 10.1007/s10495-022-01786-1] [Citation(s) in RCA: 63] [Impact Index Per Article: 31.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/17/2022] [Indexed: 11/13/2022]
Abstract
Ischemia/reperfusion (I/R) of the heart leads to increased autophagic flux. Preconditioning stimulates autophagic flux by AMPK and PI3-kinase activation and mTOR inhibition. The cardioprotective effect of postconditioning is associated with activation of autophagy and increased activity of NO-synthase and AMPK. Oxidative stress stimulates autophagy in the heart during I/R. Superoxide radicals generated by NADPH-oxidase acts as a trigger for autophagy, possibly due to AMPK activation. There is reason to believe that AMPK, GSK-3β, PINK1, JNK, hexokinase II, MEK, PKCα, and ERK kinases stimulate autophagy, while mTOR, PKCδ, Akt, and PI3-kinase can inhibit autophagy in the heart during I/R. However, there is evidence that PI3-kinase could stimulate autophagy in ischemic preconditioning of the heart. It was found that transcription factors FoxO1, FoxO3, NF-κB, HIF-1α, TFEB, and Nrf-2 enhance autophagy in the heart in I/R. Transcriptional factors STAT1, STAT3, and p53 inhibit autophagy in I/R. MicroRNAs could stimulate and inhibit autophagy in the heart in I/R. Long noncoding RNAs regulate the viability and autophagy of cardiomyocytes in hypoxia/reoxygenation (H/R). Nitric oxide (NO) donors and endogenous NO could activate autophagy of cardiomyocytes. Activation of heme oxygenase-1 promotes cardiomyocyte tolerance to H/R and enhances autophagy. Hydrogen sulfide increases cardiac tolerance to I/R and inhibits apoptosis and autophagy via mTOR and PI3-kinase activation.
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Affiliation(s)
- Sergey V Popov
- Cardiology Research Institute, Tomsk National Research Medical Centre, the Russian Academy of Sciences, Tomsk, Russia, 634012
| | - Alexander V Mukhomedzyanov
- Cardiology Research Institute, Tomsk National Research Medical Centre, the Russian Academy of Sciences, Tomsk, Russia, 634012
| | - Nikita S Voronkov
- Cardiology Research Institute, Tomsk National Research Medical Centre, the Russian Academy of Sciences, Tomsk, Russia, 634012
| | - Ivan A Derkachev
- Cardiology Research Institute, Tomsk National Research Medical Centre, the Russian Academy of Sciences, Tomsk, Russia, 634012
| | - Alla A Boshchenko
- Cardiology Research Institute, Tomsk National Research Medical Centre, the Russian Academy of Sciences, Tomsk, Russia, 634012
| | - Feng Fu
- School of Basic Medicine, Fourth Military Medical University, No.169, West Changle Road, Xi'an, 710032, China
| | | | | | - Leonid N Maslov
- Cardiology Research Institute, Tomsk National Research Medical Centre, the Russian Academy of Sciences, Tomsk, Russia, 634012.
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35
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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: 0] [Impact Index Per Article: 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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36
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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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37
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Yaping XU, Guotian Y, Dandan J, Jintao D, Xinyi L, Zhikun G. Fibroblast-derived exosomal miRNA-133 promotes cardiomyocyte-like differentiation. Acta Histochem 2022; 124:151931. [PMID: 35930994 DOI: 10.1016/j.acthis.2022.151931] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Revised: 07/21/2022] [Accepted: 07/21/2022] [Indexed: 11/01/2022]
Abstract
OBJECTIVE To investigate the role of exosomal miRNA-133 secreted by cardiac fibroblasts (CFs) in promoting cardiomyocyte differentiation. METHODS Neonatal rat CFs were cultured in vitro, and the cultured CFs were divided into three groups as follows: induction, miRNA-133 high expression, and miRNA-133 inhibition. miRNA-133 was transfected into CFs with lentivirus as a vector. CFs were transfected with the miRNA-133 inhibitor, and the markers of cardiomyocyte were detected through immunofluorescence staining, Western blotting, and real-time quantitative polymerase chain reaction (qRT-PCR) at 3, 8, and 14 days, respectively. The expression levels of cardiac troponin T (cTnT) and cardiac actin (α-actin) were determined, and qRT-PCR was used to detect the expression of miRNA-133 in the fibroblast exosomes. RESULTS CFs subjected to immunofluorescence staining expressed vimentin and discoid domain receptor 2. The exosomes secreted by CFs were observed as small vesicles of 30-100 nm via transmission electron microscopy, and Western blotting was used to detect exosome-specific protein CD63 and CD9 expression. The expression levels of cTnT, α-actin, and exosomal miRNA-133 secreted into the supernatant of the miRNA-133 high-expression group increased gradually at different time points and reached the highest level at 14 days. The expression levels of cTnT, α-actin, and exosome miRNA-133 in the miRNA-133 inhibition group were the lowest. CONCLUSION The exosomal miRNA-133, which is derived from CFs, can promote the differentiation of fibroblasts into cardiomyocyte-like cells.
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Affiliation(s)
- X U Yaping
- Henan Medical Key Laboratory of Arrhythmia, Zhengzhou No. 7 People's Hospital, Zhengzhou, Henan, 450016, PR China; Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang City, Henan 453003, PR China
| | - Yin Guotian
- Department of Cardiology, Third Affiliated Hospital of Xinxiang Medical University, Xinxiang City, Henan 453003, PR China
| | - Jia Dandan
- Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang City, Henan 453003, PR China
| | - Dou Jintao
- Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang City, Henan 453003, PR China
| | - Liu Xinyi
- Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang City, Henan 453003, PR China
| | - Guo Zhikun
- Henan Medical Key Laboratory of Arrhythmia, Zhengzhou No. 7 People's Hospital, Zhengzhou, Henan, 450016, PR China; Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang City, Henan 453003, PR China.
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38
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Lu B, Ku J, Flojo R, Olson C, Bengford D, Marriott G. Exosome- and extracellular vesicle-based approaches for the treatment of lysosomal storage disorders. Adv Drug Deliv Rev 2022; 188:114465. [PMID: 35878794 DOI: 10.1016/j.addr.2022.114465] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Revised: 06/22/2022] [Accepted: 07/19/2022] [Indexed: 12/16/2022]
Abstract
Cell-generated extracellular vesicles (EVs) are being engineered as biologically-inspired vehicles for targeted delivery of therapeutic agents to treat difficult-to-manage human diseases, including lysosomal storage disorders (LSDs). Engineered EVs offer distinct advantages for targeted delivery of therapeutics compared to existing synthetic and semi-synthetic nanoscale systems, for example with regard to their biocompatibility, circulation lifetime, efficiencies in delivery of drugs and biologics to target cells, and clearance from the body. Here, we review literature related to the design and preparation of EVs as therapeutic carriers for targeted delivery and therapy of drugs and biologics with a focus on LSDs. First, we introduce the basic pathophysiology of LDSs and summarize current approaches to diagnose and treat LSDs. Second, we will provide specific details about EVs, including subtypes, biogenesis, biological properties and their potential to treat LSDs. Third, we review state-of-the-art approaches to engineer EVs for treatments of LSDs. Finally, we summarize explorative basic research and applied applications of engineered EVs for LSDs, and highlight current challenges, and new directions in developing EV-based therapies and their potential impact on clinical medicine.
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Affiliation(s)
- Biao Lu
- Department of Bioengineering, School of Engineering, Santa Clara University, 500 El Camino Real, Santa Clara, California 95053, USA
| | - Joy Ku
- Department of Bioengineering, School of Engineering, Santa Clara University, 500 El Camino Real, Santa Clara, California 95053, USA
| | - Renceh Flojo
- Department of Bioengineering, School of Engineering, Santa Clara University, 500 El Camino Real, Santa Clara, California 95053, USA
| | - Chris Olson
- Department of Bioengineering, School of Engineering, Santa Clara University, 500 El Camino Real, Santa Clara, California 95053, USA
| | - David Bengford
- Department of Bioengineering, School of Engineering, Santa Clara University, 500 El Camino Real, Santa Clara, California 95053, USA
| | - Gerard Marriott
- Department of Bioengineering, University of California at Berkeley, California 94720, USA.
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Yedavilli S, Singh AD, Singh D, Samal R. Nano-Messengers of the Heart: Promising Theranostic Candidates for Cardiovascular Maladies. Front Physiol 2022; 13:895322. [PMID: 35899033 PMCID: PMC9313536 DOI: 10.3389/fphys.2022.895322] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2022] [Accepted: 06/06/2022] [Indexed: 11/13/2022] Open
Abstract
Till date, cardiovascular diseases remain a leading cause of morbidity and mortality across the globe. Several commonly used treatment methods are unable to offer safety from future complications and longevity to the patients. Therefore, better and more effective treatment measures are needed. A potential cutting-edge technology comprises stem cell-derived exosomes. These nanobodies secreted by cells are intended to transfer molecular cargo to other cells for the establishment of intercellular communication and homeostasis. They carry DNA, RNA, lipids, and proteins; many of these molecules are of diagnostic and therapeutic potential. Several stem cell exosomal derivatives have been found to mimic the cardioprotective attributes of their parent stem cells, thus holding the potential to act analogous to stem cell therapies. Their translational value remains high as they have minimal immunogenicity, toxicity, and teratogenicity. The current review highlights the potential of various stem cell exosomes in cardiac repair, emphasizing the recent advancements made in the development of cell-free therapeutics, particularly as biomarkers and as carriers of therapeutic molecules. With the use of genetic engineering and biomimetics, the field of exosome research for heart treatment is expected to solve various theranostic requirements in the field paving its way to the clinics.
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Affiliation(s)
- Sneha Yedavilli
- Department of Life Science, Central University of Karnataka, Kalaburagi, India
| | | | - Damini Singh
- Environmental Pollution Analysis Lab, Bhiwadi, India
| | - Rasmita Samal
- Department of Life Science, Central University of Karnataka, Kalaburagi, India
- *Correspondence: Rasmita Samal,
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Zhang B, Sun C, Liu Y, Bai F, Tu T, Liu Q. Exosomal miR-27b-3p Derived from Hypoxic Cardiac Microvascular Endothelial Cells Alleviates Rat Myocardial Ischemia/Reperfusion Injury through Inhibiting Oxidative Stress-Induced Pyroptosis via Foxo1/GSDMD Signaling. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:8215842. [PMID: 35847592 PMCID: PMC9279077 DOI: 10.1155/2022/8215842] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 05/10/2022] [Accepted: 05/31/2022] [Indexed: 12/30/2022]
Abstract
Background Exosomes derived from cardiac microvascular endothelial cells (CMECs) under hypoxia can mediate cardiac repair functions and alleviate pyroptosis and oxidative stress during ischemia-reperfusion (I/R) injury. This study is aimed at investigating the effect and mechanism of miR-27b-3p underlying hypoxic CMECs-derived exosomes against I/R injury. Methods CMECs were isolated from the left ventricle of Sprague-Dawley rats, followed by culturing under hypoxic conditions or pretreatment with the miR-27b-3p inhibitor. CMECs-derived exosomes were added into H9C2 cells before hypoxia/reoxygenation (H/R) or injected into the rat heart before I/R injury. An in vivo I/R injury model was established by ligating and releasing the left anterior descending coronary artery. Expression of pyroptosis-related factors was detected using Western blot, and heart infarcted size was determined by the 2,3,5-triphenyl-2H-tetrazpinolium chloride staining method. Dual-Luciferase Reporter assays were performed to analyze the interactions of nmiR-27b-3p-forkhead box O1 (Foxo1) and Gasdermin D- (GSDMD-) Foxo1. Chromatin-immunoprecipitation (ChIP) assays were performed to validate the interactions between forkhead box O1 (Foxo1) and Gasdermin D (GSDMD) and Foxo1-mediated histone acetylation of GSDMD. Results CMECs were successfully identified from left ventricle of Sprague-Dawley rats. The expressions of Foxo1 and pyroptosis-related proteins (GSDMD, NLPR3, cleaved caspase 1, IL-1β, and IL-18) were upregulated in the rat heart after I/R injury. Treatment of CMEC-derived exosomes, especially that under hypoxic conditions, significantly reduced pyroptosis in the rat heart. miR-27b-3p was significantly upregulated in CMEC-derived exosomes under hypoxic conditions, and miR-27b-3p inhibition in exosomes alleviated its cytoprotection and inhibited oxidative stress in H9C2 cells. Treatment with Foxo1 overexpression plasmids aggravated in vitro H/R and in vivo I/R injury by upregulating pyroptosis-related proteins. Further experiments validated that miR-27b-3p negatively targeted Foxo1, which bound to the promoter region of GSDMD. Conclusions These results demonstrated a great therapeutic efficacy of miR-27b-3p overexpression in hypoxic CMEC-derived exosomes in preventing the development of myocardial damage post I/R injury through inhibiting Foxo1/GSDMD signaling-induced oxidative stress and pyroptosis.
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Affiliation(s)
- Baojian Zhang
- Cardiac Care Unit, Affiliated Hospital of Traditional Chinese Medicine, Xinjiang Medical University, Urumqi City, Xinjiang Uygur Autonomous Region, China
- Department of Cardiology/Cardiac Catheterization Lab, Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Chao Sun
- Department of Cardiology/Cardiac Catheterization Lab, Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yaozhong Liu
- Department of Cardiology/Cardiac Catheterization Lab, Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Fan Bai
- Department of Cardiology/Cardiac Catheterization Lab, Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Tao Tu
- Department of Cardiology/Cardiac Catheterization Lab, Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Qiming Liu
- Department of Cardiology/Cardiac Catheterization Lab, Second Xiangya Hospital, Central South University, Changsha, Hunan, China
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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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Gabisonia K, Khan M, Recchia FA. Extracellular vesicle-mediated bidirectional communication between heart and other organs. Am J Physiol Heart Circ Physiol 2022; 322:H769-H784. [PMID: 35179973 PMCID: PMC8993522 DOI: 10.1152/ajpheart.00659.2021] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 01/24/2022] [Accepted: 02/15/2022] [Indexed: 02/07/2023]
Abstract
In recent years, a wealth of studies has identified various molecular species released by cardiac muscle under physiological and pathological conditions that exert local paracrine and/or remote endocrine effects. Conversely, humoral factors, principally produced by organs such as skeletal muscle, kidney, or adipose tissue, may affect the function and metabolism of normal and diseased hearts. Although this cross communication within cardiac tissue and between the heart and other organs is supported by mounting evidence, research on the role of molecular mediators carried by exosomes, microvesicles, and apoptotic bodies, collectively defined as extracellular vesicles (EVs), is at an early stage of investigation. Once released in the circulation, EVs can potentially reach any organ where they transfer their cargo of proteins, lipids, and nucleic acids that exert potent biological effects on recipient cells. Although there are a few cases where such signaling was clearly demonstrated, the results from many other studies can only be tentatively inferred based on indirect evidence obtained by infusing exogenous EVs in experimental animals or by adding them to cell cultures. This area of research is in rapid expansion and most mechanistic interpretations may change in the near future; hence, the present review on the role played by EV-carried mediators in the two-way communication between heart and skeletal muscle, kidneys, bone marrow, lungs, liver, adipose tissue, and brain is necessarily limited. Nonetheless, the available data are already unveiling new, intriguing, and ample scenarios in cardiac physiology and pathophysiology.
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Affiliation(s)
- Khatia Gabisonia
- Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa, Italy
| | - Mohsin Khan
- Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania
| | - Fabio A Recchia
- Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa, Italy
- Fondazione Gabriele Monasterio, Pisa, Italy
- Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania
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Gurudas Shivji G, Dhar R, Devi A. Role of Exosomes and its emerging therapeutic applications in the pathophysiology of Non-Infectious disease. Biomarkers 2022; 27:534-548. [PMID: 35451890 DOI: 10.1080/1354750x.2022.2067233] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
Exosomes are a type of small Extracellular Vesicles (EVs) and play crucial roles in cancer and other diseases. Exosomes role in various diseases has been studied as they regulate intercellular communication and are obtained from almost any part of the body. Exosomes use is complicated in diseases as they promote pathogenesis but also act as a very good therapeutic agent in most diseases. The presence of a complex molecular cargo consisting of nucleic acids (DNA, RNA, miRNA, siRNA, etc.,) makes it a very good delivery agent and acts as a biomarker for many cancers, cardiovascular and neurodegenerative diseases. They can be used to selectively target cells and activate immune cell responses depending on the source obtained. Exosomes based immunotherapy is an area of gaining importance due to the proteins present in them and their specificity to the targeted cells. The role of exosomes in the diagnosis and treatment of non-infectious diseases is discussed in detail in this article.
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Affiliation(s)
- Gauresh Gurudas Shivji
- Cancer Biology and Stem Cell Biology Laboratory, Department of Genetic Engineering, School of Bioengineering, College of Engineering and Technology, SRM Institute of Science and Technology, Potheri, Kattankulathur, Chengalpattu District, Tamilnadu 603203, India
| | - Rajib Dhar
- Cancer Biology and Stem Cell Biology Laboratory, Department of Genetic Engineering, School of Bioengineering, College of Engineering and Technology, SRM Institute of Science and Technology, Potheri, Kattankulathur, Chengalpattu District, Tamilnadu 603203, India
| | - Arikketh Devi
- Cancer Biology and Stem Cell Biology Laboratory, Department of Genetic Engineering, School of Bioengineering, College of Engineering and Technology, SRM Institute of Science and Technology, Potheri, Kattankulathur, Chengalpattu District, Tamilnadu 603203, India
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Heat shock proteins and the calcineurin-crz1 signaling regulate stress responses in fungi. Arch Microbiol 2022; 204:240. [PMID: 35377020 DOI: 10.1007/s00203-022-02833-w] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2021] [Revised: 03/07/2022] [Accepted: 03/09/2022] [Indexed: 12/26/2022]
Abstract
The heat shock proteins (Hsps) act as a molecular chaperone to stabilize client proteins involved in various cell functions in fungi. Hsps are classified into different families such as HSP90, HSP70, HSP60, HSP40, and small HSPs (sHsps). Hsp90, a well-studied member of the Hsp family proteins, plays a role in growth, cell survival, and pathogenicity in fungi. Hsp70 and sHsps are involved in the development, tolerance to stress conditions, and drug resistance in fungi. Hsp60 is a mitochondrial chaperone, and Hsp40 regulates fungal ATPase machinery. In this review, we describe the cell functions, regulation, and the molecular link of the Hsps with the calcineurin-crz1 calcium signaling pathway for their role in cell survival, growth, virulence, and drug resistance in fungi and related organisms.
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Lazana I, Anagnostopoulos C. A Novel, Cell-Free Therapy to Enter Our Hearts: The Potential Role of Small EVs in Prevention and Treatment of CVD. Int J Mol Sci 2022; 23:ijms23073662. [PMID: 35409022 PMCID: PMC8998514 DOI: 10.3390/ijms23073662] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 03/22/2022] [Accepted: 03/25/2022] [Indexed: 12/18/2022] Open
Abstract
Heart disease constitutes one of the leading causes of morbidity and mortality worldwide. Current therapeutic techniques, such as interventional revascularization, although lifesaving, come along with myocardial injury related to the reperfusion itself, called ischemia-reperfusion injury, which is an added factor for increased morbidity. For that reason, there is an imperative need for novel therapies to be developed that would either prevent or treat myocardial injury. Extracellular vesicles (EVs), specifically small EVs (sEVs), have proven to be important mediators of intercellular communication. The fact that they carry information reflecting that of the parental cell makes them an ideal candidate for diagnostic purposes. sEVs derived from immunoregulatory cells, such as mesenchymal stem cells or cardiac progenitor cells, could also be used therapeutically to exert the primary immunomodulatory function but without carrying the side effects related to cell therapy. Furthermore, as a natural product, they have the added advantage of low immunogenicity, offering the potential for safe drug delivery. In the field of cardiology, there has been great interest in the therapeutic and diagnostic potential of sEVs with significant translational potential. Here, we review the potential use of sEVs in the context of myocardial ischemia and ischemia-reperfusion injury.
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Affiliation(s)
- Ioanna Lazana
- King’s College Hospital NHS Foundation Trust, London SE5 9RS, UK
- Cell and Gene Therapy Laboratory, Biomedical Research Foundation of the Academy of Athens, 115 27 Athens, Greece
- Correspondence:
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Cheng L, Hill AF. Therapeutically harnessing extracellular vesicles. Nat Rev Drug Discov 2022; 21:379-399. [PMID: 35236964 DOI: 10.1038/s41573-022-00410-w] [Citation(s) in RCA: 397] [Impact Index Per Article: 132.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/20/2022] [Indexed: 02/06/2023]
Abstract
The field of extracellular vesicle (EV) research has developed rapidly over the last decade from the study of fundamental biology to a subject of significant clinical relevance. The potential of harnessing EVs in the diagnosis and treatment of diseases - including cancer and neurological and cardiovascular disorders - is now being recognized. Accordingly, the applications of EVs as therapeutic targets, biomarkers, novel drug delivery agents and standalone therapeutics are being actively explored. This Review provides a brief overview of the characteristics and physiological functions of the various classes of EV, focusing on their association with disease and emerging strategies for their therapeutic exploitation.
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Affiliation(s)
- Lesley Cheng
- La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Victoria, Australia
| | - Andrew F Hill
- La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Victoria, Australia. .,Institute for Health and Sport, Victoria University, Melbourne, Victoria, Australia.
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Kang IS, Kwon K. Potential application of biomimetic exosomes in cardiovascular disease: focused on ischemic heart disease. BMB Rep 2022. [PMID: 34903320 PMCID: PMC8810547 DOI: 10.5483/bmbrep.2022.55.1.161] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Cardiovascular disease, especially ischemic heart disease, is a major cause of mortality worldwide. Cardiac repair is one of the most promising strategies to address advanced cardiovascular diseases. Despite moderate improvement in heart function via stem cell therapy, there is no evidence of significant improvement in mortality and morbidity beyond standard therapy. The most salutary effect of stem cell therapy are attributed to the paracrine effects and the stem cell-derived exosomes are known as a major contributor. Hence, exosomes are emerging as a promising therapeutic agent and potent biomarkers of cardiovascular disease. Furthermore, they play a role as cellular cargo and facilitate intercellular communication. However, the clinical use of exosomes is hindered by the absence of a standard operating procedures for exosome isolation and characterization, problems related to yield, and heterogeneity. In addition, the successful clinical application of exosomes requires strategies to optimize cargo, improve targeted delivery, and reduce the elimination of exosomes. In this review, we discuss the basic concept of exosomes and stem cell-derived exosomes in cardiovascular disease, and introduce current efforts to overcome the limitations and maximize the benefit of exosomes including engineered biomimetic exosomes.
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Affiliation(s)
- In Sook Kang
- Department of Internal Medicine, School of Medicine, Ewha Womans University, Seoul 07804, Korea
| | - Kihwan Kwon
- Department of Internal Medicine, School of Medicine, Ewha Womans University, Seoul 07804, Korea
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Exosomes in cardiovascular diseases: a blessing or a sin for the mankind. Mol Cell Biochem 2022; 477:833-847. [PMID: 35064412 DOI: 10.1007/s11010-021-04328-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Accepted: 12/07/2021] [Indexed: 12/13/2022]
Abstract
Cardiovascular diseases (CVDs) comprises disorders of blood vessels and heart. Multiple cells in the heart suggests that hetero-cellular communication, which is an important aspect in heart functioning and there is a need to elucidate the way in which this inter-cellular communication occurs. Now a days, exosomal research has gained much attention. Exosomes, nano-shuttles, are EVs with diameters ranging from 40 to 160 nm (average 100 nm), secreted by body cells. These vesicles act as cell-to-cell communicators and are carriers of important biomolecules such as RNAs, miRNAs, Proteins and lipids. Exosomes can change the gene expression of the recipient cells, thereby, changes the cellular characteristics. Exosomes have known to play an essential role in protection as well as progression of various cardiovascular diseases. In the present review, role of exosomes in various CVDs have been discussed.
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Extracellular Vesicles as Mediators of Therapy Resistance in the Breast Cancer Microenvironment. Biomolecules 2022; 12:biom12010132. [PMID: 35053279 PMCID: PMC8773878 DOI: 10.3390/biom12010132] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 01/07/2022] [Accepted: 01/11/2022] [Indexed: 12/17/2022] Open
Abstract
Resistance to various therapies, including novel immunotherapies, poses a major challenge in the management of breast cancer and is the leading cause of treatment failure. Bidirectional communication between breast cancer cells and the tumour microenvironment is now known to be an important contributor to therapy resistance. Several studies have demonstrated that crosstalk with the tumour microenvironment through extracellular vesicles is an important mechanism employed by cancer cells that leads to drug resistance via changes in protein, lipid and nucleic acid cargoes. Moreover, the cargo content enables extracellular vesicles to be used as effective biomarkers for predicting response to treatments and as potential therapeutic targets. This review summarises the literature to date regarding the role of extracellular vesicles in promoting therapy resistance in breast cancer through communication with the tumour microenvironment.
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50
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Cancer extracellular vesicles, tumoroid models, and tumor microenvironment. Semin Cancer Biol 2022; 86:112-126. [PMID: 35032650 DOI: 10.1016/j.semcancer.2022.01.003] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 12/21/2021] [Accepted: 01/10/2022] [Indexed: 12/14/2022]
Abstract
Cancer extracellular vesicles (EVs), or exosomes, promote tumor progression through enhancing tumor growth, initiating epithelial-to-mesenchymal transition, remodeling the tumor microenvironment, and preparing metastatic niches. Three-dimensionally (3D) cultured tumoroids / spheroids aim to reproduce some aspects of tumor behavior in vitro and show increased cancer stem cell properties. These properties are transferred to their EVs that promote tumor growth. Moreover, recent tumoroid models can be furnished with aspects of the tumor microenvironment, such as vasculature, hypoxia, and extracellular matrix. This review summarizes tumor tissue culture and engineering platforms compatible with EV research. For example, the combination experiments of 3D-tumoroids and EVs have revealed multifunctional proteins loaded in EVs, such as metalloproteinases and heat shock proteins. EVs or exosomes are able to transfer their cargo molecules to recipient cells, whose fates are often largely altered. In addition, the review summarizes approaches to EV labeling technology using fluorescence and luciferase, useful for studies on EV-mediated intercellular communication, biodistribution, and metastatic niche formation.
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