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Abdi SMY, Al-Bakri SSM, Nordin N. Insights on the Characteristics and Therapeutic Potential of Mesenchymal Stem Cell-derived Exosomes for Mitigation of Alzheimer's Disease's Pathogenicity: A Systematic Review. Cell Biochem Biophys 2025; 83:1399-1414. [PMID: 39436580 DOI: 10.1007/s12013-024-01598-x] [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] [Accepted: 04/22/2024] [Indexed: 10/23/2024]
Abstract
Alzheimer's disease (AD) remains a progressive neurodegenerative disease with no cure. Treatment of AD relies on administering drugs that only subside the symptoms. In recent studies, mesenchymal stem cell (MSC)-exosomes have been marked to possess therapeutic potential for treating AD. This study aims to systematically review and analyse findings that focus on the isolation, characterisation, and sources of MSC-derived exosomes used to unravel the therapeutic potential of these exosomes targeting AD using in vitro and in vivo models. It is hypothesised that MSC-exosomes exhibit high therapeutic potential for AD treatment by exerting various modes of action. PubMed, Scopus, and Medline were used to find relevant published works from January 2016 until December 2020, using assigned keywords including "Alzheimer's disease", "secretome", and "exosomes". Only research articles meeting the predefined inclusion/exclusion criteria were selected and analysed. The risk of bias was assessed using the Office of Health Assessment and Translation tool (OHAT). A total of 17 eligible in vivo and in vitro studies were included in this review. Bone marrow-derived stem cells (BMSCs) were the most used source for exosome isolation, even though studies on exosomes from adipose-derived stem cells (ADSCs) and human umbilical cord stem cells (HUCSCs) provide more information on the characteristics. When the risk of bias was assessed, the studies presented various levels of biases. Notably, the in vitro and in vivo studies revealed neuroprotective properties of MSC-exosomes through different modes of action to alleviate AD pathology. Our review discovered that most MSC exosomes could degrade Aβ plaques, enhance neurogenesis, extenuate neuroinflammatory response through microglial activation, regulate apoptosis and reduce oxidative stress. Delivery of exosomal micro-RNAs was also found to reduce neuroinflammation. Findings from this review provided convincing systematic evidence highlighting the therapeutic properties of MSC-derived exosomes as a prospective source for cell-free (acellular) therapy in treating AD.
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Affiliation(s)
- Sarah Mohammed Yousuf Abdi
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, 43400, Selangor, Malaysia
| | - Siti Sarah Mustaffa Al-Bakri
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, 43400, Selangor, Malaysia
| | - Norshariza Nordin
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, 43400, Selangor, Malaysia.
- Malaysian Research Institute on Ageing (MyAgeing™), Universiti Putra Malaysia, 43400, Serdang, Selangor, Malaysia.
- Genetics & Regenerative Medicine (ReGEN) Research Group, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, 43400, Selangor, Malaysia.
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Ling SSM, Lilyanna S, Chong JPC, Ng JYX, Chan SP, Prickett TCR, Wong LL, Richards AM, Liew OW. Plasma Neprilysin in Heart Failure: Response Dynamics and Clinical Associations Are Immunoassay Dependent. Clin Chem 2025:hvaf056. [PMID: 40396299 DOI: 10.1093/clinchem/hvaf056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2025] [Accepted: 04/11/2025] [Indexed: 05/22/2025]
Abstract
BACKGROUND Discordance among published findings on the plasma concentrations, response dynamics, and clinical associations of plasma neprilysin (NEP) in health and heart failure (HF) require clarification. METHOD Using a newly developed glycosylation-sensitive monoclonal antibody sandwich ELISA (NEPCVRI), plasma NEP was measured in 99 non-HF controls, 95 HF patients with preserved ejection fraction, and 104 patients with reduced ejection fraction. Results were compared with those from 2 commercial polyclonal antibody-based AlphaLISA (NEPPE) and ELLA (NEPELLA) immunoassays and a fluorometric activity [NEP activity (NEPACT)] assay. RESULTS NEPCVRI did not correlate with NEPPE, NEPELLA, or NEPACT while the latter 3 assays correlated strongly and directly with each other. Compared with non-HF, NEPCVRI was significantly downregulated in HF, while NEPPE, NEPELLA, and NEPACT were significantly upregulated. Strikingly, NEPCVRI concentration was perturbed by comorbidities (hypertension, diabetes, or atrial fibrillation) and exhibited inverse relationships with clinical variables and functional biomarkers compared with those of NEPPE, NEPELLA, or NEPACT. On univariate and multivariate analyses, NEPPE, NEPELLA, and NEPACT were associated with all-cause death and the composite endpoint of HF admission and all-cause death, while NEPCVRI had no prognostic value. CONCLUSIONS Plasma NEPCVRI, NEPPE, NEPELLA, and NEPACT display altered dynamics in HF, with NEPCVRI displaying inverse trends to those exhibited by the latter 3 assays. Conflicting data in NEP research may be explained by the heterogeneity of plasma NEP and the antibodies used to detect its varied glycosylated and nonglycosylated fragments. Well-characterized and validated immunoassays are crucial for understanding changes in NEP concentrations and activity in its biological and clinical contexts.
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Affiliation(s)
- Samantha S M Ling
- Cardiovascular Research Institute, Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore ,Singapore
| | - Shera Lilyanna
- Cardiovascular Research Institute, Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore ,Singapore
| | - Jenny P C Chong
- Cardiovascular Research Institute, Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore ,Singapore
| | - Jessica Y X Ng
- Cardiovascular Research Institute, Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore ,Singapore
| | - Siew-Pang Chan
- Centre for Behavioral and Implementation Science Interventions, Yong Loo Lin School of Medicine, National University of Singapore, Singapore ,Singapore
- National University Heart Centre, National University Health System, Singapore ,Singapore
- Institute of Geriatrics and Active Aging, Tan Tock Seng Hospital, Singapore ,Singapore
| | | | - Lee Lee Wong
- Cardiovascular Research Institute, Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore ,Singapore
| | - A Mark Richards
- Cardiovascular Research Institute, Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore ,Singapore
- National University Heart Centre, National University Health System, Singapore ,Singapore
- Christchurch Heart Institute, University of Otago, Christchurch, New Zealand
| | - Oi Wah Liew
- Cardiovascular Research Institute, Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore ,Singapore
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Duan H, Siadat SH, Jasim SA, Bansal P, Kaur H, Qasim MT, Abosaoda MK, Aboqader Al-Aouadi RF, Suliman M, Ali Khiavi P. Therapeutic Potential of Exosomal miRNAs: New Insights and Future Directions. J Biochem Mol Toxicol 2025; 39:e70270. [PMID: 40272032 DOI: 10.1002/jbt.70270] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2024] [Revised: 03/13/2025] [Accepted: 04/10/2025] [Indexed: 04/25/2025]
Abstract
Modern advancements in medicine include developing targeted drug delivery systems in the medical field, which are designed to unravel the potential of therapeutic products and overcome the barriers to the effectiveness of current approaches. Various nanopolymer carrier systems have been introduced in this regard, and the simple characteristics of extracellular vesicles have drawn special attention to their application as an effective drug delivery tool. Exosomes are very similar to transport vesicles and have a lipid-biomembrane covering an aqueous core. They also contain both hydrophilic and lipophilic substances and deliver their cargo to the desired targets. These properties enable exosomes to overcome some of the limitations of liposomes. Exosomes can easily diffuse into body fluids and remain in the bloodstream for a long time, crossing physiological barriers and entering cells. Exosomes, which contain a large volume of biomolecules, do not stimulate immune responses and do not accumulate in the liver or lungs instead of target tissues. Recent advancements in regenerative medicine have enabled scientists to utilize exosomes extracted from mesenchymal stem cells (MSCs), which possess significant regenerative abilities, for treating various diseases. The contents of these exosomes are crucial for both diagnosis and treatment, as they influence disease progression. Numerous in vitro studies have confirmed the safety, effectiveness, and therapeutic promise of exosomes in conditions such as cancer, neurodegenerative disorders, cardiovascular issues, and orthopedic ailments. This article explores the therapeutic potential of MSC-derived exosomes and outlines the essential procedures for their preparation.
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Affiliation(s)
- Haili Duan
- China Three Gorges University, Yichang City, China
| | | | - Saade Abdalkareem Jasim
- Medical Laboratory Techniques department, College of Health and medical technology, University of Al-maarif, Anbar, Iraq
| | - Pooja Bansal
- Department of Biotechnology and Genetics, Jain (Deemed-to-be) University, Bengaluru, India
- Department of Allied Healthcare and Sciences, Vivekananda Global University, Jaipur, India
| | - Harpreet Kaur
- School of Basic & Applied Sciences, Shobhit University, Gangoh, India
- Department of Health & Allied Sciences, Arka Jain University, Jamshedpur, India
| | - Maytham T Qasim
- Immunology and Physiology, College of Health and Medical Technology, Al-Ayen University, Iraq
| | - Munther Kadhim Abosaoda
- College of Pharmacy, The Islamic University, Najaf, Iraq
- College of Pharmacy, The Islamic University of Al Diwaniyah, Al Diwaniyah, Iraq
- College of Pharmacy, The Islamic University of Babylon, Al Diwaniyah, Iraq
| | | | - Muath Suliman
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia
| | - Payam Ali Khiavi
- Medicine Faculty, Tabriz University of Medical Sciences, Tabriz, Iran
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Bashirrohelleh MA, Bavarsad K, Khodadadi A, Shohan M, Asadirad A. Curcumin-enhanced stem cell exosomes: A novel approach to modulating neuroinflammation and improving cognitive function in a rat model of Alzheimer's disease. Eur J Pharmacol 2025; 999:177695. [PMID: 40315951 DOI: 10.1016/j.ejphar.2025.177695] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Revised: 04/22/2025] [Accepted: 04/30/2025] [Indexed: 05/04/2025]
Abstract
The effect of Curcumin-enhanced stem cell exosomes on the learning and memory impairment induced by streptozotocin (STZ) and neuro-inflammation in rats was evaluated. An animal model of Alzheimer's disease (AD) was established by intracerebroventricular (ICV) injection of STZ (3 mg/kg) in male Wistar rats (250 ± 50 g). ICV STZ injections chronically reduce cerebral glucose uptake and produce other effects similar to pathological, molecular and behavioral features of AD. Numerous studies confirmed the anti-inflammatory and antioxidant properties of curcumin (a natural polyphenol) against free radicals, as well as its ability to inhibit the aggregation of proteins such as beta-amyloid and alpha-synuclein in disorders such as AD and Parkinson's disease. The use of extracellular vesicles has garnered a lot of interest in research studies because of the important roles that mesenchymal stem cell-derived exosomes play in permeability, retention, and drug delivery as well as their ability to reduce inflammatory cytokines (TNF-α, IL-1β, and IL-6). Furthermore, researches highlighted the positive effect of curcumin on neuronal differentiation of stem cells in vivo and in vitro. Since studies emphasized the ameliorating effect of curcumin-treated macrophage-exosomes on symptoms of Alzheimer's disease by inhibiting tau protein phosphorylation, we proposed that Curcumin-primed MSC exosomes may offer greater efficacy to alleviate AD compared to naïve MSC exosomes. In this study, we investigated the effect of curcumin in stimulating the anti-inflammatory potential of exosome-derived stem cells. We evaluated the effect of MSC-EXO and pre-treated MSC-EXO with curcumin (CUR-MSC-EXO) on inhibiting inflammation and memory and learning impairments. Following four intraperitoneal injections of MSC-EXO and CUR-MSC-EXO at a dosage of 30μg/body over 30 days, we found that MSC-EXO and CUR-MSC-EXO elevated anti-inflammatory cytokines (IL10, TGF-β) and reduced pro-inflammatory cytokines (IL1, TNF-α) in peripheral blood compared to the AD group. The elevated level of M2 anti-inflammatory microglia markers (Arg1, CD206) and decreased level expression of M1 pro-inflammatory markers (iNOS, CD86) indicated that the CUR-MSC-EXO effect was more significant in the polarization of microglia into the M2 phenotype in the rat hippocampus. Both treatment groups demonstrated improvements in memory and learning skills. The results of the passive avoidance learning in the rats with STZ-induced memory impairment, however, were better in the CUR-MSC-EXO. Additionally, after therapy, a decrease in degenerative neurons was seen. Therefore, using curcumin may stimulate the anti-inflammatory and neuroprotective potential of exosome-derived stem cells which could provide hope for Alzheimer's disease treatment in the future.
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Affiliation(s)
- Mohammad-Ali Bashirrohelleh
- Department of Immunology, Faculty of Medicine, Ahvaz Jundishapur, University of Medical Sciences, Iran; Cellular and Molecular Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Kowsar Bavarsad
- Department of Physiology, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran; Persian Gulf Physiology Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Ali Khodadadi
- Department of Immunology, Faculty of Medicine, Ahvaz Jundishapur, University of Medical Sciences, Iran; Cancer, Petroleum and Environmental Pollutants Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Mojtaba Shohan
- Department of Immunology, Faculty of Medicine, Ahvaz Jundishapur, University of Medical Sciences, Iran
| | - Ali Asadirad
- Department of Immunology, Faculty of Medicine, Ahvaz Jundishapur, University of Medical Sciences, Iran; Cellular and Molecular Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran; Cancer, Petroleum and Environmental Pollutants Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
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Zhdanova DY, Bobkova NV, Chaplygina AV, Svirshchevskaya EV, Poltavtseva RA, Vodennikova AA, Chernyshev VS, Sukhikh GT. Effect of Small Extracellular Vesicles Produced by Mesenchymal Stem Cells on 5xFAD Mice Hippocampal Cultures. Int J Mol Sci 2025; 26:4026. [PMID: 40362265 PMCID: PMC12071690 DOI: 10.3390/ijms26094026] [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: 02/16/2025] [Revised: 04/09/2025] [Accepted: 04/15/2025] [Indexed: 05/15/2025] Open
Abstract
Alzheimer's disease (AD) is one of the most common progressive neurodegenerative diseases leading to impairments in memory, orientation, and behavior. However, significant work is still needed to fully understand the progression of such disease and develop novel therapeutic agents for AD prevention and treatment. Small extracellular vesicles (sEVs) have received attention in recent years due to their potential therapeutic effects on AD. The aim of this study was to determine the potential effect of sEVs in an in vitro model of AD. sEVs were isolated from human Wharton's jelly mesenchymal stem cells (MSCs) by asymmetric depth filtration, a method developed recently by us. AD was modeled in vitro using cells obtained from the hippocampi of newborn 5xFAD transgenic mice carrying mutations involved in familial AD. After isolation, sEVs underwent detailed characterization that included scanning electron microscopy, nanoparticle tracking analysis, confocal microscopy, Western blotting, and Luminex assay. When added to 5xFAD hippocampal cells, sEVs were nontoxic, colocalized with neurons and astrocytes, decreased the level of Aβ peptide, and increased the synaptic density. These results support the possibility that sEVs can improve brain cell function during aging, decrease the risk of AD, and potentially be used for AD therapeutics.
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Affiliation(s)
- Daria Y. Zhdanova
- Institute of Cell Biophysics, Federal Research Center Pushchino Research Center for Biological Studies, Russian Academy of Sciences, Institutskaya 3, Pushchino, 142290 Moscow, Russia (A.V.C.)
| | - Natalia V. Bobkova
- Institute of Cell Biophysics, Federal Research Center Pushchino Research Center for Biological Studies, Russian Academy of Sciences, Institutskaya 3, Pushchino, 142290 Moscow, Russia (A.V.C.)
| | - Alina V. Chaplygina
- Institute of Cell Biophysics, Federal Research Center Pushchino Research Center for Biological Studies, Russian Academy of Sciences, Institutskaya 3, Pushchino, 142290 Moscow, Russia (A.V.C.)
| | - Elena V. Svirshchevskaya
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Ulitsa M0iklukho-Maklaya 16/10, 117997 Moscow, Russia;
- National Medical Research Center for Obstetrics, Gynecology and Perinatology Named After Academician V. I. Kulakov, Ministry of Healthcare of the Russian Federation, Oparina St. 4, 117997 Moscow, Russia; (R.A.P.); (V.S.C.); (G.T.S.)
| | - Rimma A. Poltavtseva
- National Medical Research Center for Obstetrics, Gynecology and Perinatology Named After Academician V. I. Kulakov, Ministry of Healthcare of the Russian Federation, Oparina St. 4, 117997 Moscow, Russia; (R.A.P.); (V.S.C.); (G.T.S.)
| | - Anastasia A. Vodennikova
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Ulitsa M0iklukho-Maklaya 16/10, 117997 Moscow, Russia;
- Institute of Bioorganic Chemistry, National Research Nuclear University “MEPhI”, Kashirskoe Shosse 31, 115409 Moscow, Russia
| | - Vasiliy S. Chernyshev
- National Medical Research Center for Obstetrics, Gynecology and Perinatology Named After Academician V. I. Kulakov, Ministry of Healthcare of the Russian Federation, Oparina St. 4, 117997 Moscow, Russia; (R.A.P.); (V.S.C.); (G.T.S.)
- Skolkovo Institute of Science and Technology, Bolshoy Boulevard 30, Bld. 1, 121205 Moscow, Russia
| | - Gennadiy T. Sukhikh
- National Medical Research Center for Obstetrics, Gynecology and Perinatology Named After Academician V. I. Kulakov, Ministry of Healthcare of the Russian Federation, Oparina St. 4, 117997 Moscow, Russia; (R.A.P.); (V.S.C.); (G.T.S.)
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Yoo D, Jung SY, Go D, Park JY, You DG, Jung WK, Li Y, Ding J, Park JH, Um W. Functionalized extracellular vesicles of mesenchymal stem cells for regenerative medicine. J Nanobiotechnology 2025; 23:219. [PMID: 40102934 PMCID: PMC11921732 DOI: 10.1186/s12951-025-03300-6] [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: 06/09/2024] [Accepted: 03/06/2025] [Indexed: 03/20/2025] Open
Abstract
Stem cell-derived extracellular vesicles (EVs) have emerged as a safe and potent alternative to regenerative medicine in recent decades. Furthermore, the adjustment of EV functions has been recently enabled by certain stem cell preconditioning methods, providing an exceptional opportunity to enhance the therapeutic potential or confer additional functions of stem cell-derived EVs. In this review, we discuss the recent progress of functionalized EVs, based on stem cell preconditioning, for treating various organ systems, such as the musculoskeletal system, nervous system, integumentary system, cardiovascular system, renal system, and respiratory system. Additionally, we summarize the expected outcomes of preconditioning methods for stem cells and their EVs. With recent progress, we suggest considerations and future directions for developing personalized medicine based on preconditioned stem cell-derived EVs.
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Affiliation(s)
- Donghyeon Yoo
- Department of Biotechnology, College of Fisheries Science, Pukyong National University, Busan, 48513, Republic of Korea
| | - Se Young Jung
- Department of Biotechnology, College of Fisheries Science, Pukyong National University, Busan, 48513, Republic of Korea
| | - Dabin Go
- Department of Biotechnology, College of Fisheries Science, Pukyong National University, Busan, 48513, Republic of Korea
| | - Ji Yeong Park
- Department of Biotechnology, College of Fisheries Science, Pukyong National University, Busan, 48513, Republic of Korea
| | - Dong Gil You
- Department of Chemical Engineering & Biotechnology, Tech University of Korea, Siheung, 15073, Republic of Korea
| | - Won-Kyo Jung
- Marine Integrated Biomedical Technology Center, The National Key Research Institutes in Universities, Pukyong National University, Busan, 48513, Republic of Korea
- Major of Biomedical Engineering, Division of Smart Healthcare, College of Information Technology and Convergence and New-senior Healthcare Innovation Center (BK21 Plus), Pukyong National University, Busan, 48513, Republic of Korea
| | - Yuce Li
- College of Life Science and Health, Wuhan University of Science and Technology (WUST), Wuhan, 430065, China
| | - Jianxun Ding
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, P. R. China
| | - Jae Hyung Park
- School of Chemical Engineering, College of Engineering, Sungkyunkwan University (SKKU), Suwon, 16419, Republic of Korea.
| | - Wooram Um
- Department of Biotechnology, College of Fisheries Science, Pukyong National University, Busan, 48513, Republic of Korea.
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Wu H, Li YL, Liu PM, Yang JJ. Global status and trends of exosomes in neurodegenerative diseases from 2014 to 2023: a bibliometric and visual analysis. Front Aging Neurosci 2025; 17:1496252. [PMID: 40134534 PMCID: PMC11933124 DOI: 10.3389/fnagi.2025.1496252] [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: 09/14/2024] [Accepted: 02/25/2025] [Indexed: 03/27/2025] Open
Abstract
Background Neurodegenerative diseases (NDs) are chronic and progressive conditions that significantly impact global public health. Recent years have highlighted exosomes as key mechanisms involved in these diseases. This study aims to visualize and analyze the structure and content of exosomes in NDs based on past research to identify new research ideas and directions. Through bibliometric analysis, we assess the current state of research on exosomes in the field of NDs worldwide over the past decade, highlighting significant findings, major research areas, and emerging trends. Methods Publications on exosomes in NDs research were obtained from the Web of Science Core Collection (WOSCC) database. Eligible literature was analyzed using Bibliometric R, VOSviewer, and Citespace. Results Between 2014 and 2023, 2,393 publications on exosomes in NDs were included in the analysis. The number of relevant publications has been increasing yearly, with China leading in international collaboration, followed by the United States. And China has the largest number of academic scholars as leading and corresponding authors in all the countries, known as the great research society and community. Notable institutions contributing to these publications include Nia, the University of San Francisco California, and Capital Medical University, which rank highly in both publication volume and citations. Dimitrios Kapogiannis is a pivotal figure in the author collaboration network, having produced the highest number of publications (Sato et al., 2011) and amassed 3,921 citations. The journal with the most published articles in this field is The International Journal of Molecular Sciences, which has published 131 articles and received 3,347 citations. A recent analysis of keyword clusters indicates that "Exosome-like liposomes," "Independent mechanisms," and "Therapeutic potential" are emerging research hotspots. Conclusion This is the first bibliometric study to provide a comprehensive summary of the research trends and developments regarding exosomes in NDs studies. Future research in this area may explore the role of mesenchymal stromal cells, microRNAs (miRNAs), and targeted drug delivery systems to further investigate the underlying mechanisms and develop new therapeutics.
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Affiliation(s)
- Hao Wu
- Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yao-lei Li
- National Institutes for Food and Drug Control, Beijing, China
| | - Pan-miao Liu
- Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jian-jun Yang
- Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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Hernandez P, Rackles E, Alboniga OE, Martínez‐Lage P, Camacho EN, Onaindia A, Fernandez M, Talamillo A, Falcon‐Perez JM. Metabolic Profiling of Brain Tissue and Brain-Derived Extracellular Vesicles in Alzheimer's Disease. J Extracell Vesicles 2025; 14:e70043. [PMID: 39901643 PMCID: PMC11791017 DOI: 10.1002/jev2.70043] [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: 09/05/2024] [Revised: 01/08/2025] [Accepted: 01/10/2025] [Indexed: 02/05/2025] Open
Abstract
Alzheimer´s disease (AD) is the most frequent neurodegenerative disorder in the world and is characterised by the loss of memory and other cognitive functions. Metabolic changes associated with AD are important players in the development of the disease. However, the mechanism underlying these changes is still unknown. Extracellular vesicles (EVs) are nano-sized particles that play an important role in regulating pathophysiological processes and are a non-invasive manner to obtain information of the cell that is secreting them. The analysis of brain-derived EVs (bdEVs) will provide new insights in the metabolic processes associated with AD. To characterize bdEVs in AD, we optimised a method to isolate them from tissue of different brain regions, obtaining the highest enrichment in isolations from the temporal cortex. We performed unbiased untargeted metabolomics analysis on post-mortem human temporal cortex tissue and bdEVs from the same region of AD patients and healthy controls. Both, univariate and multivariate statistical analysis were used to determine the metabolites that influence the separation between AD patients and controls. Interestingly, a clear separation between control and AD groups was obtained with bdEVs, which allowed to select 12 relevant features by a validated PLS-DA model. Furthermore, comparison of tissue and bdEVs identified 68 common features. The pathway enrichment analysis of the common metabolites showed that the alanine, aspartate and glutamate pathway and the arginine, phenylalanine, tyrosine pathway were the most significant ones in the separation between the AD patients and controls. The phenylalanine, tyrosine and tryptophan pathway, still had a very high influence in the separation between groups, albeit not significant. Notably, some metabolites were identified for the first time in bdEVs. For example, the N-acetyl aspartic acid (NAA) metabolite present in bdEVs was suitable to differentiate AD patients from healthy controls. Furthermore, the analysis of the hippocampus, midbrain, temporal and entorhinal cortex and their respective bdEVs indicated that the metabolic profiles of different brain areas were distinct and showed some correlation between the metabolome of the tissue and its respective bdEVs. Thus, our study highlights the potential of bdEVs to understand the metabolic fingerprint associated with AD and their potential use as diagnostic and therapeutic targets.
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Affiliation(s)
- Patricia Hernandez
- Exosomes Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE)Basque Research and Technology Alliance (BRTA)Derio, BizkaiaSpain
| | - Elisabeth Rackles
- Exosomes Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE)Basque Research and Technology Alliance (BRTA)Derio, BizkaiaSpain
| | - Oihane E. Alboniga
- Metabolomics Platform, Center for Cooperative Research in Biosciences (CIC bioGUNE)Basque Research and Technology Alliance (BRTA)Derio, BizkaiaSpain
| | - Pablo Martínez‐Lage
- Center for Research and Advanced TherapiesCITA‐Alzheimer FoundationGipuzkoaSpain
| | - Emma N. Camacho
- Anatomic PathologyAraba University HospitalVitoria‐GazteizAlavaSpain
| | - Arantza Onaindia
- Bioaraba Health Research InstituteOncohaematology Research GroupVitoria‐GasteizSpain
- Pathology DepartmentOsakidetza Basque Health ServiceAraba University HospitalVitoria‐GasteizSpain
| | - Manuel Fernandez
- Neurological DepartmentHospital Universitario Cruces (HUC)BarakaldoSpain
- Neuroscience DepartmentUniversidad del País Vasco (UPV‐EHU)LeioaSpain
| | - Ana Talamillo
- Exosomes Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE)Basque Research and Technology Alliance (BRTA)Derio, BizkaiaSpain
| | - Juan M. Falcon‐Perez
- Exosomes Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE)Basque Research and Technology Alliance (BRTA)Derio, BizkaiaSpain
- Metabolomics Platform, Center for Cooperative Research in Biosciences (CIC bioGUNE)Basque Research and Technology Alliance (BRTA)Derio, BizkaiaSpain
- Biomedical Research Centre of Hepatic and Digestive Diseases (CIBERehd)Carlos III Health Institute (ISCIII)MadridSpain
- IKERBASQUE Basque Foundation for ScienceBilbao, BizkaiaSpain
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Lerussi G, Villagrasa-Araya V, Moltó-Abad M, del Toro M, Pintos-Morell G, Seras-Franzoso J, Abasolo I. Extracellular Vesicles as Tools for Crossing the Blood-Brain Barrier to Treat Lysosomal Storage Diseases. Life (Basel) 2025; 15:70. [PMID: 39860010 PMCID: PMC11766495 DOI: 10.3390/life15010070] [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: 11/19/2024] [Revised: 01/03/2025] [Accepted: 01/08/2025] [Indexed: 01/27/2025] Open
Abstract
Extracellular vesicles (EVs) are nanosized, membrane-bound structures that have emerged as promising tools for drug delivery, especially in the treatment of lysosomal storage disorders (LSDs) with central nervous system (CNS) involvement. This review highlights the unique properties of EVs, such as their biocompatibility, capacity to cross the blood-brain barrier (BBB), and potential for therapeutic cargo loading, including that of enzymes and genetic material. Current therapies for LSDs, like enzyme replacement therapy (ERT), often fail to address neurological symptoms due to their inability to cross the BBB. EVs offer a viable alternative, allowing for targeted delivery to the CNS and improving therapeutic outcomes. We discuss recent advancements in the engineering and modification of EVs to enhance targeting, circulation time and cargo stability, and provide a detailed overview of their application in LSDs, such as Gaucher and Fabry diseases, and Sanfilippo syndrome. Despite their potential, challenges remain in scaling production, ensuring isolation purity, and meeting regulatory requirements. Future developments will focus on overcoming these barriers, paving the way for the clinical translation of EV-based therapies in LSDs and other CNS disorders.
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Affiliation(s)
- Giovanni Lerussi
- Clinical Biochemistry, Drug Delivery & Therapy (CB-DDT), Vall d’Hebron Institute of Research (VHIR), 08035 Barcelona, Spain; (G.L.); (V.V.-A.); (M.M.-A.); (G.P.-M.); (J.S.-F.)
| | - Verónica Villagrasa-Araya
- Clinical Biochemistry, Drug Delivery & Therapy (CB-DDT), Vall d’Hebron Institute of Research (VHIR), 08035 Barcelona, Spain; (G.L.); (V.V.-A.); (M.M.-A.); (G.P.-M.); (J.S.-F.)
- Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), 08035 Barcelona, Spain
- Institute of Advanced Chemistry of Catalonia (IQAC), Centro Superior de Investigaciones Científicas (CSIC), 08034 Barcelona, Spain
| | - Marc Moltó-Abad
- Clinical Biochemistry, Drug Delivery & Therapy (CB-DDT), Vall d’Hebron Institute of Research (VHIR), 08035 Barcelona, Spain; (G.L.); (V.V.-A.); (M.M.-A.); (G.P.-M.); (J.S.-F.)
- Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), 08035 Barcelona, Spain
| | - Mireia del Toro
- Pediatric Neurology Unit, Hospital Universitari Vall d’Hebron and MetabERN, 08035 Barcelona, Spain;
- Networking Research Center on Rare Diseases (CIBERER), 08035 Barcelona, Spain
| | - Guillem Pintos-Morell
- Clinical Biochemistry, Drug Delivery & Therapy (CB-DDT), Vall d’Hebron Institute of Research (VHIR), 08035 Barcelona, Spain; (G.L.); (V.V.-A.); (M.M.-A.); (G.P.-M.); (J.S.-F.)
| | - Joaquin Seras-Franzoso
- Clinical Biochemistry, Drug Delivery & Therapy (CB-DDT), Vall d’Hebron Institute of Research (VHIR), 08035 Barcelona, Spain; (G.L.); (V.V.-A.); (M.M.-A.); (G.P.-M.); (J.S.-F.)
- Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), 08035 Barcelona, Spain
| | - Ibane Abasolo
- Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), 08035 Barcelona, Spain
- Institute of Advanced Chemistry of Catalonia (IQAC), Centro Superior de Investigaciones Científicas (CSIC), 08034 Barcelona, Spain
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10
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Lou S, Hu W, Wei P, He D, Fu P, Ding K, Chen Z, Dong Z, Zheng J, Wang K. Artificial Nanovesicles Derived from Cells: A Promising Alternative to Extracellular Vesicles. ACS APPLIED MATERIALS & INTERFACES 2025; 17:22-41. [PMID: 39692623 DOI: 10.1021/acsami.4c12567] [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: 12/19/2024]
Abstract
As naturally secreted vesicles by cells, extracellular vesicles (EVs) play essential roles in modulating cell-cell communication and have significant potential in tissue regeneration, immune regulation, and drug delivery. However, the low yield and uncontrollable heterogeneity of EVs have been obstacles to their widespread translation into clinical practice. Recently, it has been discovered that artificial nanovesicles (NVs) produced by cell processing can inherit the components and functions of the parent cells and possess similar structures and functions to EVs, with significantly higher yields and more flexible functionalization, making them a powerful complement to natural EVs. This review focuses on recent advances in the research of artificial NVs as replacements for natural EVs. We provide an overview comparing natural EVs and artificial NVs and summarize the top-down preparation strategies of NVs. The applications of NVs prepared from stem cells, differentiated cells, and engineered cells are presented, as well as the latest advances in NV engineering. Finally, the main challenges of artificial NVs are discussed.
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Affiliation(s)
- Saiyun Lou
- The Second School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou 310053, China
- Department of Respiratory and Critical Care Medicine, Ningbo No. 2 Hospital, Ningbo 315010, China
| | - Wei Hu
- The Second School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou 310053, China
- Department of Respiratory and Critical Care Medicine, Ningbo No. 2 Hospital, Ningbo 315010, China
| | - Pengyao Wei
- Ningbo Key Laboratory of Biomedical Imaging Probe Materials and Technology, Ningbo Cixi Institute of Biomedical Engineering, Ningbo Institute of Materials Technology and Engineering of Chinese Academy of Sciences, Ningbo 315300, China
| | - Dongdong He
- Ningbo Key Laboratory of Biomedical Imaging Probe Materials and Technology, Ningbo Cixi Institute of Biomedical Engineering, Ningbo Institute of Materials Technology and Engineering of Chinese Academy of Sciences, Ningbo 315300, China
| | - Pan Fu
- Ningbo Key Laboratory of Biomedical Imaging Probe Materials and Technology, Ningbo Cixi Institute of Biomedical Engineering, Ningbo Institute of Materials Technology and Engineering of Chinese Academy of Sciences, Ningbo 315300, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Kejian Ding
- School of Materials Science and Chemical Engineering, Ningbo University, Ningbo,Zhejiang 315211, China
| | - Zhenyi Chen
- School of Materials Science and Chemical Engineering, Ningbo University, Ningbo,Zhejiang 315211, China
| | - Zhaoxing Dong
- Department of Respiratory and Critical Care Medicine, Ningbo No. 2 Hospital, Ningbo 315010, China
| | - Jianping Zheng
- Ningbo Key Laboratory of Biomedical Imaging Probe Materials and Technology, Ningbo Cixi Institute of Biomedical Engineering, Ningbo Institute of Materials Technology and Engineering of Chinese Academy of Sciences, Ningbo 315300, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Kaizhe Wang
- Ningbo Key Laboratory of Biomedical Imaging Probe Materials and Technology, Ningbo Cixi Institute of Biomedical Engineering, Ningbo Institute of Materials Technology and Engineering of Chinese Academy of Sciences, Ningbo 315300, China
- University of Chinese Academy of Sciences, Beijing 100049, China
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11
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Zheng B, Wang X, Guo M, Tzeng CM. Current Development of Mesenchymal Stem Cell-Derived Extracellular Vesicles. Cell Transplant 2025; 34:9636897241297623. [PMID: 39874070 PMCID: PMC11775985 DOI: 10.1177/09636897241297623] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2024] [Revised: 10/11/2024] [Accepted: 10/17/2024] [Indexed: 01/30/2025] Open
Abstract
Mesenchymal stem cells (MSCs) are pluripotent stem cells with self-renewal. They play a critical role in cell therapy due to their powerful immunomodulatory and regenerative effects. Recent studies suggest that one of the key therapeutic mechanisms of MSCs seems to derive from their paracrine product, called extracellular vesicles (EVs). The EVs contain much DNA, messenger RNA (mRNA), microRNA, and protein components, which can exert intracellular communication to target cells. In clinical applications, the MSC-EVs have been widely used in tissue repair and immune disorder diseases. However, there are serval issues need to be considered such as how to accomplish the large-scale production of EVs and how to verify the exact mechanism of EVs. In this review, we summarize the current progress of MSC-EVs and discuss the challenges and future of MSC-EVs.
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Affiliation(s)
- Bingyi Zheng
- Cells Good (Xiamen) Inc. Huli, Xiamen Torch Development Zone, Fujian, China
- Translational Medicine Research Center, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China
| | - Xueting Wang
- Cells Good (Xiamen) Inc. Huli, Xiamen Torch Development Zone, Fujian, China
- Translational Medicine Research Center, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China
| | - Meizhai Guo
- Cells Good (Xiamen) Inc. Huli, Xiamen Torch Development Zone, Fujian, China
- Translational Medicine Research Center, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China
| | - Chi-Meng Tzeng
- Cells Good (Xiamen) Inc. Huli, Xiamen Torch Development Zone, Fujian, China
- Translational Medicine Research Center, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China
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12
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Xing X, Liu H, Zhang M, Li Y. Mapping the current trends and hotspots of extracellular vesicles in Alzheimer's disease: a bibliometric analysis. Front Aging Neurosci 2024; 16:1485750. [PMID: 39759397 PMCID: PMC11697149 DOI: 10.3389/fnagi.2024.1485750] [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: 08/24/2024] [Accepted: 12/06/2024] [Indexed: 01/07/2025] Open
Abstract
Background Extracellular vesicles (EVs) have garnered significant attention in Alzheimer's disease (AD) research over the past decade, largely due to their potential in diagnostics and therapeutics. Although the investigation of EVs in AD is a relatively recent endeavor, a comprehensive bibliometric analysis of this rapidly growing field has yet to be conducted. Methods This study aims to elucidate and synthesize the relationship between EVs and AD, offering critical insights to guide future research and expand therapeutic possibilities. Over the past 10-15 years, substantial progress has been made in this domain. Through bibliometric techniques, this analysis assesses research performance by examining scientific publications and metrics, including productivity indicators, impact measurements, data mining, and visualization tools. Results A total of 602 publications were analyzed using various online platforms for bibliometric analysis. Notably, the number of publications began to increase rapidly in 2018, with China and the United States emerging as leaders in this research area. The National Institute on Aging produced the highest number of publications among institutions. The Journal of Molecular Sciences and the Journal of Biological Chemistry were the most prolific and most frequently cited journals, respectively. Among individual contributors, Dimitrios Kapogiannis was identified as the most productive author, while Edward J. Goetzl was the most co-cited. The most prevalent keywords included "neurodegenerative diseases," "exosomes," "blood biomarkers," "amyloid beta," "microglia," and "tau protein." Current research hotspots involve microRNA dysregulation, oxidative stress, carboxyl-terminal fragments, small EVs, and mesenchymal stem cell-derived EVs, indicating key areas for future research. Conclusion Research on microRNA dysregulation, oxidative stress, carboxyl-terminal fragments, small EVs, and mesenchymal stem cell-derived EVs represents a critical frontier in the study of Alzheimer's disease. The role of EV-mediated neuroinflammation in AD is a focal point of ongoing investigation and will likely shape future developments in the field.
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Affiliation(s)
- Xiaolian Xing
- Department of Neurology, First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
- Department of Neurology, Taiyuan Central Hospital, Taiyuan, Shanxi, China
| | - Hongwei Liu
- Department of Neurology, Taiyuan Central Hospital, Taiyuan, Shanxi, China
| | - Minheng Zhang
- Department of Gerontology, The First People's Hospital of Jinzhong, Yuci, Shanxi, China
| | - Yang Li
- Department of Neurology, First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
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13
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Wang L, Zhang X, Yang Z, Wang B, Gong H, Zhang K, Lin Y, Sun M. Extracellular vesicles: biological mechanisms and emerging therapeutic opportunities in neurodegenerative diseases. Transl Neurodegener 2024; 13:60. [PMID: 39643909 PMCID: PMC11622582 DOI: 10.1186/s40035-024-00453-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Accepted: 11/14/2024] [Indexed: 12/09/2024] Open
Abstract
Extracellular vesicles (EVs) are membrane vesicles originating from different cells within the brain. The pathophysiological role of EVs in neurodegenerative diseases is progressively acknowledged. This field has advanced from basic biological research to essential clinical significance. The capacity to selectively enrich specific subsets of EVs from biofluids via distinctive surface markers has opened new avenues for molecular understandings across various tissues and organs, notably in the brain. In recent years, brain-derived EVs have been extensively investigated as biomarkers, therapeutic targets, and drug-delivery vehicles for neurodegenerative diseases. This review provides a brief overview of the characteristics and physiological functions of the various classes of EVs, focusing on the biological mechanisms by which various types of brain-derived EVs mediate the occurrence and development of neurodegenerative diseases. Concurrently, novel therapeutic approaches and challenges for the use of EVs as delivery vehicles are delineated.
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Affiliation(s)
- Ling Wang
- The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, 211166, China
| | - Xiaoyan Zhang
- The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, 211166, China
| | - Ziyi Yang
- The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, 211166, China
| | - Binquan Wang
- The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, 211166, China
| | - Hongyang Gong
- The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, 211166, China
| | - Ke Zhang
- The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, 211166, China
| | - Yi Lin
- The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, 211166, China
| | - Mingkuan Sun
- The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, 211166, China.
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14
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Hassaan NA, Mansour HA. Exosomal therapy is a luxury area for regenerative medicine. Tissue Cell 2024; 91:102570. [PMID: 39383641 DOI: 10.1016/j.tice.2024.102570] [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: 06/28/2024] [Revised: 09/02/2024] [Accepted: 09/17/2024] [Indexed: 10/11/2024]
Abstract
Stem cell-based therapies have made significant advancements in tissue regeneration and medical engineering. However, there are limitations to cell transplantation therapy, such as immune rejection and limited cell viability. These limitations greatly impede the translation of stem cell-based tissue regeneration into clinical practice. In recent years, exosomes, which are packaged vesicles released from cells, have shown promising progress. Specifically, exosomes derived from stem cells have demonstrated remarkable therapeutic benefits. Exosomes are nanoscale extracellular vesicles that act as paracrine mediators. They transfer functional cargos, such as miRNA and mRNA molecules, peptides, proteins, cytokines, and lipids, from MSCs to recipient cells. By participating in intercellular communication events, exosomes contribute to the healing of injured or diseased tissues and organs. Studies have shown that the therapeutic effects of MSCs in various experimental paradigms can be solely attributed to their exosomes. Consequently, MSC-derived exosomes can be modified and utilized to develop a unique cell-free therapeutic approach for treating multiple diseases, including neurological, immunological, heart, and other diseases. This review is divided into several categories, including the current understanding of exosome biogenesis, isolation techniques, and their application as therapeutic tools.
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Affiliation(s)
- Nahla A Hassaan
- Department of Zoology, Faculty of Science, Al-Azhar University, Cairo, Egypt.
| | - Hanaa A Mansour
- Department of Pharmacology, National Organization for Drug Control and Research (NODCAR), Giza, Egypt
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15
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Sueca-Comes M, Rusu EC, Ashworth JC, Collier P, Probert C, Ritchie A, Meakin M, Mongan NP, Egbuniwe IU, Andersen JB, Bates DO, Grabowska AM. The role of mesenchymal cells in cholangiocarcinoma. Dis Model Mech 2024; 17:dmm050716. [PMID: 39492622 DOI: 10.1242/dmm.050716] [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: 01/28/2024] [Accepted: 10/17/2024] [Indexed: 11/05/2024] Open
Abstract
The tumour microenvironment (TME) significantly influences tumour formation and progression through dynamic interactions. Cholangiocarcinoma (CCA), a highly desmoplastic tumour, lacks early diagnostic biomarkers and has limited effective treatments owing to incomplete understanding of its molecular pathogenesis. Investigating the role of the TME in CCA progression could lead to better therapies. RNA sequencing was performed on seven CCA patient-derived xenografts (PDXs) and their corresponding patient samples. Differential expression analysis was conducted, and Qiagen Ingenuity Pathway Analysis was used to predict dysregulated pathways and upstream regulators. PDX- and cell line-derived spheroids, with and without immortalised mesenchymal stem cells, were grown and analysed for morphology, growth and viability. Histological analysis confirmed biliary phenotypes. RNA sequencing indicated upregulation of extracellular matrix-receptor interaction and PI3K-AKT pathways in the presence of mesenchymal cells, with several genes linked to poor survival. Mesenchymal cells restored the activity of inhibited cancer-associated kinases. Thus, adding mesenchymal cells to CCA spheroid models restored key paracrine signalling pathways lost in PDXs, enhancing tumour growth and viability. These findings highlight the importance of including stromal components in cancer models to improve pre-clinical studies.
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Affiliation(s)
- Mireia Sueca-Comes
- Translational Medical Science, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham NG7 2RD, UK
| | - Elena Cristina Rusu
- Institute of Integrative Systems Biology (I2Sysbio), University of Valencia and Consejo Superior de Investigaciones Científicas (CSIC), 46980 Valencia, Spain
| | - Jennifer C Ashworth
- Translational Medical Science, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham NG7 2RD, UK
- School of Veterinary Medicine and Science, Sutton Bonington Campus, University of Nottingham, Leicestershire LE12 5RD, UK
| | - Pamela Collier
- Translational Medical Science, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham NG7 2RD, UK
| | - Catherine Probert
- Translational Medical Science, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham NG7 2RD, UK
| | - Alison Ritchie
- Translational Medical Science, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham NG7 2RD, UK
| | - Marian Meakin
- Translational Medical Science, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham NG7 2RD, UK
| | - Nigel P Mongan
- School of Veterinary Medicine and Science, Sutton Bonington Campus, University of Nottingham, Leicestershire LE12 5RD, UK
- Department of Pharmacology, Weill Cornell Medicine, New York, NY 10065, USA
| | - Isioma U Egbuniwe
- Translational Medical Science, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham NG7 2RD, UK
| | - Jesper Bøje Andersen
- Biotech Research and Innovation Centre (BRIC), Department of Health and Medical Sciences, University of Copenhagen, Copenhagen DK-2200, Denmark
| | - David O Bates
- Translational Medical Science, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham NG7 2RD, UK
| | - Anna M Grabowska
- Translational Medical Science, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham NG7 2RD, UK
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16
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Verma H, Kaur S, Jeeth P, Kumar P, Kadhirvel S, Dhiman M, Mantha AK. Understanding Aβ 25-35 peptide altered exosomal proteome and associated pathways linked with the Alzheimer's disease pathogenesis using human neuroblastoma SH-SY5Y Cells. Metab Brain Dis 2024; 40:25. [PMID: 39565424 DOI: 10.1007/s11011-024-01469-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Accepted: 09/11/2024] [Indexed: 11/21/2024]
Abstract
The central nervous system (CNS) involves a complex interplay of communications between the neurons and various glial cells, which is crucial for brain functions. The major interactomes are exosomes that transmit sundry molecules (DNA, miRNAs, and proteins) between the cells and thus alter cell physiology. Exosomes can act as neuroprotective or neurodegenerative agents depending on the microenvironment of cells secreting them. Therefore, revealing exosome proteome becomes important to understand donor cells' physiology and its effect on the recipient cell. In this study, oxidative stress was induced by Aβ25-35 in the human neuroblastoma SH-SY5Y cells and the protective effects of phytochemical ferulic acid (FA) were evaluated alone and in combination with Aβ25-35 (pre-treated for 3 h before Aβ25-35 exposure) and proteome of their secreted exosomes was analyzed, which was carried out via a high-resolution LC-MS Triple-ToF and further network-based analysis has been carried out using various bioinformatics tools. The proteomic profiling enlightened the multiple roles of exosomes as proteins associated with the various pathways advocate that exosomes can mediate a wide range of effects, from normal physiological processes like synaptic plasticity, neuronal metabolic support, nerve regeneration, DNA repair, axon guidance, and long-term potentiation (LTP) to abnormal pathological processes like inflammatory responses, oxidative stress, apoptosis, and formation of neutrophil extracellular traps (NETs). On comparison, treatment with Aβ25-35 resulted in a significant modulation of the exosomal proteome, promoting pathways associated with neurodegeneration. Conversely, the phytochemical FA displayed a protective effect by effectively countering Aβ25-35-induced oxidative stress responses linked with neurodegeneration, as seen in Alzheimer's disease (AD). Taken together, this study highlights the dual role of exosomes in physiological and pathophysiological neurodegenerative AD, which intricately depend on the particular cellular milieu.
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Affiliation(s)
- Harkomal Verma
- Department of Zoology, School of Basic Sciences, Central University of Punjab, VPO - Ghudda, Bathinda, 151 401, Punjab, India
| | - Sharanjot Kaur
- Department of Microbiology, School of Basic Sciences, Central University of Punjab, Ghudda, Bathinda, Punjab, India
| | - Priyanka Jeeth
- Department of Computational Sciences, School of Basic Sciences, Central University of Punjab, Ghudda, Bathinda, Punjab, India
| | - Puneet Kumar
- Department of Pharmacology, Central University of Punjab, Ghudda, Bathinda, Punjab, India
| | - Saraboji Kadhirvel
- Department of Computational Sciences, School of Basic Sciences, Central University of Punjab, Ghudda, Bathinda, Punjab, India
| | - Monisha Dhiman
- Department of Microbiology, School of Basic Sciences, Central University of Punjab, Ghudda, Bathinda, Punjab, India
| | - Anil Kumar Mantha
- Department of Zoology, School of Basic Sciences, Central University of Punjab, VPO - Ghudda, Bathinda, 151 401, Punjab, India.
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17
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Wang HD, Lv CL, Feng L, Guo JX, Zhao SY, Jiang P. The role of autophagy in brain health and disease: Insights into exosome and autophagy interactions. Heliyon 2024; 10:e38959. [PMID: 39524893 PMCID: PMC11546156 DOI: 10.1016/j.heliyon.2024.e38959] [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: 09/21/2023] [Revised: 09/27/2024] [Accepted: 10/03/2024] [Indexed: 11/16/2024] Open
Abstract
Effective management of cellular components is essential for maintaining brain health, and studies have identified several crucial biological processes in the brain. Among these, autophagy and the role of exosomes in cellular communication are critical for brain health and disease. The interaction between autophagy and exosomes in the nervous system, as well as their contributions to brain damage, have garnered significant attention. This review summarizes that exosomes and their cargoes have been implicated in the autophagy process in the pathophysiology of nervous system diseases. Furthermore, the onset and progression of neurological disorders may be affected by autophagy regulation of the secretion and release of exosomes. These findings may provide new insights into the potential mechanism by which autophagy mediates different exosome secretion and release, as well as the valuable biomedical applications of exosomes in the prevention and treatment of various brain diseases by targeting autophagy.
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Affiliation(s)
- Hai-Dong Wang
- Department of Pharmacy, The Affiliated Lianyungang Hospital of Xuzhou Medical University/Nanjing Medical University Kangda College First Affiliated Hospital/The First People's Hospital of Lianyungang, Lianyungang, 222000, China
| | - Chao-Liang Lv
- Department of Spine Surgery, Jining First People's Hospital, Shandong First Medical University, Jining, 272000, China
| | - Lei Feng
- Department of Neurosurgery, Jining First People's Hospital, Shandong First Medical University, Jining, 272000, China
| | - Jin-Xiu Guo
- Translational Pharmaceutical Laboratory, Jining First People's Hospital, Shandong First Medical University, Jining, 272000, China
- Institute of Translational Pharmacy, Jining Medical Research Academy, Jining, 272000, China
| | - Shi-Yuan Zhao
- Translational Pharmaceutical Laboratory, Jining First People's Hospital, Shandong First Medical University, Jining, 272000, China
- Institute of Translational Pharmacy, Jining Medical Research Academy, Jining, 272000, China
| | - Pei Jiang
- Translational Pharmaceutical Laboratory, Jining First People's Hospital, Shandong First Medical University, Jining, 272000, China
- Institute of Translational Pharmacy, Jining Medical Research Academy, Jining, 272000, China
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18
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Shanmugam I, Radhakrishnan S, Santosh S, Ramnath A, Anil M, Devarajan Y, Maheswaran S, Narayanan V, Pitchaimani A. Emerging role and translational potential of small extracellular vesicles in neuroscience. Life Sci 2024; 355:122987. [PMID: 39151884 DOI: 10.1016/j.lfs.2024.122987] [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: 04/26/2024] [Revised: 08/08/2024] [Accepted: 08/13/2024] [Indexed: 08/19/2024]
Abstract
Small extracellular vesicles (sEV) are endogenous lipid-bound membrane vesicles secreted by both prokaryotic and eukaryotic cells into the extracellular environment, performs several biological functions such as cell-cell communication, transfer of proteins, mRNA, and ncRNA to target cells in distant sites. Due to their role in molecular pathogenesis and its potential to deliver biological cargo to target cells, it has become a prominent area of interest in recent research in the field of Neuroscience. However, their role in neurological disorders, like neurodegenerative diseases is more complex and still unaddressed. Thus, this review focuses on the role of sEV in neurodegenerative and neurodevelopmental diseases, including their biogenesis, classification, and pathogenesis, with translational advantages and limitations in the area of neurobiology.
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Affiliation(s)
- Iswarya Shanmugam
- Precision Nanomedicine and Microfluidic Lab, Centre for Biomaterials, Cellular and Molecular Theranostics (CBCMT), Vellore Institute of Technology, Vellore. TN, India; School of Biosciences and Technology, Vellore Institute of Technology, Vellore Campus, Tiruvalam Rd, Katpadi, Vellore, Tamil Nadu 632014, India
| | - Sivani Radhakrishnan
- School of Biosciences and Technology, Vellore Institute of Technology, Vellore Campus, Tiruvalam Rd, Katpadi, Vellore, Tamil Nadu 632014, India
| | - Shradha Santosh
- School of Biosciences and Technology, Vellore Institute of Technology, Vellore Campus, Tiruvalam Rd, Katpadi, Vellore, Tamil Nadu 632014, India
| | - Akansha Ramnath
- School of Biosciences and Technology, Vellore Institute of Technology, Vellore Campus, Tiruvalam Rd, Katpadi, Vellore, Tamil Nadu 632014, India
| | - Meghna Anil
- School of Biosciences and Technology, Vellore Institute of Technology, Vellore Campus, Tiruvalam Rd, Katpadi, Vellore, Tamil Nadu 632014, India
| | - Yogesh Devarajan
- Precision Nanomedicine and Microfluidic Lab, Centre for Biomaterials, Cellular and Molecular Theranostics (CBCMT), Vellore Institute of Technology, Vellore. TN, India; School of Biosciences and Technology, Vellore Institute of Technology, Vellore Campus, Tiruvalam Rd, Katpadi, Vellore, Tamil Nadu 632014, India
| | - Saravanakumar Maheswaran
- Precision Nanomedicine and Microfluidic Lab, Centre for Biomaterials, Cellular and Molecular Theranostics (CBCMT), Vellore Institute of Technology, Vellore. TN, India; School of Biosciences and Technology, Vellore Institute of Technology, Vellore Campus, Tiruvalam Rd, Katpadi, Vellore, Tamil Nadu 632014, India
| | - Vaibav Narayanan
- Precision Nanomedicine and Microfluidic Lab, Centre for Biomaterials, Cellular and Molecular Theranostics (CBCMT), Vellore Institute of Technology, Vellore. TN, India; School of Biosciences and Technology, Vellore Institute of Technology, Vellore Campus, Tiruvalam Rd, Katpadi, Vellore, Tamil Nadu 632014, India
| | - Arunkumar Pitchaimani
- Precision Nanomedicine and Microfluidic Lab, Centre for Biomaterials, Cellular and Molecular Theranostics (CBCMT), Vellore Institute of Technology, Vellore. TN, India; School of Biosciences and Technology, Vellore Institute of Technology, Vellore Campus, Tiruvalam Rd, Katpadi, Vellore, Tamil Nadu 632014, India.
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Abid AI, Conzatti G, Toti F, Anton N, Vandamme T. Mesenchymal stem cell-derived exosomes as cell free nanotherapeutics and nanocarriers. NANOMEDICINE : NANOTECHNOLOGY, BIOLOGY, AND MEDICINE 2024; 61:102769. [PMID: 38914247 DOI: 10.1016/j.nano.2024.102769] [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: 02/27/2024] [Revised: 05/18/2024] [Accepted: 06/20/2024] [Indexed: 06/26/2024]
Abstract
Many strategies for regenerating the damaged tissues or degenerating cells are employed in regenerative medicine. Stem cell technology is a modern strategy of the recent approaches, particularly the use of mesenchymal stem cells (MCSs). The ability of MSCs to differentiate as well as their characteristic behaviour as paracrine effector has established them as key elements in tissue repair. Recently, extracellular vesicles (EVs) shed by MSCs have emerged as a promising cell free therapy. This comprehensive review encompasses MSCs-derived exosomes and their therapeutic potential as nanotherapeutics. We also discuss their potency as drug delivery nano-carriers in comparison with liposomes. A better knowledge of EVs behaviour in vivo and of their mechanism of action are key to determine parameters of an optimal formulation in pilot studies and to establish industrial processes.
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Affiliation(s)
- Ali Imran Abid
- UMR 1260, Regenerative Nanomedicine (RNM), INSERM (French National Institute of Health and Medical Research), University of Strasbourg, F-67000 Strasbourg, France
| | - Guillaume Conzatti
- UMR 1260, Regenerative Nanomedicine (RNM), INSERM (French National Institute of Health and Medical Research), University of Strasbourg, F-67000 Strasbourg, France; Faculty of Pharmacy, University of Strasbourg, 67400 Illkirch-Graffenstaden, France.
| | - Florence Toti
- UMR 1260, Regenerative Nanomedicine (RNM), INSERM (French National Institute of Health and Medical Research), University of Strasbourg, F-67000 Strasbourg, France; Faculty of Pharmacy, University of Strasbourg, 67400 Illkirch-Graffenstaden, France
| | - Nicolas Anton
- UMR 1260, Regenerative Nanomedicine (RNM), INSERM (French National Institute of Health and Medical Research), University of Strasbourg, F-67000 Strasbourg, France; Faculty of Pharmacy, University of Strasbourg, 67400 Illkirch-Graffenstaden, France
| | - Thierry Vandamme
- UMR 1260, Regenerative Nanomedicine (RNM), INSERM (French National Institute of Health and Medical Research), University of Strasbourg, F-67000 Strasbourg, France; Faculty of Pharmacy, University of Strasbourg, 67400 Illkirch-Graffenstaden, France.
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20
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Zhang W, Uyemura R, Zhong K, Guo R, Zhong L. Current Advances and Future Perspectives on Mesenchymal Stem Cell-Derived Extracellular Vesicles in Alzheimer's Disease. Aging Dis 2024; 15:2015-2027. [PMID: 38270122 PMCID: PMC11346404 DOI: 10.14336/ad.2023.1206] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Accepted: 12/06/2023] [Indexed: 01/26/2024] Open
Abstract
The incidence of Alzheimer's disease (AD) has been increasing in recent years as the world's population ages, which poses a significant challenge to public health. Due to the complexity of pathogenesis of AD, currently there is no effective treatment for it. In recent years, cell and gene therapy has attracted widespread attention in the treatment of neurodegenerative diseases. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) represent a novel cell-free therapy with numerous advantages over cell-based therapies owing to their low immunogenicity and high safety profile. We summarize recent progress in the application of EVs for treating AD and the specific mechanisms and outline the underlying mechanisms. We also explore various methods for optimizing the function of MSC-EVs, including gene editing, modifying stem cell culture conditions and peptide modification. In addition, we discuss the therapeutic potentials of MSC-EVs, as well as the obstacles that currently impede their clinical utilization.
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Affiliation(s)
- Wenjing Zhang
- College of Life Sciences, Institute of Life Science and Green Development, Hebei University, Baoding 071002, China
| | - Russell Uyemura
- College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, California 91766, USA
| | - Kun Zhong
- American Center of Stem Cell Research and Regenerative Medicine, Farmington Hills, Michigan 48336, USA
| | - Rui Guo
- College of Life Sciences, Institute of Life Science and Green Development, Hebei University, Baoding 071002, China
| | - Li Zhong
- College of Life Sciences, Institute of Life Science and Green Development, Hebei University, Baoding 071002, China
- College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, California 91766, USA
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21
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Deng H, Zhao J, Li J, Chen C, Hu Z, Wu X, Ge L. Therapeutic Efficacy of Extracellular Vesicles Derived from Stem Cell for Alzheimer's Disease: A Meta-Analysis Study. FRONT BIOSCI-LANDMRK 2024; 29:340. [PMID: 39344329 DOI: 10.31083/j.fbl2909340] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Revised: 07/29/2024] [Accepted: 08/06/2024] [Indexed: 10/01/2024]
Abstract
BACKGROUND Alzheimer's disease (AD) poses a significant public health challenge, increasingly affecting patients' finances, mental health, and functional abilities as the global population ages. Stem cell-derived extracellular vesicles (SC-EVs) have emerged as a promising cell-free therapeutic approach for AD, although their precise mechanisms remain unclear. This meta-analysis aims to evaluate the effectiveness of SC-EVs in treating AD. METHODS We systematically searched PubMed, EMBASE, and Web of Science databases up to December 31, 2023, identifying studies investigating SC-EVs therapy in AD rodent models. Outcome measures included Morris water maze and Y maze tests, β-amyloid pathology, and inflammatory markers. Statistical analyses utilized Stata 15.1 and R software. RESULTS This meta-analysis of 16 studies (2017-2023, 314 animals) demonstrates significant efficacy of SC-EVs therapy in AD models. Pooled analyses demonstrated that SC-EVs therapy significantly increased the learning function as measured by Morris water maze tests (MWM) by -1.83 (95% CI = -2.51 to -1.15, p < 0.0001), Y maze test by 1.66 (95% CI = 1.03 to 2.28, p < 0.0001), decreased Aβ plaques in the hippocampal by -2.10 (95% CI = -2.96 to -1.23, p < 0.0001), and proinflammatory cytokines Tumor necrosis factor alpha (TNFα) by -2.61 (95% CI = -4.87 to -0.35, p < 0.05), Interleukin-1 beta (IL-1β) by -2.37 (95% CI = -3.68 to -1.05, p < 0.001). CONCLUSIONS SC-EVs therapy shows promise in enhancing cognitive function and mitigating AD progression in preclinical models. Future research should focus on standardizing methodologies and comparing SC-EVs isolation techniques and dosing strategies to facilitate clinical translation.
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Affiliation(s)
- Huiyin Deng
- Department of Neurology, The Second Xiangya Hospital, Central South University, 410011 Changsha, Hunan, China
- Department of Anesthesiology, The Third Xiangya Hospital, Central South University, 410011 Changsha, Hunan, China
| | - Jing Zhao
- Department of Neurology, The Second Xiangya Hospital, Central South University, 410011 Changsha, Hunan, China
- Clinical Medical Research Center for Stroke Prevention and Treatment of Hunan Province, Department of Neurology, The Second Xiangya Hospital, Central South University, 410011 Changsha, Hunan, China
| | - Jiuyi Li
- Department of Anesthesiology, the Fouth People's Hospital of Changsha, 410006 Changsha, Hunan, China
| | - Chunli Chen
- Department of Neurology, The Second Xiangya Hospital, Central South University, 410011 Changsha, Hunan, China
- Clinical Medical Research Center for Stroke Prevention and Treatment of Hunan Province, Department of Neurology, The Second Xiangya Hospital, Central South University, 410011 Changsha, Hunan, China
| | - Zhiping Hu
- Department of Neurology, The Second Xiangya Hospital, Central South University, 410011 Changsha, Hunan, China
- Clinical Medical Research Center for Stroke Prevention and Treatment of Hunan Province, Department of Neurology, The Second Xiangya Hospital, Central South University, 410011 Changsha, Hunan, China
| | - Xiaomei Wu
- Department of Neurology, The Second Xiangya Hospital, Central South University, 410011 Changsha, Hunan, China
- Clinical Medical Research Center for Stroke Prevention and Treatment of Hunan Province, Department of Neurology, The Second Xiangya Hospital, Central South University, 410011 Changsha, Hunan, China
| | - Lite Ge
- Department of Neurology, The Second Xiangya Hospital, Central South University, 410011 Changsha, Hunan, China
- Clinical Medical Research Center for Stroke Prevention and Treatment of Hunan Province, Department of Neurology, The Second Xiangya Hospital, Central South University, 410011 Changsha, Hunan, China
- Hunan Provincial Key Laboratory of Neurorestoratology, the Second Affiliated Hospital, Hunan Normal University, 410003 Changsha, Hunan, China
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Bhatt A, Bhardwaj H, Srivastava P. Mesenchymal stem cell therapy for Alzheimer's disease: A novel therapeutic approach for neurodegenerative diseases. Neuroscience 2024; 555:52-68. [PMID: 39032806 DOI: 10.1016/j.neuroscience.2024.07.019] [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: 04/22/2024] [Revised: 07/10/2024] [Accepted: 07/11/2024] [Indexed: 07/23/2024]
Abstract
Alzheimer's disease (AD) is one of the most progressive and prevalent types of neurodegenerative diseases in the aging population (aged >65 years) and is considered a major factor for dementia, affecting 55 million people worldwide. In the current scenario, drug-based therapies have been employed for the treatment of Alzheimer's disease but are only able to provide symptomatic relief to patients rather than a permanent solution from Alzheimer's. Recent advancements in stem cell research unlock new horizons for developing effective and highly potential therapeutic approaches due to their self-renewal, self-replicating, regenerative, and high differentiation capabilities. Stem cells come in multiple lineages such as embryonic, neural, and induced pluripotent, among others. Among different kinds of stem cells, mesenchymal stem cells are the most investigated for Alzheimer's treatment due to their multipotent nature, low immunogenicity, ability to penetrate the blood-brain barrier, and low risk of tumorigenesis, immune & inflammatory modulation, etc. They have been seen to substantially promote neurogenesis, synaptogenesis by secreting neurotrophic growth factors, as well as in ameliorating the Aβ and tau-mediated toxicity. This review covers the pathophysiology of AD, new medications, and therapies. Further, it will focus on the advancements and benefits of Mesenchymal Stem Cell therapies, their administration methods, clinical trials concerning AD progression, along with their future prospective.
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Affiliation(s)
- Aditya Bhatt
- Department of Biosciences, Institute of Management Studies Ghaziabad (University Courses Campus), NH09, Adhyatmik Nagar, Ghaziabad, Uttar Pradesh, India
| | - Harshita Bhardwaj
- Department of Biosciences, Institute of Management Studies Ghaziabad (University Courses Campus), NH09, Adhyatmik Nagar, Ghaziabad, Uttar Pradesh, India
| | - Priyanka Srivastava
- Department of Biosciences, Institute of Management Studies Ghaziabad (University Courses Campus), NH09, Adhyatmik Nagar, Ghaziabad, Uttar Pradesh, India.
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23
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Putthanbut N, Lee JY, Borlongan CV. Extracellular vesicle therapy in neurological disorders. J Biomed Sci 2024; 31:85. [PMID: 39183263 PMCID: PMC11346291 DOI: 10.1186/s12929-024-01075-w] [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: 06/17/2024] [Accepted: 08/16/2024] [Indexed: 08/27/2024] Open
Abstract
Extracellular vesicles (EVs) are vital for cell-to-cell communication, transferring proteins, lipids, and nucleic acids in various physiological and pathological processes. They play crucial roles in immune modulation and tissue regeneration but are also involved in pathogenic conditions like inflammation and degenerative disorders. EVs have heterogeneous populations and cargo, with numerous subpopulations currently under investigations. EV therapy shows promise in stimulating tissue repair and serving as a drug delivery vehicle, offering advantages over cell therapy, such as ease of engineering and minimal risk of tumorigenesis. However, challenges remain, including inconsistent nomenclature, complex characterization, and underdeveloped large-scale production protocols. This review highlights the recent advances and significance of EVs heterogeneity, emphasizing the need for a better understanding of their roles in disease pathologies to develop tailored EV therapies for clinical applications in neurological disorders.
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Affiliation(s)
- Napasiri Putthanbut
- Department of Neurosurgery, Center of Aging and Brain Repair, University of South Florida, Tampa, USA
- Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Salaya, Thailand
| | - Jea Young Lee
- Department of Neurosurgery, Center of Aging and Brain Repair, University of South Florida, Tampa, USA
| | - Cesario V Borlongan
- Department of Neurosurgery, Center of Aging and Brain Repair, University of South Florida, Tampa, USA.
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24
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Zanirati G, dos Santos PG, Alcará AM, Bruzzo F, Ghilardi IM, Wietholter V, Xavier FAC, Gonçalves JIB, Marinowic D, Shetty AK, da Costa JC. Extracellular Vesicles: The Next Generation of Biomarkers and Treatment for Central Nervous System Diseases. Int J Mol Sci 2024; 25:7371. [PMID: 39000479 PMCID: PMC11242541 DOI: 10.3390/ijms25137371] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Revised: 05/22/2024] [Accepted: 05/23/2024] [Indexed: 07/16/2024] Open
Abstract
It has been widely established that the characterization of extracellular vesicles (EVs), particularly small EVs (sEVs), shed by different cell types into biofluids, helps to identify biomarkers and therapeutic targets in neurological and neurodegenerative diseases. Recent studies are also exploring the efficacy of mesenchymal stem cell-derived extracellular vesicles naturally enriched with therapeutic microRNAs and proteins for treating various diseases. In addition, EVs released by various neural cells play a crucial function in the modulation of signal transmission in the brain in physiological conditions. However, in pathological conditions, such EVs can facilitate the spread of pathological proteins from one brain region to the other. On the other hand, the analysis of EVs in biofluids can identify sensitive biomarkers for diagnosis, prognosis, and disease progression. This review discusses the potential therapeutic use of stem cell-derived EVs in several central nervous system diseases. It lists their differences and similarities and confers various studies exploring EVs as biomarkers. Further advances in EV research in the coming years will likely lead to the routine use of EVs in therapeutic settings.
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Affiliation(s)
- Gabriele Zanirati
- Brain Institute of Rio Grande do Sul (BraIns), Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre 90610-000, RS, Brazil; (P.G.d.S.); (F.B.); (I.M.G.); (V.W.); (F.A.C.X.); (J.I.B.G.); (D.M.); (J.C.d.C.)
| | - Paula Gabrielli dos Santos
- Brain Institute of Rio Grande do Sul (BraIns), Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre 90610-000, RS, Brazil; (P.G.d.S.); (F.B.); (I.M.G.); (V.W.); (F.A.C.X.); (J.I.B.G.); (D.M.); (J.C.d.C.)
| | - Allan Marinho Alcará
- Brain Institute of Rio Grande do Sul (BraIns), Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre 90610-000, RS, Brazil; (P.G.d.S.); (F.B.); (I.M.G.); (V.W.); (F.A.C.X.); (J.I.B.G.); (D.M.); (J.C.d.C.)
| | - Fernanda Bruzzo
- Brain Institute of Rio Grande do Sul (BraIns), Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre 90610-000, RS, Brazil; (P.G.d.S.); (F.B.); (I.M.G.); (V.W.); (F.A.C.X.); (J.I.B.G.); (D.M.); (J.C.d.C.)
| | - Isadora Machado Ghilardi
- Brain Institute of Rio Grande do Sul (BraIns), Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre 90610-000, RS, Brazil; (P.G.d.S.); (F.B.); (I.M.G.); (V.W.); (F.A.C.X.); (J.I.B.G.); (D.M.); (J.C.d.C.)
| | - Vinicius Wietholter
- Brain Institute of Rio Grande do Sul (BraIns), Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre 90610-000, RS, Brazil; (P.G.d.S.); (F.B.); (I.M.G.); (V.W.); (F.A.C.X.); (J.I.B.G.); (D.M.); (J.C.d.C.)
| | - Fernando Antônio Costa Xavier
- Brain Institute of Rio Grande do Sul (BraIns), Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre 90610-000, RS, Brazil; (P.G.d.S.); (F.B.); (I.M.G.); (V.W.); (F.A.C.X.); (J.I.B.G.); (D.M.); (J.C.d.C.)
| | - João Ismael Budelon Gonçalves
- Brain Institute of Rio Grande do Sul (BraIns), Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre 90610-000, RS, Brazil; (P.G.d.S.); (F.B.); (I.M.G.); (V.W.); (F.A.C.X.); (J.I.B.G.); (D.M.); (J.C.d.C.)
| | - Daniel Marinowic
- Brain Institute of Rio Grande do Sul (BraIns), Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre 90610-000, RS, Brazil; (P.G.d.S.); (F.B.); (I.M.G.); (V.W.); (F.A.C.X.); (J.I.B.G.); (D.M.); (J.C.d.C.)
| | - Ashok K. Shetty
- Institute for Regenerative Medicine, Department of Cell Biology and Genetics, Texas A&M University School of Medicine, College Station, TX 77807, USA;
| | - Jaderson Costa da Costa
- Brain Institute of Rio Grande do Sul (BraIns), Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre 90610-000, RS, Brazil; (P.G.d.S.); (F.B.); (I.M.G.); (V.W.); (F.A.C.X.); (J.I.B.G.); (D.M.); (J.C.d.C.)
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25
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Cabrera-Pastor A. Extracellular Vesicles as Mediators of Neuroinflammation in Intercellular and Inter-Organ Crosstalk. Int J Mol Sci 2024; 25:7041. [PMID: 39000150 PMCID: PMC11241119 DOI: 10.3390/ijms25137041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Revised: 06/20/2024] [Accepted: 06/22/2024] [Indexed: 07/16/2024] Open
Abstract
Neuroinflammation, crucial in neurological disorders like Alzheimer's disease, multiple sclerosis, and hepatic encephalopathy, involves complex immune responses. Extracellular vesicles (EVs) play a pivotal role in intercellular and inter-organ communication, influencing disease progression. EVs serve as key mediators in the immune system, containing molecules capable of activating molecular pathways that exacerbate neuroinflammatory processes in neurological disorders. However, EVs from mesenchymal stem cells show promise in reducing neuroinflammation and cognitive deficits. EVs can cross CNS barriers, and peripheral immune signals can influence brain function via EV-mediated communication, impacting barrier function and neuroinflammatory responses. Understanding EV interactions within the brain and other organs could unveil novel therapeutic targets for neurological disorders.
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Affiliation(s)
- Andrea Cabrera-Pastor
- Departamento de Farmacología, Facultad de Medicina y Odontología, Universitat de València, 46010 Valencia, Spain; or
- Fundación de Investigación del Hospital Clínico Universitario de Valencia, INCLIVA, 46010 Valencia, Spain
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26
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Sun M, Chen Z. Unveiling the Complex Role of Exosomes in Alzheimer's Disease. J Inflamm Res 2024; 17:3921-3948. [PMID: 38911990 PMCID: PMC11193473 DOI: 10.2147/jir.s466821] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Accepted: 06/11/2024] [Indexed: 06/25/2024] Open
Abstract
Alzheimer's disease (AD) is the most common neurodegenerative illness, characterized by memory loss and cognitive decline, accounting for 60-80% of dementia cases. AD is characterized by senile plaques made up of amyloid β (Aβ) protein, intracellular neurofibrillary tangles caused by hyperphosphorylation of tau protein linked with microtubules, and neuronal loss. Currently, therapeutic treatments and nanotechnological developments are effective in treating the symptoms of AD, but a cure for the illness has not yet been found. Recently, the increased study of extracellular vesicles (EVs) has led to a growing awareness of their significant involvement in neurodegenerative disorders, including AD. Exosomes are small extracellular vesicles that transport various components including messenger RNAs, non-coding RNAs, proteins, lipids, DNA, and other bioactive compounds from one cell to another, facilitating information transmission and material movement. There is growing evidence indicating that exosomes have complex functions in AD. Exosomes may have a dual role in Alzheimer's disease by contributing to neuronal death and also helping to alleviate the pathological progression of the disease. Therefore, the primary aim of this review is to outline the updated understandings on exosomes biogenesis and many functions of exosomes in the generation, conveyance, distribution, and elimination of hazardous proteins related to Alzheimer's disease. This review is intended to provide novel insights for understanding the development, specific treatment, and early detection of Alzheimer's disease.
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Affiliation(s)
- Mingyue Sun
- Department of Neurology, The Affiliated Changzhou No. 2 People’s Hospital of Nanjing Medical University, Changzhou, 213000, People’s Republic of China
| | - Zhuoyou Chen
- Department of Neurology, The Affiliated Changzhou No. 2 People’s Hospital of Nanjing Medical University, Changzhou, 213000, People’s Republic of China
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27
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Jang E, Yu H, Kim E, Hwang J, Yoo J, Choi J, Jeong HS, Jang S. The Therapeutic Effects of Blueberry-Treated Stem Cell-Derived Extracellular Vesicles in Ischemic Stroke. Int J Mol Sci 2024; 25:6362. [PMID: 38928069 PMCID: PMC11203670 DOI: 10.3390/ijms25126362] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Revised: 05/23/2024] [Accepted: 06/04/2024] [Indexed: 06/28/2024] Open
Abstract
An ischemic stroke, one of the leading causes of morbidity and mortality, is caused by ischemia and hemorrhage resulting in impeded blood supply to the brain. According to many studies, blueberries have been shown to have a therapeutic effect in a variety of diseases. Therefore, in this study, we investigated whether blueberry-treated mesenchymal stem cell (MSC)-derived extracellular vesicles (B-EVs) have therapeutic effects in in vitro and in vivo stroke models. We isolated the extracellular vesicles using cryo-TEM and characterized the particles and concentrations using NTA. MSC-derived extracellular vesicles (A-EVs) and B-EVs were round with a lipid bilayer structure and a diameter of ~150 nm. In addition, A-EVs and B-EVs were shown to affect angiogenesis, cell cycle, differentiation, DNA repair, inflammation, and neurogenesis following KEGG pathway and GO analyses. We investigated the protective effects of A-EVs and B-EVs against neuronal cell death in oxygen-glucose deprivation (OGD) cells and a middle cerebral artery occlusion (MCAo) animal model. The results showed that the cell viability was increased with EV treatment in HT22 cells. In the animal, the size of the cerebral infarction was decreased, and the behavioral assessment was improved with EV injections. The levels of NeuN and neurofilament heavy chain (NFH)-positive cells were also increased with EV treatment yet decreased in the MCAo group. In addition, the number of apoptotic cells was decreased with EV treatment compared with ischemic animals following TUNEL and Bax/Bcl-2 staining. These data suggested that EVs, especially B-EVs, had a therapeutic effect and could reduce apoptotic cell death after ischemic injury.
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Affiliation(s)
- Eunjae Jang
- Department of Physiology, Chonnam National University Medical School, Hwasun-gun 58128, Republic of Korea; (E.J.); (H.Y.); (J.H.); (J.C.)
- Jeonnam Bioindustry Foundation Biopharmaceutical Research Center, Hwasun-gun 58141, Republic of Korea
| | - Hee Yu
- Department of Physiology, Chonnam National University Medical School, Hwasun-gun 58128, Republic of Korea; (E.J.); (H.Y.); (J.H.); (J.C.)
- Jeonnam Bioindustry Foundation Biopharmaceutical Research Center, Hwasun-gun 58141, Republic of Korea
| | - Eungpil Kim
- Infrastructure Project Organization for Global Industrialization of Vaccine, Sejong-si 30121, Republic of Korea;
| | - Jinsu Hwang
- Department of Physiology, Chonnam National University Medical School, Hwasun-gun 58128, Republic of Korea; (E.J.); (H.Y.); (J.H.); (J.C.)
| | - Jin Yoo
- Department of Physical Education, Chonnam National University, Gwangju 61186, Republic of Korea;
| | - Jiyun Choi
- Department of Physiology, Chonnam National University Medical School, Hwasun-gun 58128, Republic of Korea; (E.J.); (H.Y.); (J.H.); (J.C.)
| | - Han-Seong Jeong
- Department of Physiology, Chonnam National University Medical School, Hwasun-gun 58128, Republic of Korea; (E.J.); (H.Y.); (J.H.); (J.C.)
| | - Sujeong Jang
- Department of Physiology, Chonnam National University Medical School, Hwasun-gun 58128, Republic of Korea; (E.J.); (H.Y.); (J.H.); (J.C.)
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28
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Ding Z, Greenberg ZF, Serafim MF, Ali S, Jamieson JC, Traktuev DO, March K, He M. Understanding molecular characteristics of extracellular vesicles derived from different types of mesenchymal stem cells for therapeutic translation. EXTRACELLULAR VESICLE 2024; 3:100034. [PMID: 38957857 PMCID: PMC11218754 DOI: 10.1016/j.vesic.2024.100034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 07/04/2024]
Abstract
Mesenchymal stem cells (MSCs) have been studied for decades as candidates for cellular therapy, and their secretome, including secreted extracellular vesicles (EVs), has been identified to contribute significantly to regenerative and reparative functions. Emerging evidence has suggested that MSC-EVs alone, could be used as therapeutics that emulate the biological function of MSCs. However, just as with MSCs, MSC-EVs have been shown to vary in composition, depending on the tissue source of the MSCs as well as the protocols employed in culturing the MSCs and obtaining the EVs. Therefore, the importance of careful choice of cell sources and culture environments is receiving increasing attention. Many factors contribute to the therapeutic potential of MSC-EVs, including the source tissue, isolation technique, and culturing conditions. This review illustrates the molecular landscape of EVs derived from different types of MSC cells along with culture strategies. A thorough analysis of publicly available omic datasets was performed to advance the precision understanding of MSC-EVs with unique tissue source-dependent molecular characteristics. The tissue-specific protein and miRNA-driven Reactome ontology analysis was used to reveal distinct patterns of top Reactome ontology pathways across adipose, bone marrow, and umbilical MSC-EVs. Moreover, a meta-analysis assisted by an AI technique was used to analyze the published literature, providing insights into the therapeutic translation of MSC-EVs based on their source tissues.
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Affiliation(s)
- Zuo Ding
- Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL, 32611, USA
| | - Zachary F. Greenberg
- Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL, 32611, USA
| | - Maria Fernanda Serafim
- Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL, 32611, USA
| | - Samantha Ali
- Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL, 32611, USA
| | - Julia C. Jamieson
- Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL, 32611, USA
| | - Dmitry O. Traktuev
- UF Center for Regenerative Medicine, Division of Cardiovascular Medicine, Department of Medicine, College of Medicine, University of Florida, Gainesville, FL, 32610, USA
| | - Keith March
- UF Center for Regenerative Medicine, Division of Cardiovascular Medicine, Department of Medicine, College of Medicine, University of Florida, Gainesville, FL, 32610, USA
| | - Mei He
- Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL, 32611, USA
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Rajendran K, Krishnan UM. Mechanistic insights and emerging therapeutic stratagems for Alzheimer's disease. Ageing Res Rev 2024; 97:102309. [PMID: 38615895 DOI: 10.1016/j.arr.2024.102309] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Revised: 04/10/2024] [Accepted: 04/10/2024] [Indexed: 04/16/2024]
Abstract
Alzheimer's disease (AD), a multi-factorial neurodegenerative disorder has affected over 30 million individuals globally and these numbers are expected to increase in the coming decades. Current therapeutic interventions are largely ineffective as they focus on a single target. Development of an effective drug therapy requires a deep understanding of the various factors influencing the onset and progression of the disease. Aging and genetic factors exert a major influence on the development of AD. Other factors like post-viral infections, iron overload, gut dysbiosis, and vascular dysfunction also exacerbate the onset and progression of AD. Further, post-translational modifications in tau, DRP1, CREB, and p65 proteins increase the disease severity through triggering mitochondrial dysfunction, synaptic loss, and differential interaction of amyloid beta with different receptors leading to impaired intracellular signalling. With advancements in neuroscience tools, new inter-relations that aggravate AD are being discovered including pre-existing diseases and exposure to other pathogens. Simultaneously, new therapeutic strategies involving modulation of gene expression through targeted delivery or modulation with light, harnessing the immune response to promote clearance of amyloid deposits, introduction of stem cells and extracellular vesicles to replace the destroyed neurons, exploring new therapeutic molecules from plant, marine and biological sources delivered in the free state or through nanoparticles and use of non-pharmacological interventions like music, transcranial stimulation and yoga. Polypharmacology approaches involving combination of therapeutic agents are also under active investigation for superior therapeutic outcomes. This review elaborates on various disease-causing factors, their underlying mechanisms, the inter-play between different disease-causing players, and emerging therapeutic options including those under clinical trials, for treatment of AD. The challenges involved in AD therapy and the way forward have also been discussed.
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Affiliation(s)
- Kayalvizhi Rajendran
- School of Chemical & Biotechnology, SASTRA Deemed University, Thanjavur, Tamilnadu 613401, India; Centre for Nanotechnology & Advanced Biomaterials, SASTRA Deemed University, Thanjavur, Tamilnadu 613401, India
| | - Uma Maheswari Krishnan
- School of Chemical & Biotechnology, SASTRA Deemed University, Thanjavur, Tamilnadu 613401, India; Centre for Nanotechnology & Advanced Biomaterials, SASTRA Deemed University, Thanjavur, Tamilnadu 613401, India; School of Arts, Sciences, Humanities & Education, SASTRA Deemed University, Thanjavur, Tamilnadu 613401, India.
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Liao HJ, Yang YP, Liu YH, Tseng HC, Huo TI, Chiou SH, Chang CH. Harnessing the potential of mesenchymal stem cells-derived exosomes in degenerative diseases. Regen Ther 2024; 26:599-610. [PMID: 39253597 PMCID: PMC11382214 DOI: 10.1016/j.reth.2024.08.001] [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: 06/28/2024] [Revised: 07/17/2024] [Accepted: 08/02/2024] [Indexed: 09/11/2024] Open
Abstract
Mesenchymal stem cells (MSCs) have gained attention as a promising therapeutic approach in both preclinical and clinical osteoarthritis (OA) settings. Various joint cell types, such as chondrocytes, synovial fibroblasts, osteoblasts, and tenocytes, can produce and release extracellular vesicles (EVs), which subsequently influence the biological activities of recipient cells. Recently, extracellular vesicles derived from mesenchymal stem cells (MSC-EVs) have shown the potential to modulate various physiological and pathological processes through the modulation of cellular differentiation, immune responses, and tissue repair. This review explores the roles and therapeutic potential of MSC-EVs in OA and rheumatoid arthritis, cardiovascular disease, age-related macular degeneration, Alzheimer's disease, and other degenerative diseases. Notably, we provide a comprehensive summary of exosome biogenesis, microRNA composition, mechanisms of intercellular transfer, and their evolving role in the highlight of exosome-based treatments in both preclinical and clinical avenues.
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Affiliation(s)
- Hsiu-Jung Liao
- Department of Medical Research, Far Eastern Memorial Hospital, New Taipei City, Taiwan
- Institute of Biopharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Yi-Ping Yang
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan
- School of Medicine, National Yang-Ming Chiao Tung University, Taipei, Taiwan
| | - Yu-Hao Liu
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan
- Department of Physical Medicine and Rehabilitation, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Huan-Chin Tseng
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Teh-Ia Huo
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- Institute of Pharmacology, National Yang-Ming Chiao Tung University, Taipei, Taiwan
| | - Shih-Hwa Chiou
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan
- School of Medicine, National Yang-Ming Chiao Tung University, Taipei, Taiwan
- Institute of Pharmacology, National Yang-Ming Chiao Tung University, Taipei, Taiwan
| | - Chih-Hung Chang
- Department of Orthopedic Surgery, Far Eastern Memorial Hospital, New Taipei City, Taiwan
- Graduate School of Biotechnology and Bioengineering, Yuan Ze University, Taoyuan City, Taiwan
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Wu YL, Lin ZJ, Li CC, Lin X, Shan SK, Guo B, Zheng MH, Wang Y, Li F, Yuan LQ. Adipose exosomal noncoding RNAs: Roles and mechanisms in metabolic diseases. Obes Rev 2024; 25:e13740. [PMID: 38571458 DOI: 10.1111/obr.13740] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 02/02/2024] [Accepted: 02/28/2024] [Indexed: 04/05/2024]
Abstract
Exosomes are extracellular vesicles, measuring 40-160 nm in diameter, that are released by many cell types and tissues, including adipose tissue. Exosomes are critical mediators of intercellular communication and their contents are complex and diverse. In recent years, accumulating evidence has proved that multiple adipose tissue-derived exosomal noncoding RNAs (ncRNAs), including microRNAs (miRNAs), long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs), play pivotal roles in the pathogenesis of diverse metabolic diseases, such as obesity. In this narrative review, we focus on the adipose tissue-derived exosomal ncRNAs, especially exosomal miRNAs, and their dysregulation in multiple types of metabolic diseases. A deeper understanding of the role of adipose tissue-derived exosomal ncRNAs may help provide new diagnostic and treatment methods for metabolic diseases.
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Affiliation(s)
- Yan-Lin Wu
- National Clinical Research Center for Metabolic Disease, Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Zheng-Jun Lin
- National Clinical Research Center for Metabolic Disease, Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Chang-Chun Li
- National Clinical Research Center for Metabolic Disease, Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Xiao Lin
- Department of Radiology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Su-Kang Shan
- National Clinical Research Center for Metabolic Disease, Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Bei Guo
- National Clinical Research Center for Metabolic Disease, Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Ming-Hui Zheng
- National Clinical Research Center for Metabolic Disease, Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yi Wang
- National Clinical Research Center for Metabolic Disease, Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Fuxingzi Li
- National Clinical Research Center for Metabolic Disease, Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Ling-Qing Yuan
- National Clinical Research Center for Metabolic Disease, Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
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Sarkar S, Patranabis S. Emerging Role of Extracellular Vesicles in Intercellular Communication in the Brain: Implications for Neurodegenerative Diseases and Therapeutics. Cell Biochem Biophys 2024; 82:379-398. [PMID: 38300375 DOI: 10.1007/s12013-024-01221-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Accepted: 01/17/2024] [Indexed: 02/02/2024]
Abstract
Extracellular vesicles (EVs) are minute lipid-bilayer sacs discharged by cells, encompassing a diverse array of proteins, nucleic acids, and lipids. The identification of EVs as pivotal agents in intercellular communication has sparked compelling research pathways in the realms of cell biology and neurodegenerative diseases. Utilizing EVs for medicinal reasons has garnered interest due to the adaptability of EV-mediated communication. EVs can be classified based on their physical characteristics, biochemical composition, or cell of origin following purification. This review delves into the primary sub-types of EVs, providing an overview of the biogenesis of each type. Additionally, it explores the diverse environmental conditions triggering EV release and the originating cells, including stem cells and those from the Central Nervous System. Within the brain, EVs play a pivotal role as essential mediators of intercellular communication, significantly impacting synaptic plasticity, brain development, and the etiology of neurological diseases. Their potential diagnostic and therapeutic applications in various brain-related conditions are underscored, given their ability to carry specific cargo. Specially engineered EVs hold promise for treating diverse diseases, including neurodegenerative disorders. This study primarily emphasizes the diagnostic and potential therapeutic uses of EVs in neurological disorders such as Alzheimer's Disease, Huntington's Disease, Parkinson's Disease, Amyotrophic Lateral Sclerosis, and Prions disease. It also summarizes innovative techniques for detecting EVs in the brain, suggesting that EVs could serve as non-invasive biomarkers for early detection, disease monitoring, and prognosis in neurological disorders.
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Zhang X, Kuang Q, Xu J, Lin Q, Chi H, Yu D. MSC-Based Cell Therapy in Neurological Diseases: A Concise Review of the Literature in Pre-Clinical and Clinical Research. Biomolecules 2024; 14:538. [PMID: 38785945 PMCID: PMC11117494 DOI: 10.3390/biom14050538] [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: 03/25/2024] [Revised: 04/17/2024] [Accepted: 04/22/2024] [Indexed: 05/25/2024] Open
Abstract
Mesenchymal stem cells (MSCs) are multipotent stromal cells with the ability to self-renew and multi-directional differentiation potential. Exogenously administered MSCs can migrate to damaged tissue sites and participate in the repair of damaged tissues. A large number of pre-clinical studies and clinical trials have demonstrated that MSCs have the potential to treat the abnormalities of congenital nervous system and neurodegenerative diseases. Therefore, MSCs hold great promise in the treatment of neurological diseases. Here, we summarize and highlight current progress in the understanding of the underlying mechanisms and strategies of MSC application in neurological diseases.
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Affiliation(s)
- Xiaorui Zhang
- University Key Laboratory for Integrated Chinese Traditional and Western Veterinary Medicine and Animal Healthcare in Fujian Province/Fujian Key Laboratory of Traditional Chinese Veterinary Medicine and Animal Health, Fujian Agriculture and Forestry University, Fuzhou 350002, China
| | - Qihong Kuang
- University Key Laboratory for Integrated Chinese Traditional and Western Veterinary Medicine and Animal Healthcare in Fujian Province/Fujian Key Laboratory of Traditional Chinese Veterinary Medicine and Animal Health, Fujian Agriculture and Forestry University, Fuzhou 350002, China
- College of Life Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002, China
| | - Jianguang Xu
- University Key Laboratory for Integrated Chinese Traditional and Western Veterinary Medicine and Animal Healthcare in Fujian Province/Fujian Key Laboratory of Traditional Chinese Veterinary Medicine and Animal Health, Fujian Agriculture and Forestry University, Fuzhou 350002, China
| | - Qing Lin
- University Key Laboratory for Integrated Chinese Traditional and Western Veterinary Medicine and Animal Healthcare in Fujian Province/Fujian Key Laboratory of Traditional Chinese Veterinary Medicine and Animal Health, Fujian Agriculture and Forestry University, Fuzhou 350002, China
| | - Haoming Chi
- University Key Laboratory for Integrated Chinese Traditional and Western Veterinary Medicine and Animal Healthcare in Fujian Province/Fujian Key Laboratory of Traditional Chinese Veterinary Medicine and Animal Health, Fujian Agriculture and Forestry University, Fuzhou 350002, China
| | - Daojin Yu
- University Key Laboratory for Integrated Chinese Traditional and Western Veterinary Medicine and Animal Healthcare in Fujian Province/Fujian Key Laboratory of Traditional Chinese Veterinary Medicine and Animal Health, Fujian Agriculture and Forestry University, Fuzhou 350002, China
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Alzahrani FA, Riza YM, Eid TM, Almotairi R, Scherschinski L, Contreras J, Nadeem M, Perez SE, Raikwar SP, Jha RM, Preul MC, Ducruet AF, Lawton MT, Bhatia K, Akhter N, Ahmad S. Exosomes in Vascular/Neurological Disorders and the Road Ahead. Cells 2024; 13:670. [PMID: 38667285 PMCID: PMC11049650 DOI: 10.3390/cells13080670] [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: 03/22/2024] [Revised: 04/05/2024] [Accepted: 04/09/2024] [Indexed: 04/28/2024] Open
Abstract
Neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), stroke, and aneurysms, are characterized by the abnormal accumulation and aggregation of disease-causing proteins in the brain and spinal cord. Recent research suggests that proteins linked to these conditions can be secreted and transferred among cells using exosomes. The transmission of abnormal protein buildup and the gradual degeneration in the brains of impacted individuals might be supported by these exosomes. Furthermore, it has been reported that neuroprotective functions can also be attributed to exosomes in neurodegenerative diseases. The potential neuroprotective functions may play a role in preventing the formation of aggregates and abnormal accumulation of proteins associated with the disease. The present review summarizes the roles of exosomes in neurodegenerative diseases as well as elucidating their therapeutic potential in AD, PD, ALS, HD, stroke, and aneurysms. By elucidating these two aspects of exosomes, valuable insights into potential therapeutic targets for treating neurodegenerative diseases may be provided.
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Affiliation(s)
- Faisal A. Alzahrani
- Department of Biochemistry, King Fahad Center for Medical Research, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Yasir M. Riza
- Department of Biochemistry, King Fahad Center for Medical Research, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Thamir M. Eid
- Department of Biochemistry, King Fahad Center for Medical Research, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Reema Almotairi
- Department of Medical Laboratory Technology, Prince Fahad bin Sultan Chair for Biomedical Research, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk 71491, Saudi Arabia
| | - Lea Scherschinski
- Department of Translational Neuroscience, Barrow Neurological Institute, St Joseph’s Hospital and Medical Center, Phoenix, AZ 85013, USA (J.C.)
| | - Jessica Contreras
- Department of Translational Neuroscience, Barrow Neurological Institute, St Joseph’s Hospital and Medical Center, Phoenix, AZ 85013, USA (J.C.)
| | - Muhammed Nadeem
- Department of Translational Neuroscience, Barrow Neurological Institute, St Joseph’s Hospital and Medical Center, Phoenix, AZ 85013, USA (J.C.)
| | - Sylvia E. Perez
- Department of Translational Neuroscience, Barrow Neurological Institute, St Joseph’s Hospital and Medical Center, Phoenix, AZ 85013, USA (J.C.)
| | - Sudhanshu P. Raikwar
- Department of Translational Neuroscience, Barrow Neurological Institute, St Joseph’s Hospital and Medical Center, Phoenix, AZ 85013, USA (J.C.)
| | - Ruchira M. Jha
- Department of Neurology, Barrow Neurological Institute, St Joseph’s Hospital and Medical Center, Phoenix, AZ 85013, USA
| | - Mark C. Preul
- Department of Neurosurgery, Barrow Neurological Institute, St Joseph’s Hospital and Medical Center, Phoenix, AZ 85013, USA
| | - Andrew F. Ducruet
- Department of Neurosurgery, Barrow Neurological Institute, St Joseph’s Hospital and Medical Center, Phoenix, AZ 85013, USA
| | - Michael T. Lawton
- Department of Neurosurgery, Barrow Neurological Institute, St Joseph’s Hospital and Medical Center, Phoenix, AZ 85013, USA
| | - Kanchan Bhatia
- School of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306, USA
| | - Naseem Akhter
- Department of Biology, Arizona State University, Lake Havasu City, AZ 86403, USA
| | - Saif Ahmad
- Department of Translational Neuroscience, Barrow Neurological Institute, St Joseph’s Hospital and Medical Center, Phoenix, AZ 85013, USA (J.C.)
- Department of Neurosurgery, Barrow Neurological Institute, St Joseph’s Hospital and Medical Center, Phoenix, AZ 85013, USA
- Phoenix Veterans Affairs (VA) Health Care System, Phoenix, AZ 85012, USA
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Chang J, Feng Z, Li Y, Lv H, Liu S, Luo Y, Hao N, Zhao L, Liu J. Mesenchymal stem cell-derived extracellular vesicles: A novel promising neuroprotective agent for Alzheimer's disease. Biochem Pharmacol 2024; 222:116064. [PMID: 38373595 DOI: 10.1016/j.bcp.2024.116064] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Revised: 01/25/2024] [Accepted: 02/16/2024] [Indexed: 02/21/2024]
Abstract
Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive loss of neurons in the brain. However, there are no effective drugs for AD. Mesenchymal stem cell-derived extracellular vesicles (MSCs-EVs), as a new mediator of intercellular communication, are associated with low immunogenicity, low risk of tumor formation, and good safety profile. Therefore, MSCs-EVs may be a safe and attractive cell-free nanotherapeutics, offering a new perspective for AD treatment. Although preclinical studies have demonstrated that MSCs-EVs have significant neuroprotective effects, the underlying mechanism is unclear. This study aimed to: outline the diagnostic and delivery roles of MSCs-EVs for AD treatment; summarize the optimal sources and delivery methods of MSCs-EVs; provide a comprehensive review on the neuroprotective mechanisms of MSCs-EVs; explore how to enhance the neuroprotective effects of MSCs-EVs; and discuss the limitations and potential of their translation to the clinic. Therefore, this study may provide a more precise theoretical reference and practical basis for clinical research of MSCs-EVs.
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Affiliation(s)
- Jun Chang
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China; National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Zihang Feng
- School of Nursing, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yujiao Li
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China; National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Honglin Lv
- Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Shuzhen Liu
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China; National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Yongyin Luo
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China; National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Nan Hao
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China; National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Lan Zhao
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China; National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China.
| | - Jianwei Liu
- Tianjin University of Traditional Chinese Medicine, Tianjin, China.
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Shigematsu K, Komori N, Ideno M, Yamagishi H. "Evaluation of neprilysin activity in Adipose-Derived stem cells from Alzheimer's disease patients". Neurosci Lett 2024; 825:137705. [PMID: 38428725 DOI: 10.1016/j.neulet.2024.137705] [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: 11/30/2023] [Revised: 02/14/2024] [Accepted: 02/26/2024] [Indexed: 03/03/2024]
Abstract
INTRODUCTION The antibody drugs targeting β-amyloid in Alzheimer's disease pose risks of inflammation and vascular damage. It is known that neprilysin, an endogenous enzyme responsible for β-amyloid degradation, is reduced in areas with β-amyloid deposition. Supplementation of neprilysin could potentially contribute to Alzheimer's disease treatment. When considering the use of adipose tissue-derived stem cells (ADSCs) for Alzheimer's disease therapy, it is crucial to ensure that Alzheimer's disease patient-derived ADSCs maintain neprilysin activity. If so, the use of autologous ADSCs may lead to a treatment with minimal risks of rejection or infection. Therefore, we investigated the neprilysin activity in Alzheimer's disease patient-derived adipose tissue-derived stem cells to assess their potential in Alzheimer's disease treatment. METHODS Five Alzheimer's disease patients (MSC1-5) and two Chronic Obstructive Pulmonary Disease (COPD) patients (MSC6-7) were enrolled. ADSCs were cultured for 6 days with varying seeding densities. On the 3rd day, the medium was replaced, and on the 6th day, ADSCs were harvested. Cells were stained for PE-Cy7 Mouse IgG1 κ Isotype control and PE-Cy Mouse Anti-Human CD10, and CD10 expression was assessed by flow cytometry. Ethical approval and informed consent were obtained. RESULTS Neprilysin activity, crucial for β-amyloid degradation, was assessed in ADSCs. Positivity rates for CD10 expression in ADSCs from Alzheimer's patients were consistently high: 99.6%, 99.5%, 99.9%, 99.3%, 99.8%, and 100.0%. Control ADSCs from COPD patients (MSC6-7) exhibited comparable positivity rates. Flow cytometry plots for all seven cases are presented in Figures 1-7. DISCUSSION This study confirms the presence and maintenance of neprilysin activity in ADSCs from Alzheimer's disease patients. The high positivity rates for CD10 expression in these cells suggest that neprilysin, a key enzyme in β-amyloid degradation, remains active. The implications are significant, as ADSCs offer immune-compatible and low infection risk advantages. The study underscores the potential of autologous ADSCs as a therapeutic approach in Alzheimer's disease. Their ability to naturally harbor neprilysin activity, coupled with their safety profile, makes them a promising candidate for further exploration. While acknowledging the need for larger, more diverse cohorts and long-term studies, these findings contribute to the growing body of evidence supporting the development of stem cell-based interventions in Alzheimer's disease treatment.
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Affiliation(s)
| | | | | | - Hisakazu Yamagishi
- Ex-university president and honorary professor, Kyoto Prefectural University of Medicine
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Sun Y, Chen D, Dai T, Yu Z, Xie H, Wang X, Zhang W. Cell-free fat extract promotes axon regeneration and retinal ganglion cells survival in traumatic optic neuropathy. Front Cell Neurosci 2024; 18:1344853. [PMID: 38515790 PMCID: PMC10954833 DOI: 10.3389/fncel.2024.1344853] [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: 11/26/2023] [Accepted: 02/27/2024] [Indexed: 03/23/2024] Open
Abstract
Injuries to axons within the central nervous system (CNS) pose a substantial clinical challenge due to their limited regenerative capacity. This study investigates the therapeutic potential of Cell-free fat extract (CEFFE) in CNS injury. CEFFE was injected intravitreally after the optic nerve was crushed. Two weeks post-injury, quantification of regenerated axons and survival rates of retinal ganglion cells (RGCs) were performed. Subsequently, comprehensive gene ontology (GO) an-notation elucidated the cellular origins and functional attributes of CEFFE components. Molecular mechanisms underlying CEFFE's therapeutic effects were explored through Western blotting (WB). Additionally, levels of inflammatory factors within CEFFE were determined using enzyme-linked immunosorbent assay (ELISA), and histological staining of microglia was conducted to assess its impact on neuroinflammation. CEFFE demonstrated a significant capacity to promote axon re-generation and enhance RGCs survival. GO annotation revealed the involvement of 146 proteins within CEFFE in axonogenesis and neurogenesis. WB analysis unveiled the multifaceted pathways through which CEFFE exerts its therapeutic effects. Elevated levels of inflammatory factors were detected through ELISA, and CEFFE exhibited a modulatory effect on microglial activation in the retinal tissue following optic nerve crush (ONC). The present study highlights the therapeutic promise of CEFFE in the management of CNS injuries, exemplified by its ability to foster axon regeneration and improve RGCs survival.
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Affiliation(s)
- Yiyu Sun
- Department of Wound Reconstructive Surgery, Tongji Hospital Affiliated to Tongji University, School of Medicine, Tongji University, Shanghai, China
| | - Di Chen
- Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Tao Dai
- Department of Wound Reconstructive Surgery, Tongji Hospital Affiliated to Tongji University, School of Medicine, Tongji University, Shanghai, China
| | - Ziyou Yu
- Shanghai Key Laboratory of Tissue Engineering, Department of Plastic and Reconstructive Surgery, Shanghai 9th People’s Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Hui Xie
- Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Xiangsheng Wang
- Department of Plastic and Reconstructive Surgery, Affiliated Hangzhou First People’s Hospital, School of Medicine, Westlake University, Hangzhou, Zhejiang, China
| | - Wenjie Zhang
- Shanghai Key Laboratory of Tissue Engineering, Department of Plastic and Reconstructive Surgery, Shanghai 9th People’s Hospital, Shanghai Jiao Tong University, Shanghai, China
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Wang T, Zhao H, Zhang Y, Liu Y, Liu J, Chen G, Duan K, Li Z, Hui HPJ, Yan J. A novel extracellular vesicles production system harnessing matrix homeostasis and macrophage reprogramming mitigates osteoarthritis. J Nanobiotechnology 2024; 22:79. [PMID: 38419097 PMCID: PMC10903078 DOI: 10.1186/s12951-024-02324-8] [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: 11/20/2023] [Accepted: 01/30/2024] [Indexed: 03/02/2024] Open
Abstract
Osteoarthritis (OA) is a degenerative disease that significantly impairs quality of life. There is a pressing need for innovative OA therapies. While small extracellular vesicles (sEVs) show promising therapeutic effects against OA, their limited yield restricts clinical translation. Here, we devised a novel production system for sEVs that enhances both their yield and therapeutic properties. By stimulating mesenchymal stem cells (MSCs) using electromagnetic field (EMF) combined with ultrasmall superparamagnetic iron oxide (USPIO) particles, we procured an augmented yield of EMF-USPIO-sEVs. These vesicles not only activate anabolic pathways but also inhibit catabolic activities, and crucially, they promote M2 macrophage polarization, aiding cartilage regeneration. In an OA mouse model triggered by anterior cruciate ligament transection surgery, EMF-USPIO-sEVs reduced OA severity, and augmented matrix synthesis. Moreover, they decelerated OA progression through the microRNA-99b/MFG-E8/NF-κB signaling axis. Consequently, EMF-USPIO-sEVs present a potential therapeutic option for OA, acting by modulating matrix homeostasis and macrophage polarization.
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Affiliation(s)
- Tianqi Wang
- Departments of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Hongqi Zhao
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Yi Zhang
- School of Public Health, Southwest Medical University, Luzhou, 646000, Sichuan, China
| | - Yanshi Liu
- Department of Orthopaedics, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, China
| | - Jialin Liu
- Department of Oral Implantology, The Affiliated Stomatology Hospital of Southwest Medical University, Luzhou, Sichuan, 64600, China
| | - Ge Chen
- Department of Orthopaedics, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, China
| | - Ke Duan
- Sichuan Provincial Laboratory of Orthopaedic Engineering, Luzhou, Sichuan, 646000, China
| | - Zhong Li
- Department of Orthopaedics, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, China
| | - Hoi Po James Hui
- Departments of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore
- Tissue Engineering Program, Yong Loo Lin School of Medicine, Life Sciences Institute, National University of Singapore, Singapore, 117597, Singapore
| | - Jiyuan Yan
- Department of Orthopaedics, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, China.
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Kumar MA, Baba SK, Sadida HQ, Marzooqi SA, Jerobin J, Altemani FH, Algehainy N, Alanazi MA, Abou-Samra AB, Kumar R, Al-Shabeeb Akil AS, Macha MA, Mir R, Bhat AA. Extracellular vesicles as tools and targets in therapy for diseases. Signal Transduct Target Ther 2024; 9:27. [PMID: 38311623 PMCID: PMC10838959 DOI: 10.1038/s41392-024-01735-1] [Citation(s) in RCA: 166] [Impact Index Per Article: 166.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2023] [Revised: 12/20/2023] [Accepted: 12/24/2023] [Indexed: 02/06/2024] Open
Abstract
Extracellular vesicles (EVs) are nano-sized, membranous structures secreted into the extracellular space. They exhibit diverse sizes, contents, and surface markers and are ubiquitously released from cells under normal and pathological conditions. Human serum is a rich source of these EVs, though their isolation from serum proteins and non-EV lipid particles poses challenges. These vesicles transport various cellular components such as proteins, mRNAs, miRNAs, DNA, and lipids across distances, influencing numerous physiological and pathological events, including those within the tumor microenvironment (TME). Their pivotal roles in cellular communication make EVs promising candidates for therapeutic agents, drug delivery systems, and disease biomarkers. Especially in cancer diagnostics, EV detection can pave the way for early identification and offers potential as diagnostic biomarkers. Moreover, various EV subtypes are emerging as targeted drug delivery tools, highlighting their potential clinical significance. The need for non-invasive biomarkers to monitor biological processes for diagnostic and therapeutic purposes remains unfulfilled. Tapping into the unique composition of EVs could unlock advanced diagnostic and therapeutic avenues in the future. In this review, we discuss in detail the roles of EVs across various conditions, including cancers (encompassing head and neck, lung, gastric, breast, and hepatocellular carcinoma), neurodegenerative disorders, diabetes, viral infections, autoimmune and renal diseases, emphasizing the potential advancements in molecular diagnostics and drug delivery.
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Affiliation(s)
- Mudasir A Kumar
- Watson-Crick Centre for Molecular Medicine, Islamic University of Science and Technology, Awantipora, Kashmir, 192122, India
| | - Sadaf K Baba
- Watson-Crick Centre for Molecular Medicine, Islamic University of Science and Technology, Awantipora, Kashmir, 192122, India
| | - Hana Q Sadida
- Department of Human Genetics-Precision Medicine in Diabetes, Obesity and Cancer Program, Sidra Medicine, Doha, Qatar
| | - Sara Al Marzooqi
- Department of Human Genetics-Precision Medicine in Diabetes, Obesity and Cancer Program, Sidra Medicine, Doha, Qatar
| | - Jayakumar Jerobin
- Qatar Metabolic Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Faisal H Altemani
- Department of Medical Laboratory Technology, Prince Fahad Bin Sultan Chair for Biomedical Research, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk, Saudi Arabia
| | - Naseh Algehainy
- Department of Medical Laboratory Technology, Prince Fahad Bin Sultan Chair for Biomedical Research, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk, Saudi Arabia
| | - Mohammad A Alanazi
- Department of Medical Laboratory Technology, Prince Fahad Bin Sultan Chair for Biomedical Research, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk, Saudi Arabia
| | - Abdul-Badi Abou-Samra
- Qatar Metabolic Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Rakesh Kumar
- School of Biotechnology, Shri Mata Vaishno Devi University, Katra, India
| | - Ammira S Al-Shabeeb Akil
- Department of Human Genetics-Precision Medicine in Diabetes, Obesity and Cancer Program, Sidra Medicine, Doha, Qatar
| | - Muzafar A Macha
- Watson-Crick Centre for Molecular Medicine, Islamic University of Science and Technology, Awantipora, Kashmir, 192122, India
| | - Rashid Mir
- Department of Medical Laboratory Technology, Prince Fahad Bin Sultan Chair for Biomedical Research, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk, Saudi Arabia.
| | - Ajaz A Bhat
- Department of Human Genetics-Precision Medicine in Diabetes, Obesity and Cancer Program, Sidra Medicine, Doha, Qatar.
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Miron RJ, Zhang Y. Understanding exosomes: Part 1-Characterization, quantification and isolation techniques. Periodontol 2000 2024; 94:231-256. [PMID: 37740431 DOI: 10.1111/prd.12520] [Citation(s) in RCA: 24] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Revised: 07/21/2023] [Accepted: 07/25/2023] [Indexed: 09/24/2023]
Abstract
Exosomes are the smallest subset of extracellular signaling vesicles secreted by most cells with a diameter in the range of 30-150 nm. Their use has gained great momentum recently due to their ability to be utilized as diagnostic tools with a vast array of therapeutic applications. Over 5000 publications are currently being published yearly on this topic, and this number is only expected to dramatically increase as novel therapeutic strategies continue to be investigated. This review article first focuses on understanding exosomes, including their cellular origin, biogenesis, function, and characterization. Thereafter, overviews of the quantification methods and isolation techniques are given with discussion over their potential use as novel therapeutics in regenerative medicine.
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Affiliation(s)
- Richard J Miron
- Department of Periodontology, University of Bern, Bern, Switzerland
| | - Yufeng Zhang
- Department of Oral Implantology, University of Wuhan, Wuhan, China
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Ling SSM, Lilyanna S, Ng JYX, Chong JPC, Lin Q, Yong XE, Lim TK, Lin Q, Richards AM, Liew OW. Multiple circulating forms of neprilysin detected with novel epitope-directed monoclonal antibodies. Cell Mol Life Sci 2024; 81:42. [PMID: 38217709 PMCID: PMC10787894 DOI: 10.1007/s00018-023-05083-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Revised: 12/04/2023] [Accepted: 12/06/2023] [Indexed: 01/15/2024]
Abstract
Neprilysin (NEP) is an emerging biomarker for various diseases including heart failure (HF). However, major inter-assay inconsistency in the reported concentrations of circulating NEP and uncertainty with respect to its correlations with type and severity of disease are in part attributed to poorly characterized antibodies supplied in commercial ELISA kits. Validated antibodies with well-defined binding footprints are critical for understanding the biological and clinical context of NEP immunoassay data. To achieve this, we applied in silico epitope prediction and rational peptide selection to generate monoclonal antibodies (mAbs) against spatially distant sites on NEP. One of the selected epitopes contained published N-linked glycosylation sites at N285 and N294. The best antibody pair, mAb 17E11 and 31E1 (glycosylation-sensitive), were characterized by surface plasmon resonance, isotyping, epitope mapping, and western blotting. A validated two-site sandwich NEP ELISA with a limit of detection of 2.15 pg/ml and working range of 13.1-8000 pg/ml was developed with these mAbs. Western analysis using a validated commercial polyclonal antibody (PE pAb) and our mAbs revealed that non-HF and HF plasma NEP circulates as a heterogenous mix of moieties that possibly reflect proteolytic processing, post-translational modifications and homo-dimerization. Both our mAbs detected a ~ 33 kDa NEP fragment which was not apparent with PE pAb, as well as a common ~ 57-60 kDa moiety. These antibodies exhibit different affinities for the various NEP targets. Immunoassay results are dependent on NEP epitopes variably detected by the antibody pairs used, explaining the current discordant NEP measurements derived from different ELISA kits.
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Affiliation(s)
- Samantha S M Ling
- Cardiovascular Research Institute, Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, 14 Medical Drive, Singapore, 117599, Singapore
| | - Shera Lilyanna
- Cardiovascular Research Institute, Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, 14 Medical Drive, Singapore, 117599, Singapore
| | - Jessica Y X Ng
- Cardiovascular Research Institute, Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, 14 Medical Drive, Singapore, 117599, Singapore
| | - Jenny P C Chong
- Cardiovascular Research Institute, Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, 14 Medical Drive, Singapore, 117599, Singapore
| | - Qifeng Lin
- Department of Biological Sciences, National University of Singapore, Singapore, Singapore
| | - Xin Ee Yong
- Department of Biological Sciences, National University of Singapore, Singapore, Singapore
| | - Teck Kwang Lim
- Department of Biological Sciences, National University of Singapore, Singapore, Singapore
| | - Qingsong Lin
- Department of Biological Sciences, National University of Singapore, Singapore, Singapore
| | - A Mark Richards
- Cardiovascular Research Institute, Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, 14 Medical Drive, Singapore, 117599, Singapore
- Christchurch Heart Institute, University of Otago, Otago, New Zealand
| | - Oi Wah Liew
- Cardiovascular Research Institute, Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, 14 Medical Drive, Singapore, 117599, Singapore.
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42
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Ye Y, Gao M, Shi W, Gao Y, Li Y, Yang W, Zheng X, Lu X. The immunomodulatory effects of mesenchymal stem cell-derived extracellular vesicles in Alzheimer's disease. Front Immunol 2024; 14:1325530. [PMID: 38259476 PMCID: PMC10800421 DOI: 10.3389/fimmu.2023.1325530] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2023] [Accepted: 12/15/2023] [Indexed: 01/24/2024] Open
Abstract
Neuroinflammation has been identified as another significant pathogenic factor in Alzheimer's disease following Aβ amyloid deposition and tau protein hyperphosphorylation, activated in the central nervous system by glial cells in response to injury-related and pathogen-related molecular patterns. Moderate glial cell activity can be neuroprotective; however, excessive glial cell activation advances the pathology of Alzheimer's disease and is accompanied by structural changes in the brain interface, with peripheral immune cells entering the brain through the blood-brain barrier, creating a vicious circle. The immunomodulatory properties of mesenchymal stem cells (MSCs) are primarily conveyed through extracellular vesicles (EVs). MSC-EVs participate in chronic inflammatory and immune processes by transferring nucleic acids, proteins and lipids from the parent cell to the recipient cell, thus MSC-EVs retain their immunomodulatory capacity while avoiding the safety issues associated with living cell therapy, making them a promising focus for immunomodulatory therapy. In this review, we discuss the modulatory effects of MSC-EVs on Alzheimer's disease-associated immune cells and the mechanisms involved in their treatment of the condition. We have found a clinical trial of MSC-EVs in Alzheimer's disease treatment and outlined the challenges of this approach. Overall, MSC-EVs have the potential to provide a safe and effective treatment option for Alzheimer's disease by targeting neuroinflammation.
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Affiliation(s)
- Yang Ye
- Research Institute for Reproductive Health and Genetic Diseases, Wuxi Maternity and Child Health Care Hospital, Wuxi School of Medicine, Jiangnan University, Wuxi, China
- Neuroscience Center, Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Mingzhu Gao
- Neuroscience Center, Wuxi School of Medicine, Jiangnan University, Wuxi, China
- Central Hospital of Jiangnan University, Wuxi No.2 People’s Hospital, Wuxi, China
| | - Wentao Shi
- Neuroscience Center, Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Yan Gao
- Neuroscience Center, Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Yilu Li
- Neuroscience Center, Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Wenhui Yang
- Neuroscience Center, Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Xiaomin Zheng
- Research Institute for Reproductive Health and Genetic Diseases, Wuxi Maternity and Child Health Care Hospital, Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Xiaojie Lu
- Neuroscience Center, Wuxi School of Medicine, Jiangnan University, Wuxi, China
- Central Hospital of Jiangnan University, Wuxi No.2 People’s Hospital, Wuxi, China
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43
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Jang HJ, Shim KS, Lee J, Park JH, Kang SJ, Shin YM, Lee JB, Baek W, Yoon JK. Engineering of Cell Derived-Nanovesicle as an Alternative to Exosome Therapy. Tissue Eng Regen Med 2024; 21:1-19. [PMID: 38066355 PMCID: PMC10764700 DOI: 10.1007/s13770-023-00610-4] [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: 10/04/2023] [Revised: 10/24/2023] [Accepted: 10/27/2023] [Indexed: 01/04/2024] Open
Abstract
BACKGROUND Exosomes, nano-sized vesicles ranging between 30 and 150 nm secreted by human cells, play a pivotal role in long-range intercellular communication and have attracted significant attention in the field of regenerative medicine. Nevertheless, their limited productivity and cost-effectiveness pose challenges for clinical applications. These issues have recently been addressed by cell-derived nanovesicles (CDNs), which are physically synthesized exosome-mimetic nanovesicles from parent cells, as a promising alternative to exosomes. CDNs exhibit structural, physical, and biological properties similar to exosomes, containing intracellular protein and genetic components encapsulated by the cell plasma membrane. These characteristics allow CDNs to be used as regenerative medicine and therapeutics on their own, or as a drug delivery system. METHODS The paper reviews diverse methods for CDN synthesis, current analysis techniques, and presents engineering strategies to improve lesion targeting efficiency and/or therapeutic efficacy. RESULTS CDNs, with their properties similar to those of exosomes, offer a cost-effective and highly productive alternative due to their non-living biomaterial nature, nano-size, and readiness for use, allowing them to overcome several limitations of conventional cell therapy methods. CONCLUSION Ongoing research and enhancement of CDNs engineering, along with comprehensive safety assessments and stability analysis, exhibit vast potential to advance regenerative medicine by enabling the development of efficient therapeutic interventions.
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Affiliation(s)
- Hye-Jeong Jang
- Department of Systems Biotechnology, Chung-Ang University, Anseong-Si, Gyeonggi-Do, 17546, Republic of Korea
| | - Kyu-Sik Shim
- Department of Plastic and Reconstructive Surgery, Institute for Human Tissue Restoration, Severance Hospital, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea
| | - Jinah Lee
- Department of Biological Science, Research Institute of Women's Health, Brain Korea 21 Project, Sookmyung Women's University, Seoul, 04310, Republic of Korea
| | - Joo Hyeon Park
- Department of Biological Science, Research Institute of Women's Health, Brain Korea 21 Project, Sookmyung Women's University, Seoul, 04310, Republic of Korea
| | - Seong-Jun Kang
- Department of Systems Biotechnology, Chung-Ang University, Anseong-Si, Gyeonggi-Do, 17546, Republic of Korea
| | - Young Min Shin
- Department of Biological Science, Research Institute of Women's Health, Brain Korea 21 Project, Sookmyung Women's University, Seoul, 04310, Republic of Korea
| | - Jung Bok Lee
- Department of Biological Science, Research Institute of Women's Health, Brain Korea 21 Project, Sookmyung Women's University, Seoul, 04310, Republic of Korea.
| | - Wooyeol Baek
- Department of Plastic and Reconstructive Surgery, Institute for Human Tissue Restoration, Severance Hospital, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea.
| | - Jeong-Kee Yoon
- Department of Systems Biotechnology, Chung-Ang University, Anseong-Si, Gyeonggi-Do, 17546, Republic of Korea.
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Koprivec S, Majdič G. Extracellular Vesicles in Domestic Animals: Cellular Communication in Health and Disease. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1450:39-57. [PMID: 37421538 DOI: 10.1007/5584_2023_779] [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: 07/10/2023]
Abstract
Apoptotic and healthy cells of domestic animals release membrane-enclosed particles from their plasma membrane. These special structures, called extracellular vesicles, play an important role in intercellular communication. In the past, it was believed that their function was mainly to dispose unwanted cell contents and to help maintain cell homeostasis. However, we now know that they have important roles in health and disease and have diagnostic value as well as great potential for therapy in veterinary medicine. Extracellular vesicles facilitate cellular exchanges by delivering functional cargo molecules to nearby or distant tissues. They are produced by various cell types and are found in all body fluids. Their cargo reflects the state of the releasing parent cell, and despite their small size, this cargo is extraordinarily complex. Numerous different types of molecules contained in vesicles make them an extremely promising tool in the field of regenerative veterinary medicine. To further increase research interest and discover their full potential, some of the basic biological mechanisms behind their function need to be better understood. Only then will we be able to maximize the clinical relevance for targeted diagnostic and therapeutic purposes in various domestic animal species.
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Affiliation(s)
- Saša Koprivec
- Veterinary Faculty, Institute of Preclinical Sciences, University of Ljubljana, Ljubljana, Slovenia
| | - Gregor Majdič
- Veterinary Faculty, Institute of Preclinical Sciences, University of Ljubljana, Ljubljana, Slovenia.
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Zhang F, Zhang L, Yu H. Potential Druggability of Mesenchymal Stem/Stromal Cell-derived Exosomes. Curr Stem Cell Res Ther 2024; 19:1195-1209. [PMID: 38523514 DOI: 10.2174/011574888x311270240319084835] [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: 02/19/2024] [Revised: 03/05/2024] [Accepted: 03/12/2024] [Indexed: 03/26/2024]
Abstract
Exosomes secreted by mesenchymal stem/stromal cells (MSC-Exos) are advantageous candidate sources for novel acellular therapy. Despite the current standards of good manufacturing practice (GMP), the deficiency of suitable quality-control methods and the difficulties in large-scale preparation largely restrict the development of therapeutic products and their clinical applications worldwide. Herein, we mainly focus on three dominating issues commonly encountered in exosomal GMP, including issues upstream of the cell culture process, downstream of the purification process, exosomes quality control, and the drug properties of exosomes and their druggability from a corporate perspective. Collectively, in this review article, we put forward the issues of preparing clinical exosome drugs for the treatment of diverse diseases and provide new references for the clinical application of GMP-grade MSC-Exos.
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Affiliation(s)
- Fan Zhang
- Faculty of Life Sciences and Medicine, Kunming University of Science and Technology, Kunming, 650500, China
| | - Leisheng Zhang
- Science and Technology Innovation Center, The Fourth People's Hospital of Jinan (The Third Affiliated Hospital of Shandong First Medical University), Jinan, 250031, China
- National Health Commission (NHC) Key Laboratory of Diagnosis and Therapy of Gastrointestinal Tumor, Gansu Provincial Hospital, Lanzhou, 730000, China
| | - Hao Yu
- The Postdoctoral Research Station, School of Medicine, Nankai University, Tianjin, 300071, China
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46
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Farzaneh M, Khoshnam SE. Functional Roles of Mesenchymal Stem Cell-derived Exosomes in Ischemic Stroke Treatment. Curr Stem Cell Res Ther 2024; 19:2-14. [PMID: 36567297 DOI: 10.2174/1574888x18666221222123818] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Revised: 08/28/2022] [Accepted: 10/18/2022] [Indexed: 12/27/2022]
Abstract
Stroke is a life-threatening disease and one of the leading causes of death and physical disability worldwide. Currently, no drugs on the market promote neural recovery after stroke insult, and spontaneous remodeling processes are limited to induce recovery in the ischemic regions. Therefore, promoting a cell-based therapy has been needed to elevate the endogenous recovery process. Mesenchymal stem cells (MSCs) have been regarded as candidate cell sources for therapeutic purposes of ischemic stroke, and their therapeutic effects are mediated by exosomes. The microRNA cargo in these extracellular vesicles is mostly responsible for the positive effects. When it comes to the therapeutic viewpoint, MSCsderived exosomes could be a promising therapeutic strategy against ischemic stroke. The aim of this review is to discuss the current knowledge around the potential of MSCs-derived exosomes in the treatment of ischemic stroke.
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Affiliation(s)
- Maryam Farzaneh
- Fertility, Infertility and Perinatology Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Seyed Esmaeil Khoshnam
- Persian Gulf Physiology Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
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47
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Rhim WK, Kim JY, Lee SY, Cha SG, Park JM, Park HJ, Park CG, Han DK. Recent advances in extracellular vesicle engineering and its applications to regenerative medicine. Biomater Res 2023; 27:130. [PMID: 38082304 PMCID: PMC10712135 DOI: 10.1186/s40824-023-00468-6] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2023] [Accepted: 11/24/2023] [Indexed: 01/02/2025] Open
Abstract
Extracellular vesicles (EVs) are nanosized particles that are released from cells and reflect the characteristics of the mother cell. Recently, the EVs have been used in several types of studies across many different fields. In the field of EV research, multiple cell culture and EV isolation techniques have been highlighted in importance. Various strategies, including exclusive component culture media, three-dimensional (3D) cultures, and hypoxic conditions, have been proposed for the cell culture to control function of the EVs. Ultracentrifugation, ultrafiltration, precipitation, and tangential flow filtration (TFF) have been utilized for EV isolation. Although isolated EVs have their own functionalities, several researchers are trying to functionalize EVs by applying various engineering approaches. Gene editing, exogenous, endogenous, and hybridization methods are the four well-known types of EV functionalization strategies. EV engineered through these processes has been applied in the field of regenerative medicine, including kidney diseases, osteoarthritis, rheumatoid arthritis, nervous system-related diseases, and others. In this review, it was focused on engineering approaches for EV functionalization and their applications in regenerative medicine.
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Affiliation(s)
| | - Jun Yong Kim
- Department of Biomedical Science, CHA University, 335 Pangyo-ro Bundang-gu, Seongnam-si, Gyeonggi-do, 13488, Republic of Korea
- Department of Biomedical Engineering, 2066 Seobu-ro Jangan-gu, Suwon-si, Gyeonggi-do, 16419, Republic of Korea
- Intelligent Precision of Healthcare Convergence, SKKU Institute for Convergence, Sungkyunkwan University (SKKU), 2066 Seobu-ro Jangan-gu, Suwon-si, Gyeonggi-do, 16419, Republic of Korea
| | - Seung Yeon Lee
- Department of Biomedical Science, CHA University, 335 Pangyo-ro Bundang-gu, Seongnam-si, Gyeonggi-do, 13488, Republic of Korea
| | - Seung-Gyu Cha
- Department of Biomedical Science, CHA University, 335 Pangyo-ro Bundang-gu, Seongnam-si, Gyeonggi-do, 13488, Republic of Korea
| | - Jeong Min Park
- Department of Biomedical Science, CHA University, 335 Pangyo-ro Bundang-gu, Seongnam-si, Gyeonggi-do, 13488, Republic of Korea
| | - Hyeon Jeong Park
- Department of Biomedical Science, CHA University, 335 Pangyo-ro Bundang-gu, Seongnam-si, Gyeonggi-do, 13488, Republic of Korea
| | - Chun Gwon Park
- Department of Biomedical Engineering, 2066 Seobu-ro Jangan-gu, Suwon-si, Gyeonggi-do, 16419, Republic of Korea
- Intelligent Precision of Healthcare Convergence, SKKU Institute for Convergence, Sungkyunkwan University (SKKU), 2066 Seobu-ro Jangan-gu, Suwon-si, Gyeonggi-do, 16419, Republic of Korea
| | - Dong Keun Han
- Department of Biomedical Science, CHA University, 335 Pangyo-ro Bundang-gu, Seongnam-si, Gyeonggi-do, 13488, Republic of Korea.
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48
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Bicer M. Exploring therapeutic avenues: mesenchymal stem/stromal cells and exosomes in confronting enigmatic biofilm-producing fungi. Arch Microbiol 2023; 206:11. [PMID: 38063945 DOI: 10.1007/s00203-023-03744-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Revised: 11/10/2023] [Accepted: 11/12/2023] [Indexed: 12/18/2023]
Abstract
Fungal infections concomitant with biofilms can demonstrate an elevated capacity to withstand substantially higher concentrations of antifungal agents, contrasted with infectious diseases caused by planktonic cells. This inherent resilience intrinsic to biofilm-associated infections engenders a formidable impediment to effective therapeutic interventions. The different mechanisms that are associated with the intrinsic resistance of Candida species encompass drug sequestration by the matrix, drug efflux pumps, stress response cell density, and the presence of persister cells. These persisters, a subset of fungi capable of surviving hostile conditions, pose a remarkable challenge in clinical settings in virtue of their resistance to conventional antifungal therapies. Hence, an exigent imperative has arisen for the development of novel antifungal therapeutics with specific targeting capabilities focused on these pathogenic persisters. On a global scale, fungal persistence and their resistance within biofilms generate an urgent clinical need for investigating recently introduced therapeutic strategies. This review delves into the unique characteristics of Mesenchymal stem/stromal cells (MSCs) and their secreted exosomes, which notably exhibit immunomodulatory and regenerative properties. By comprehensively assessing the current literature and ongoing research in this field, this review sheds light on the plausible mechanisms by which MSCs and their exosomes can be harnessed to selectively target fungal persisters. Additionally, prospective approaches in the use of cell-based therapeutic modalities are examined, emphasizing the importance of further research to overcome the enigmatic fungal persistence.
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Affiliation(s)
- Mesude Bicer
- Department of Bioengineering, Faculty of Life and Natural Sciences, Abdullah Gul University, Kayseri, 38080, Turkey.
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Massaro F, Corrillon F, Stamatopoulos B, Dubois N, Ruer A, Meuleman N, Bron D, Lagneaux L. Age-related changes in human bone marrow mesenchymal stromal cells: morphology, gene expression profile, immunomodulatory activity and miRNA expression. Front Immunol 2023; 14:1267550. [PMID: 38130717 PMCID: PMC10733451 DOI: 10.3389/fimmu.2023.1267550] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Accepted: 11/21/2023] [Indexed: 12/23/2023] Open
Abstract
Introduction Mesenchymal stromal cells (MSC) are one of the main cellular components of bone marrow (BM) microenvironment. MSC play a key role in tissue regeneration, but they are also capable of immunomodulating activity. With host aging, MSC undergo age-related changes, which alter these functions, contributing to the set-up of "inflammaging", which is known to be the basis for the development of several diseases of the elderly, including cancer. However, there's few data investigating this facet of MSC, mainly obtained using murine models or replicative senescence. The aim of this research was to identify morphological, molecular and functional alterations of human bone marrow-derived MSC from young (yBM-MSC) and old (oBM-MSC) healthy donors. Methods MSC were identified by analysis of cell-surface markers according to the ISCT criteria. To evaluate response to inflammatory status, MSC were incubated for 24h in the presence of IL-1β, IFN-α, IFN-ɣ and TNF-α. Macrophages were obtained by differentiation of THP-1 cells through PMA exposure. For M1 polarization experiments, a 24h incubation with LPS and IFN-ɣ was performed. MSC were plated at the bottom of the co-culture transwell system for all the time of cytokine exposure. Gene expression was evaluated by real-time PCR after RNA extraction from BM-MSC or THP-1 culture. Secreted cytokines levels were quantitated through ELISA assays. Results Aging MSC display changes in size, morphology and granularity. Higher levels of β-Gal, reactive oxygen species (ROS), IL-6 and IL-8 and impaired colony-forming and cell cycle progression abilities were found in oBM-MSC. Gene expression profile seems to vary according to subjects' age and particularly in oBM-MSC seem to be characterized by an impaired immunomodulating activity, with a reduced inhibition of macrophage M1 status. The comparative analysis of microRNA (miRNA) expression in yBM-MSC and oBM-MSC revealed a significant difference for miRNA known to be involved in macrophage polarization and particularly miR-193b-3p expression is strongly increased after co-culture of macrophages with yBM-MSC. Conclusion There are profound differences in terms of morphology, gene and miRNA expression and immunomodulating properties among yBM-MSC and oBM-MSC, supporting the critical role of aging BM microenvironment on senescence, immune-mediated disorders and cancer pathogenesis.
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Affiliation(s)
- Fulvio Massaro
- Department of Hematology, Jules Bordet Institute, Université Libre de Bruxelles (ULB), Brussels, Belgium
- PhD Program in Clinical and Experimental Medicine, University of Modena and Reggio Emilia, Modena, Italy
| | - Florent Corrillon
- Laboratory of Clinical Cell Therapy, Jules Bordet Institute, ULB Cancer Research Center (U-CRC) - Université Libre de Bruxelles (ULB), Brussels, Belgium
| | - Basile Stamatopoulos
- Laboratory of Clinical Cell Therapy, Jules Bordet Institute, ULB Cancer Research Center (U-CRC) - Université Libre de Bruxelles (ULB), Brussels, Belgium
| | - Nathan Dubois
- Laboratory of Clinical Cell Therapy, Jules Bordet Institute, ULB Cancer Research Center (U-CRC) - Université Libre de Bruxelles (ULB), Brussels, Belgium
| | - Achille Ruer
- Laboratory of Clinical Cell Therapy, Jules Bordet Institute, ULB Cancer Research Center (U-CRC) - Université Libre de Bruxelles (ULB), Brussels, Belgium
| | - Nathalie Meuleman
- Department of Hematology, Jules Bordet Institute, Université Libre de Bruxelles (ULB), Brussels, Belgium
| | - Dominique Bron
- Department of Hematology, Jules Bordet Institute, Université Libre de Bruxelles (ULB), Brussels, Belgium
| | - Laurence Lagneaux
- Laboratory of Clinical Cell Therapy, Jules Bordet Institute, ULB Cancer Research Center (U-CRC) - Université Libre de Bruxelles (ULB), Brussels, Belgium
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Han W, Zhang H, Feng L, Dang R, Wang J, Cui C, Jiang P. The emerging role of exosomes in communication between the periphery and the central nervous system. MedComm (Beijing) 2023; 4:e410. [PMID: 37916034 PMCID: PMC10616655 DOI: 10.1002/mco2.410] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 09/18/2023] [Accepted: 09/21/2023] [Indexed: 11/03/2023] Open
Abstract
Exosomes, membrane-enclosed vesicles, are secreted by all types of cells. Exosomes can transport various molecules, including proteins, lipids, functional mRNAs, and microRNAs, and can be circulated to various recipient cells, leading to the production of local paracrine or distal systemic effects. Numerous studies have proved that exosomes can pass through the blood-brain barrier, thus, enabling the transfer of peripheral substances into the central nervous system (CNS). Consequently, exosomes may be a vital factor in the exchange of information between the periphery and CNS. This review will discuss the structure, biogenesis, and functional characterization of exosomes and summarize the role of peripheral exosomes deriving from tissues like the lung, gut, skeletal muscle, and various stem cell types in communicating with the CNS and influencing the brain's function. Then, we further discuss the potential therapeutic effects of exosomes in brain diseases and the clinical opportunities and challenges. Gaining a clearer insight into the communication between the CNS and the external areas of the body will help us to ascertain the role of the peripheral elements in the maintenance of brain health and illness and will facilitate the design of minimally invasive techniques for diagnosing and treating brain diseases.
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Affiliation(s)
- Wenxiu Han
- Translational Pharmaceutical LaboratoryJining First People's HospitalShandong First Medical UniversityJiningP. R. China
- Institute of Translational PharmacyJining Medical Research AcademyJiningP. R. China
| | - Hailiang Zhang
- Translational Pharmaceutical LaboratoryJining First People's HospitalShandong First Medical UniversityJiningP. R. China
- Institute of Translational PharmacyJining Medical Research AcademyJiningP. R. China
| | - Lei Feng
- Department of NeurosurgeryJining First People's HospitalShandong First Medical UniversityJiningP. R. China
| | - Ruili Dang
- Translational Pharmaceutical LaboratoryJining First People's HospitalShandong First Medical UniversityJiningP. R. China
- Institute of Translational PharmacyJining Medical Research AcademyJiningP. R. China
| | - Jing Wang
- Translational Pharmaceutical LaboratoryJining First People's HospitalShandong First Medical UniversityJiningP. R. China
- Institute of Translational PharmacyJining Medical Research AcademyJiningP. R. China
| | - Changmeng Cui
- Department of NeurosurgeryAffiliated Hospital of Jining Medical UniversityJiningP. R. China
| | - Pei Jiang
- Translational Pharmaceutical LaboratoryJining First People's HospitalShandong First Medical UniversityJiningP. R. China
- Institute of Translational PharmacyJining Medical Research AcademyJiningP. R. China
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