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Scuteri A, Donzelli E. Dual role of extracellular vesicles in neurodegenerative diseases. World J Stem Cells 2024; 16:1002-1011. [PMID: 39734484 PMCID: PMC11669982 DOI: 10.4252/wjsc.v16.i12.1002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Revised: 10/17/2024] [Accepted: 11/22/2024] [Indexed: 12/13/2024] Open
Abstract
Extracellular vesicles (EVs) are cell-to-cell interaction tools that are attracting increasing interest in the literature in two opposing areas. In addition to their role in physiological development, there is growing evidence of their involvement in healing and protective processes. However, EVs also mediate pathological conditions, particularly contributing to the progression of several chronic diseases, such as neurodegenerative diseases. On the other hand, EVs also form the core of a new therapeutic strategy for neuroprotection, which is based on the administration of EVs derived from a wide range of donor cells. In particular, the possibility of obtaining numerous EVs from stem cells of different origins, which is feasible for therapeutic aims, is now under investigation. In this review, we focused on neurodegenerative diseases, in which EVs could have a propagative detrimental effect or could also be exploited to deliver protective factors. This review explores the different hypotheses concerning the dual role of EVs, with the aim of shedding light on the following question: Can vesicles be used to fight vesicle-propagated diseases?
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Affiliation(s)
- Arianna Scuteri
- Experimental Neurology Unit and Milan Center for Neuroscience, School of Medicine and Surgery, University of Milano-Bicocca, Monza 20900, Italy.
| | - Elisabetta Donzelli
- Experimental Neurology Unit and Milan Center for Neuroscience, School of Medicine and Surgery, University of Milano-Bicocca, Monza 20900, Italy
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Hao X, Zhu H, Qin C, Li L, Lin Z, Jiang H, Li Q, Huo Y, Zhang H, Geng X, Huang Y, Li B. Study on Preclinical Safety and Toxic Mechanism of Human Umbilical Cord Mesenchymal Stem Cells in F344RG Rats. Stem Cell Rev Rep 2024; 20:2236-2252. [PMID: 39243336 PMCID: PMC11554750 DOI: 10.1007/s12015-024-10780-w] [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: 08/18/2024] [Indexed: 09/09/2024]
Abstract
Mesenchymal stem cells have made remarkable progress in recent years. Many studies have reported that human umbilical cord mesenchymal stem cells (hUC-MSCs) have no toxicity, but thromboembolism appeared in patients treated with hUC-MSCs. Therefore, people are still worried about the safety of clinical application. The study aims to determine the safety, potential toxic mechanism and biodistribution of hUC-MSCs. F344RG rats were given 5 or 50 million cells/kg of hUC-MSCs by single administration in compliance with Good Laboratory Practice standards. Standard toxicity was performed. RNA sequencing was then performed to explore the potential toxic mechanisms. In parallel, the biodistribution of hUC-MSCs was examined. The dose of 5 million cells/kg hUC-MSCs had no obvious toxicity on symptom, weight, food intake, hematology, serum biochemistry, urine biochemistry, cytokines, and histopathology. However, blood-tinged secretions in the urethral orifice and 20% mortality occurred at 50 million cells/kg. Disseminated intravascular coagulopathy (DIC) is the leading cause of death. hUC-MSCs significantly upregulated complement and coagulation cascade pathways gene expression, resulting in DIC. Besides, hUC-MSCs upregulated fibrinolytic system suppressor genes A2m, Serping1 and Serpinf2. hUC-MSCs survived in rats for less than 28 days, no hUC-MSC was detected in tissues outside the lungs. There was no toxicity in F344RG rats at 5 million cells/kg, but some toxicities were detected at 50 million cells/kg. hUC-MSCs significantly upregulated complement and coagulation cascade pathways, upregulated the expression of fibrinolytic system suppressor genes A2m, Serping1 and Serpinf2, to inhibit fibrinolytic system, caused DIC, which provided a new insight into the toxic mechanism of hUC-MSCs.
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Affiliation(s)
- Xiaofang Hao
- National Institutes for Food and Drug Control, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
- National Institutes for Food and Drug Control, National Center for Safety Evaluation of Drugs, Key Laboratory of Beijing for Safety Evaluation of Drugs, Beijing, China
| | - Hao Zhu
- Sinoneural Cell Engineering Group Co., Ltd, Shanghai, China
| | - Chao Qin
- National Institutes for Food and Drug Control, National Center for Safety Evaluation of Drugs, Key Laboratory of Beijing for Safety Evaluation of Drugs, Beijing, China
| | - Lulu Li
- National Institutes for Food and Drug Control, National Center for Safety Evaluation of Drugs, Key Laboratory of Beijing for Safety Evaluation of Drugs, Beijing, China
| | - Zhi Lin
- National Institutes for Food and Drug Control, National Center for Safety Evaluation of Drugs, Key Laboratory of Beijing for Safety Evaluation of Drugs, Beijing, China
| | - Hua Jiang
- National Institutes for Food and Drug Control, National Center for Safety Evaluation of Drugs, Key Laboratory of Beijing for Safety Evaluation of Drugs, Beijing, China
| | - Qianqian Li
- National Institutes for Food and Drug Control, National Center for Safety Evaluation of Drugs, Key Laboratory of Beijing for Safety Evaluation of Drugs, Beijing, China
| | - Yan Huo
- National Institutes for Food and Drug Control, National Center for Safety Evaluation of Drugs, Key Laboratory of Beijing for Safety Evaluation of Drugs, Beijing, China
| | - Hezhan Zhang
- National Institutes for Food and Drug Control, National Center for Safety Evaluation of Drugs, Key Laboratory of Beijing for Safety Evaluation of Drugs, Beijing, China
| | - Xingchao Geng
- National Institutes for Food and Drug Control, National Center for Safety Evaluation of Drugs, Key Laboratory of Beijing for Safety Evaluation of Drugs, Beijing, China
| | - Ying Huang
- National Institutes for Food and Drug Control, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
- National Institutes for Food and Drug Control, National Center for Safety Evaluation of Drugs, Key Laboratory of Beijing for Safety Evaluation of Drugs, Beijing, China.
| | - Bo Li
- National Institutes for Food and Drug Control, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
- National Institutes for Food and Drug Control, National Center for Safety Evaluation of Drugs, Key Laboratory of Beijing for Safety Evaluation of Drugs, Beijing, China.
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Salehpour A, Karimi Z, Ghasemi Zadeh M, Afshar M, Kameli A, Mooseli F, Zare M, Afshar A. Therapeutic potential of mesenchymal stem cell-derived exosomes and miRNAs in neuronal regeneration and rejuvenation in neurological disorders: a mini review. Front Cell Neurosci 2024; 18:1427525. [PMID: 39429946 PMCID: PMC11486650 DOI: 10.3389/fncel.2024.1427525] [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: 05/03/2024] [Accepted: 09/24/2024] [Indexed: 10/22/2024] Open
Abstract
Mesenchymal stem cells (MSCs) have gained considerable attention in the field of regenerative medicine due to their ability to secrete small extracellular vesicles (EVs) known as exosomes. This review delves into the various biological activities of MSCs and the cell interactions enabled by these exosomes, with a focus on their potential for neuronal regeneration and the treatment of neurological disorders. We scrutinize findings from multiple studies that underscore the neuroprotective and neuro-regenerative effects of exosomes derived from MSCs, illuminating their mechanisms of action and therapeutic applications. This review thoroughly investigates all related pathways, miRNAs, and factors to suggest potential strategies for enhancing therapy for neurological disorders using exosomes and miRNAs, and for boosting neuronal regeneration.
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Affiliation(s)
- Aria Salehpour
- The Persian Gulf Marine Biotechnology Research Center, The Persian Gulf Biomedical Sciences Research Institute, Bushehr University of Medical Sciences, Bushehr, Iran
| | - Zahra Karimi
- The Persian Gulf Marine Biotechnology Research Center, The Persian Gulf Biomedical Sciences Research Institute, Bushehr University of Medical Sciences, Bushehr, Iran
| | - Mokhtar Ghasemi Zadeh
- The Persian Gulf Marine Biotechnology Research Center, The Persian Gulf Biomedical Sciences Research Institute, Bushehr University of Medical Sciences, Bushehr, Iran
- Student Research Committee, Bushehr University of Medical Sciences, Bushehr, Iran
| | - Mohammadreza Afshar
- The Persian Gulf Marine Biotechnology Research Center, The Persian Gulf Biomedical Sciences Research Institute, Bushehr University of Medical Sciences, Bushehr, Iran
- Student Research Committee, Bushehr University of Medical Sciences, Bushehr, Iran
| | - Ali Kameli
- The Persian Gulf Marine Biotechnology Research Center, The Persian Gulf Biomedical Sciences Research Institute, Bushehr University of Medical Sciences, Bushehr, Iran
| | - Fatemeh Mooseli
- The Persian Gulf Marine Biotechnology Research Center, The Persian Gulf Biomedical Sciences Research Institute, Bushehr University of Medical Sciences, Bushehr, Iran
- Student Research Committee, Bushehr University of Medical Sciences, Bushehr, Iran
| | - Masoud Zare
- The Persian Gulf Marine Biotechnology Research Center, The Persian Gulf Biomedical Sciences Research Institute, Bushehr University of Medical Sciences, Bushehr, Iran
| | - Alireza Afshar
- The Persian Gulf Marine Biotechnology Research Center, The Persian Gulf Biomedical Sciences Research Institute, Bushehr University of Medical Sciences, Bushehr, Iran
- Student Research Committee, Bushehr University of Medical Sciences, Bushehr, Iran
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Chen A, Qu J, You Y, Pan J, Scheper V, Lin Y, Tian X, Shu F, Luo Y, Tang J, Zhang H. Intratympanic injection of MSC-derived small extracellular vesicles protects spiral ganglion neurons from degeneration. Biomed Pharmacother 2024; 179:117392. [PMID: 39232388 DOI: 10.1016/j.biopha.2024.117392] [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: 06/05/2024] [Revised: 08/23/2024] [Accepted: 08/30/2024] [Indexed: 09/06/2024] Open
Abstract
Sensorineural hearing loss is one of the most prevalent sensory deficits. Spiral ganglion neurons (SGNs) exhibit very limited regeneration capacity and their degeneration leads to profound hearing loss. Mesenchymal stem cell-derived small extracellular vesicles (MSC-sEV) have been demonstrated to repair tissue damage in various degenerative diseases. However, the effects of MSC-sEV on SGN degeneration remain unclear. In this study, we investigated the efficacy of MSC-sEV for protection against ouabain-induced SGN degeneration. MSC-sEV were derived from rat bone marrow and their components related to neuron growth were determined by proteomic analysis. In primary culture SGNs, MSC-sEV significantly promoted neurite growth and growth cone development. The RNA-Seq analysis of SGNs showed that enriched pathways include neuron development and axon regeneration, consistent with proteomics. In ouabain induced SGN degeneration rat model, MSC-sEV administration via intratympanic injection significantly enhanced SGN survival and mitigated hearing loss. Furthermore, after ouabain treatment, SGNs displayed evident signs of apoptosis, including nuclei condensation and fragmentation, with numerous cells exhibiting TUNEL-positive. However, administration of MSC-sEV effectively decreased the number of TUNEL-positive cells and reduced caspase-3 activation. In conclusion, our findings demonstrate the potential of MSC-sEV in preventing SGN degeneration and promoting neural growth, suggesting intratympanic injection of MSC-sEV is a specific and efficient strategy for neural hearing loss.
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Affiliation(s)
- Anning Chen
- Department of Otolaryngology Head & Neck Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China; Ear Research Institute, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China
| | - Jiaxi Qu
- Department of Otolaryngology Head & Neck Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China; Ear Research Institute, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China
| | - Yunyou You
- Department of Otolaryngology Head & Neck Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China; Ear Research Institute, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China
| | - Jing Pan
- Department of Otolaryngology Head & Neck Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China; Ear Research Institute, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China
| | - Verena Scheper
- Department of Otolaryngology, Hannover Medical School, Hannover 30625, Germany; Cluster of Excellence "Hearing4all", German Research Foundation, Hannover Medical School, Hannover 30625, Germany
| | - Yongdong Lin
- Department of Otolaryngology Head & Neck Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China; Ear Research Institute, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China
| | - Xuexin Tian
- Department of Otolaryngology Head & Neck Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China; Ear Research Institute, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China
| | - Fan Shu
- Department of Otolaryngology Head & Neck Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China; Ear Research Institute, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China
| | - Yanjing Luo
- Department of Otolaryngology, Hannover Medical School, Hannover 30625, Germany; Cluster of Excellence "Hearing4all", German Research Foundation, Hannover Medical School, Hannover 30625, Germany
| | - Jie Tang
- Department of Otolaryngology Head & Neck Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China; Ear Research Institute, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China; Department of Physiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China; Key Laboratory of Mental Health of the Ministry of Education, Southern Medical University, Guangzhou 510515, China.
| | - Hongzheng Zhang
- Department of Otolaryngology Head & Neck Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China; Ear Research Institute, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China.
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Amiri M, Kaviari MA, Rostaminasab G, Barimani A, Rezakhani L. A novel cell-free therapy using exosomes in the inner ear regeneration. Tissue Cell 2024; 88:102373. [PMID: 38640600 DOI: 10.1016/j.tice.2024.102373] [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: 12/22/2023] [Revised: 03/01/2024] [Accepted: 04/03/2024] [Indexed: 04/21/2024]
Abstract
Cellular and molecular alterations associated with hearing loss are now better understood with advances in molecular biology. These changes indicate the participation of distinct damage and stress pathways that are unlikely to be fully addressed by conventional pharmaceutical treatment. Sensorineural hearing loss is a common and debilitating condition for which comprehensive pharmacologic intervention is not available. The complex and diverse molecular pathology that underlies hearing loss currently limits our ability to intervene with small molecules. The present review focuses on the potential for the use of extracellular vesicles in otology. It examines a variety of inner ear diseases and hearing loss that may be treatable using exosomes (EXOs). The role of EXOs as carriers for the treatment of diseases related to the inner ear as well as EXOs as biomarkers for the recognition of diseases related to the ear is discussed.
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Affiliation(s)
- Masoumeh Amiri
- Faculty of Medicine, Kermanshah University of Medical Science, Kermanshah, Iran
| | - Mohammad Amin Kaviari
- Student Research Committee, Kermanshah University of Medical Sciences, Kermanshah, Iran; Universal Scientific Education and Research Network (USERN) Office, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Gelavizh Rostaminasab
- Clinical Research Development Center, Imam Khomeini and Mohammad Kermanshahi and Farabi Hospitals, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Amir Barimani
- Clinical Research Development Center, Imam Khomeini and Mohammad Kermanshahi and Farabi Hospitals, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Leila Rezakhani
- Fertility and Infertility Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran; Department of Tissue Engineering, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran.
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Poongodi R, Yang TH, Huang YH, Yang KD, Chen HZ, Chu TY, Wang TY, Lin HC, Cheng JK. Stem cell exosome-loaded Gelfoam improves locomotor dysfunction and neuropathic pain in a rat model of spinal cord injury. Stem Cell Res Ther 2024; 15:143. [PMID: 38764049 PMCID: PMC11103960 DOI: 10.1186/s13287-024-03758-5] [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: 08/02/2023] [Accepted: 05/09/2024] [Indexed: 05/21/2024] Open
Abstract
BACKGROUND Spinal cord injury (SCI) is a debilitating illness in humans that causes permanent loss of movement or sensation. To treat SCI, exosomes, with their unique benefits, can circumvent limitations through direct stem cell transplantation. Therefore, we utilized Gelfoam encapsulated with exosomes derived from human umbilical cord mesenchymal stem cells (HucMSC-EX) in a rat SCI model. METHODS SCI model was established through hemisection surgery in T9 spinal cord of female Sprague-Dawley rats. Exosome-loaded Gelfoam was implanted into the lesion site. An in vivo uptake assay using labeled exosomes was conducted on day 3 post-implantation. Locomotor functions and gait analyses were assessed using Basso-Beattie-Bresnahan (BBB) locomotor rating scale and DigiGait Imaging System from weeks 1 to 8. Nociceptive responses were evaluated through von Frey filament and noxious radiant heat tests. The therapeutic effects and potential mechanisms were analyzed using Western blotting and immunofluorescence staining at week 8 post-SCI. RESULTS For the in vivo exosome uptake assay, we observed the uptake of labeled exosomes by NeuN+, Iba1+, GFAP+, and OLIG2+ cells around the injured area. Exosome treatment consistently increased the BBB score from 1 to 8 weeks compared with the Gelfoam-saline and SCI control groups. Additionally, exosome treatment significantly improved gait abnormalities including right-to-left hind paw contact area ratio, stance/stride, stride length, stride frequency, and swing duration, validating motor function recovery. Immunostaining and Western blotting revealed high expression of NF200, MBP, GAP43, synaptophysin, and PSD95 in exosome treatment group, indicating the promotion of nerve regeneration, remyelination, and synapse formation. Interestingly, exosome treatment reduced SCI-induced upregulation of GFAP and CSPG. Furthermore, levels of Bax, p75NTR, Iba1, and iNOS were reduced around the injured area, suggesting anti-inflammatory and anti-apoptotic effects. Moreover, exosome treatment alleviated SCI-induced pain behaviors and reduced pain-associated proteins (BDNF, TRPV1, and Cav3.2). Exosomal miRNA analysis revealed several promising therapeutic miRNAs. The cell culture study also confirmed the neurotrophic effect of HucMSCs-EX. CONCLUSION Implantation of HucMSCs-EX-encapsulated Gelfoam improves SCI-induced motor dysfunction and neuropathic pain, possibly through its capabilities in nerve regeneration, remyelination, anti-inflammation, and anti-apoptosis. Overall, exosomes could serve as a promising therapeutic alternative for SCI treatment.
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Affiliation(s)
- Raju Poongodi
- Department of Medical Research, MacKay Memorial Hospital, Taipei, 10449, Taiwan
| | - Tao-Hsiang Yang
- Department of Medical Research, MacKay Memorial Hospital, Taipei, 10449, Taiwan
| | - Ya-Hsien Huang
- Department of Anesthesiology, MacKay Memorial Hospital, Taipei, 10449, Taiwan
- Department of Medicine, MacKay Medical College, New Taipei City, 25245, Taiwan
| | - Kuender D Yang
- Institute of Long-Term Care, MacKay Medical College, New Taipei City, 25245, Taiwan.
- Department of Pediatrics, MacKay Memorial Hospital, Taipei, 10449, Taiwan.
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, 11221, Taiwan.
| | - Hong-Zhao Chen
- Department of Medical Research, MacKay Memorial Hospital, Taipei, 10449, Taiwan
| | - Tsuei-Yu Chu
- Department of Medical Research, MacKay Memorial Hospital, Taipei, 10449, Taiwan
| | - Tao-Yeuan Wang
- Department of Medicine, MacKay Medical College, New Taipei City, 25245, Taiwan
- Department of Pathology, MacKay Memorial Hospital, Taipei, 10449, Taiwan
| | - Hsin-Chieh Lin
- Department of Materials Science and Engineering, National Yang Ming Chiao Tung University, Hsinchu, 300093, Taiwan
- Center for Intelligent Drug Systems and Smart Bio-Devices (IDS 2 B), National Yang Ming Chiao Tung University, Hsinchu, 30068, Taiwan
| | - Jen-Kun Cheng
- Department of Medical Research, MacKay Memorial Hospital, Taipei, 10449, Taiwan.
- Department of Anesthesiology, MacKay Memorial Hospital, Taipei, 10449, Taiwan.
- Department of Medicine, MacKay Medical College, New Taipei City, 25245, Taiwan.
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Krishnan I, Chan AML, Law JX, Ng MH, Jayapalan JJ, Lokanathan Y. Proteomic Analysis of Umbilical Cord Mesenchymal Stem Cell-Derived Extracellular Vesicles: A Systematic Review. Int J Mol Sci 2024; 25:5340. [PMID: 38791378 PMCID: PMC11121203 DOI: 10.3390/ijms25105340] [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: 03/26/2024] [Revised: 04/29/2024] [Accepted: 05/01/2024] [Indexed: 05/26/2024] Open
Abstract
Numerous challenges remain within conventional cell-based therapy despite the growing trend of stem cells used to treat various life-debilitating diseases. These limitations include batch-to-batch heterogeneity, induced alloreactivity, cell survival and integration, poor scalability, and high cost of treatment, thus hindering successful translation from lab to bedside. However, recent pioneering technology has enabled the isolation and enrichment of small extracellular vesicles (EVs), canonically known as exosomes. EVs are described as a membrane-enclosed cargo of functional biomolecules not limited to lipids, nucleic acid, and proteins. Interestingly, studies have correlated the biological role of MSC-EVs to the paracrine activity of MSCs. This key evidence has led to rigorous studies on MSC-EVs as an acellular alternative. Using EVs as a therapy was proposed as a model leading to improvements through increased safety; enhanced bioavailability due to size and permeability; reduced heterogeneity by selective and quantifiable properties; and prolonged shelf-life via long-term freezing or lyophilization. Yet, the identity and potency of EVs are still relatively unknown due to various methods of preparation and to qualify the final product. This is reflected by the absence of regulatory strategies overseeing manufacturing, quality control, clinical implementation, and product registration. In this review, the authors review the various production processes and the proteomic profile of MSC-EVs.
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Affiliation(s)
- Illayaraja Krishnan
- Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur 56000, Malaysia; (I.K.); (A.M.L.C.); (J.X.L.); (M.H.N.)
| | - Alvin Man Lung Chan
- Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur 56000, Malaysia; (I.K.); (A.M.L.C.); (J.X.L.); (M.H.N.)
| | - Jia Xian Law
- Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur 56000, Malaysia; (I.K.); (A.M.L.C.); (J.X.L.); (M.H.N.)
| | - Min Hwei Ng
- Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur 56000, Malaysia; (I.K.); (A.M.L.C.); (J.X.L.); (M.H.N.)
| | | | - Yogeswaran Lokanathan
- Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur 56000, Malaysia; (I.K.); (A.M.L.C.); (J.X.L.); (M.H.N.)
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Xu Y, Zhao H, Wang F, Xu S, Wang C, Li Y, Wang Y, Nong H, Zhang J, Cao Z, Chen C, Li J. SERCA2 protects against cisplatin-induced damage of auditory cells: Possible relation with alleviation of ER stress. Toxicol Appl Pharmacol 2024; 486:116947. [PMID: 38688426 DOI: 10.1016/j.taap.2024.116947] [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: 02/04/2024] [Revised: 04/10/2024] [Accepted: 04/25/2024] [Indexed: 05/02/2024]
Abstract
AIMS SERCA2, one of the P-type pumps encoded by gene ATP2A2, is the only calcium reflux channel of the endoplasmic reticulum (ER) and participates in maintaining calcium homeostasis. The present study was designed to explore SERCA2 expression pattern in auditory hair cells and the possible mechanism underlying the effects of SERCA2 on cisplatin-induced ototoxicity. MAIN METHODS The SERCA2 expression pattern in cochlea hair cells and HEI-OC1 cells was measured by Western blot (WB) and immunofluorescence staining. The apoptosis and its related factors were detected by TUNEL assay and WB. The expression levels of ER stress-related factors, ATF6, PERK, IRE1α, and GRP78, were measured via WB. As for the determination of SERCA2 overexpression and knockdown, plasmids and lentiviral vectors were constructed, respectively. KEY FINDINGS We found that SERCA2 was highly expressed in cochlea hair cells and HEI-OC1 cells. Of note, the level of SERCA2 expression in neonatal mice was remarkably higher than that in adult mice. Under the exposure of 30 μM cisplatin, SERCA2 was down-regulated significantly compared with the control group. In addition, cisplatin administration triggered the occurrence of ER stress and apoptosis. Those events were reversed by overexpressing SERCA2. On the contrary, SERCA2 knockdown could aggravate the above processes. SIGNIFICANCE The findings from the present study disclose, for the first time, that SERCA2 is abundantly expressed in cochlea hair cells, and the suppression of SERCA2 caused by cisplatin could trigger ER homeostasis disruption, thereby implying that SERCA2 might be a promising target to prevent cisplatin-induced cytotoxicity of hair cells.
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Affiliation(s)
- Yue Xu
- Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial Hospital, Shandong University, Jinan, Shandong 250021, China
| | - Hao Zhao
- Department of Otolaryngology-Head and Neck Surgery, People's Hospital, Peking University, Beijing 100000, China
| | - Fan Wang
- Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial Hospital, Shandong University, Jinan, Shandong 250021, China
| | - Shuai Xu
- Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial Hospital, Shandong University, Jinan, Shandong 250021, China
| | - Chen Wang
- Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial Hospital, Shandong University, Jinan, Shandong 250021, China
| | - Yanan Li
- Department of Otolaryngology-Head and Neck Surgery Shandong Provincial Hospital affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China
| | - Yajie Wang
- Department of Otolaryngology-Head and Neck Surgery Shandong Provincial Hospital affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China
| | - Huiming Nong
- Department of Otolaryngology-Head and Neck Surgery Shandong Provincial Hospital affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China
| | - Junhong Zhang
- Department of Otolaryngology-Head and Neck Surgery Shandong Provincial Hospital affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China
| | - Zhixin Cao
- Department of Pathology Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China
| | - Chengfang Chen
- Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial Hospital, Shandong University, Jinan, Shandong 250021, China; Department of Otolaryngology-Head and Neck Surgery Shandong Provincial Hospital affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China.
| | - Jianfeng Li
- Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial Hospital, Shandong University, Jinan, Shandong 250021, China; Department of Otolaryngology-Head and Neck Surgery Shandong Provincial Hospital affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China; Shandong Provincial Key Laboratory of Otology, Jinan, Shandong 250021, China.
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Zhang X, Che X, Zhang S, Wang R, Li M, Jin Y, Wang T, Song Y. Mesenchymal stem cell-derived extracellular vesicles for human diseases. EXTRACELLULAR VESICLES AND CIRCULATING NUCLEIC ACIDS 2024; 5:64-82. [PMID: 39698413 PMCID: PMC11648454 DOI: 10.20517/evcna.2023.47] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Revised: 01/26/2024] [Accepted: 02/01/2024] [Indexed: 12/20/2024]
Abstract
Stem cell therapy is a novel approach for treating various severe and intractable diseases, including autoimmune disorders, organ transplants, tumors, and neurodegenerative diseases. Nevertheless, the extensive utilization of stem cells is constrained by potential tumorigenicity, challenges in precise differentiation, rejection concerns, and ethical considerations. Extracellular vesicles possess the ability to carry diverse bioactive factors from stem cells and deliver them to specific target cells or tissues. Moreover, they offer the advantage of low immunogenicity. Consequently, they have the potential to facilitate the therapeutic potential of stem cells, mitigating the risks associated with direct stem cell application. Therefore, the use of stem cell extracellular vesicles in clinical diseases has received increasing attention. This review summarizes advances in the use of extracellular vesicles from mesenchymal stem cells (MSC). MSC extracellular vesicles are used in the treatment of inflammatory diseases such as rheumatoid arthritis, liver injury, COVID-19, and allergies; in the repair of tissue damage in heart disease, kidney injury, and osteoarthritic diseases; as a carrier in the treatment of tumors; and as a regenerative agent in neurodegenerative disorders such as Alzheimer's and Parkinson's.
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Affiliation(s)
- Xiaofang Zhang
- Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Cancer Hospital of Dalian University of Technology, Faculty of Medicine, Dalian University of Technology, Shenyang 110042, Liaoning, China
- Authors contributed equally
| | - Xiaofang Che
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang 110001, Liaoning, China
- Authors contributed equally
| | - Sibo Zhang
- The Fourth Hospital of China Medical University, Shenyang 110032, Liaoning, China
- Authors contributed equally
| | - Runze Wang
- Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Cancer Hospital of Dalian University of Technology, Faculty of Medicine, Dalian University of Technology, Shenyang 110042, Liaoning, China
| | - Mo Li
- Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Cancer Hospital of Dalian University of Technology, Faculty of Medicine, Dalian University of Technology, Shenyang 110042, Liaoning, China
| | - Yi Jin
- Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Cancer Hospital of Dalian University of Technology, Faculty of Medicine, Dalian University of Technology, Shenyang 110042, Liaoning, China
| | - Tianlu Wang
- Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Cancer Hospital of Dalian University of Technology, Faculty of Medicine, Dalian University of Technology, Shenyang 110042, Liaoning, China
| | - Yingqiu Song
- Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Cancer Hospital of Dalian University of Technology, Faculty of Medicine, Dalian University of Technology, Shenyang 110042, Liaoning, China
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10
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Wang Y, Xu R, Yan Y, He B, Miao C, Fang Y, Wan H, Zhou G. Exosomes-Mediated Signaling Pathway: A New Direction for Treatment of Organ Ischemia-Reperfusion Injury. Biomedicines 2024; 12:353. [PMID: 38397955 PMCID: PMC10886966 DOI: 10.3390/biomedicines12020353] [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: 12/31/2023] [Revised: 01/24/2024] [Accepted: 01/31/2024] [Indexed: 02/25/2024] Open
Abstract
Ischemia reperfusion (I/R) is a common pathological process which occurs mostly in organs like the heart, brain, kidney, and lung. The injury caused by I/R gradually becomes one of the main causes of fatal diseases, which is an urgent clinical problem to be solved. Although great progress has been made in therapeutic methods, including surgical, drug, gene therapy, and transplant therapy for I/R injury, the development of effective methods to cure the injury remains a worldwide challenge. In recent years, exosomes have attracted much attention for their important roles in immune response, antigen presentation, cell migration, cell differentiation, and tumor invasion. Meanwhile, exosomes have been shown to have great potential in the treatment of I/R injury in organs. The study of the exosome-mediated signaling pathway can not only help to reveal the mechanism behind exosomes promoting reperfusion injury recovery, but also provide a theoretical basis for the clinical application of exosomes. Here, we review the research progress in utilizing various exosomes from different cell types to promote the healing of I/R injury, focusing on the classical signaling pathways such as PI3K/Akt, NF-κB, Nrf2, PTEN, Wnt, MAPK, toll-like receptor, and AMPK. The results suggest that exosomes regulate these signaling pathways to reduce oxidative stress, regulate immune responses, decrease the expression of inflammatory cytokines, and promote tissue repair, making exosomes a competitive emerging vector for treating I/R damage in organs.
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Affiliation(s)
- Yanying Wang
- The Second Clinical Medical College, Zhejiang Chinese Medical University, 548 Binwen Road, Hangzhou 310053, China; (Y.W.); (B.H.); (C.M.)
| | - Ruojiao Xu
- College of Life Science, Zhejiang Chinese Medical University, 548 Binwen Road, Hangzhou 310053, China; (R.X.); (Y.Y.); (Y.F.)
| | - Yujia Yan
- College of Life Science, Zhejiang Chinese Medical University, 548 Binwen Road, Hangzhou 310053, China; (R.X.); (Y.Y.); (Y.F.)
| | - Binyu He
- The Second Clinical Medical College, Zhejiang Chinese Medical University, 548 Binwen Road, Hangzhou 310053, China; (Y.W.); (B.H.); (C.M.)
| | - Chaoyi Miao
- The Second Clinical Medical College, Zhejiang Chinese Medical University, 548 Binwen Road, Hangzhou 310053, China; (Y.W.); (B.H.); (C.M.)
| | - Yifeng Fang
- College of Life Science, Zhejiang Chinese Medical University, 548 Binwen Road, Hangzhou 310053, China; (R.X.); (Y.Y.); (Y.F.)
| | - Haitong Wan
- College of Life Science, Zhejiang Chinese Medical University, 548 Binwen Road, Hangzhou 310053, China; (R.X.); (Y.Y.); (Y.F.)
| | - Guoying Zhou
- College of Life Science, Zhejiang Chinese Medical University, 548 Binwen Road, Hangzhou 310053, China; (R.X.); (Y.Y.); (Y.F.)
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11
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Pan X, Li Y, Huang P, Staecker H, He M. Extracellular vesicles for developing targeted hearing loss therapy. J Control Release 2024; 366:460-478. [PMID: 38182057 DOI: 10.1016/j.jconrel.2023.12.050] [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: 10/12/2023] [Revised: 12/19/2023] [Accepted: 12/28/2023] [Indexed: 01/07/2024]
Abstract
Substantial efforts have been made for local administration of small molecules or biologics in treating hearing loss diseases caused by either trauma, genetic mutations, or drug ototoxicity. Recently, extracellular vesicles (EVs) naturally secreted from cells have drawn increasing attention on attenuating hearing impairment from both preclinical studies and clinical studies. Highly emerging field utilizing diverse bioengineering technologies for developing EVs as the bioderived therapeutic materials, along with artificial intelligence (AI)-based targeting toolkits, shed the light on the unique properties of EVs specific to inner ear delivery. This review will illuminate such exciting research field from fundamentals of hearing protective functions of EVs to biotechnology advancement and potential clinical translation of functionalized EVs. Specifically, the advancements in assessing targeting ligands using AI algorithms are systematically discussed. The overall translational potential of EVs is reviewed in the context of auditory sensing system for developing next generation gene therapy.
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Affiliation(s)
- Xiaoshu Pan
- Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, Florida 32610, United States
| | - Yanjun Li
- Department of Medicinal Chemistry, Center for Natural Products, Drug Discovery and Development, University of Florida, Gainesville, Florida 32610, United States
| | - Peixin Huang
- Department of Otolaryngology, Head and Neck Surgery, University of Kansas School of Medicine, Kansas City, Kansas 66160, United States
| | - Hinrich Staecker
- Department of Otolaryngology, Head and Neck Surgery, University of Kansas School of Medicine, Kansas City, Kansas 66160, United States.
| | - Mei He
- Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, Florida 32610, United States.
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12
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Huang JP, Lin CH, Tseng CW, Chien MH, Lee HC, Yang KD. First-trimester urinary extracellular vesicles as predictors of preterm birth: an insight into immune programming. Front Cell Dev Biol 2024; 11:1330049. [PMID: 38357529 PMCID: PMC10864598 DOI: 10.3389/fcell.2023.1330049] [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: 10/30/2023] [Accepted: 12/20/2023] [Indexed: 02/16/2024] Open
Abstract
Background: The programming of innate and adaptive immunity plays a pivotal role in determining the course of pregnancy, leading to either normal term birth (TB) or preterm birth (PB) through the modulation of macrophage (M1/M2) differentiation. Extracellular vesicles (EVs) in maternal blood, harboring a repertoire of physiological and pathological messengers, are integral players in pregnancy outcomes. It is unknown whether urinary EVs (UEVs) could serve as a non-invasive mechanistic biomarker for predicting PB. Methods: This study investigated first-trimester UEVs carrying M1 messengers with altered immune programming, aiming to discern their correlation to subsequent PB. A birth cohort comprising 501 pregnant women, with 40 women experiencing PB matched to 40 women experiencing TB on the same day, was examined. First-trimester UEVs were isolated for the quantification of immune mediators. Additionally, we evaluated the UEV modulation of "trained immunity" on macrophage and lymphocyte differentiations, including mRNA expression profiles, and chromatin activation modification at histone 3 lysine 4 trimethylation (H3K4me3). Results: We found a significant elevation (p < 0.05) in the particles of UEVs bearing characteristic exosome markers (CD9/CD63/CD81/syntenin) during the first trimester of pregnancy compared to non-pregnant samples. Furthermore, UEVs from PB demonstrated significantly heightened levels of MCP-1 (p = 0.003), IL-6 (p = 0.041), IL-17A (p = 0.007), IP-10 (p = 0.036), TNFα (p = 0.004), IL-12 (p = 0.045), and IFNγ (p = 0.030) relative to those from TB, indicative of altered M1 and Th17 differentiation. Notably, MCP-1 (>174 pg/mL) exhibited a sensitivity of 71.9% and specificity of 64.6%, and MCP-1 (>174 pg/mL) and IFNγ (>8.7 pg/mL) provided a higher sensitivity (84.6%) of predicting PB and moderate specificity of 66.7%. Subsequent investigations showed that UEVs from TB exerted a significant suppression of M1 differentiation (iNOS expression) and Th17 differentiation (RORrT expression) compared to those of PB. Conversely, UEVs derived from PB induced a significantly higher expression of chromatin modification at H3K4me3 with higher production of IL-8 and TNFα cytokines (p < 0.001). Implications: This pioneering study provides critical evidence for the early detection of altered M1 and Th17 responses within UEVs as a predictor of PB and early modulation of altered M1 and Th17 polarization associated with better T-cell regulatory differentiation as a potential prevention of subsequent PB.
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Affiliation(s)
- Jian-Pei Huang
- Department of Obstetrics and Gynecology, Mackay Memorial Hospital, Taipei, Taiwan
- Department of Medicine, Mackay Medical College, New Taipei City, Taiwan
- MacKay Junior College of Medicine, Nursing and Management, New Taipei City, Taiwan
| | - Chia-Hsueh Lin
- Department of Medical Research, Mackay Memorial Hospital, Taipei, Taiwan
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Chih-Wen Tseng
- Department of Medical Research, Mackay Memorial Hospital, Taipei, Taiwan
| | - Ming-Hui Chien
- Department of Medical Research, Mackay Memorial Hospital, Taipei, Taiwan
| | | | - Kuender D. Yang
- Department of Medical Research, Mackay Memorial Hospital, Taipei, Taiwan
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Mackay Children’s Hospital, Taipei, Taiwan
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13
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Zhu K, Wang T, Li S, Liu Z, Zhan Y, Zhang Q. NcRNA: key and potential in hearing loss. Front Neurosci 2024; 17:1333131. [PMID: 38298898 PMCID: PMC10827912 DOI: 10.3389/fnins.2023.1333131] [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: 11/04/2023] [Accepted: 12/18/2023] [Indexed: 02/02/2024] Open
Abstract
Hearing loss has an extremely high prevalence worldwide and brings incredible economic and social burdens. Mechanisms such as epigenetics are profoundly involved in the initiation and progression of hearing loss and potentially yield definite strategies for hearing loss treatment. Non-coding genes occupy 97% of the human genome, and their transcripts, non-coding RNAs (ncRNAs), are widely participated in regulating various physiological and pathological situations. NcRNAs, mainly including micro-RNAs (miRNAs), long-stranded non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), are involved in the regulation of cell metabolism and cell death by modulating gene expression and protein-protein interactions, thus impacting the occurrence and prognosis of hearing loss. This review provides a detailed overview of ncRNAs, especially miRNAs and lncRNAs, in the pathogenesis of hearing loss. We also discuss the shortcomings and issues that need to be addressed in the study of hearing loss ncRNAs in the hope of providing viable therapeutic strategies for the precise treatment of hearing loss.
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Affiliation(s)
- Keyu Zhu
- Department of Plastic and Cosmetic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ting Wang
- Department of Medical Ultrasound, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
| | - Sicheng Li
- Department of Plastic Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Zeming Liu
- Department of Plastic and Cosmetic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yuanyuan Zhan
- Department of Plastic and Cosmetic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qi Zhang
- Department of Plastic and Cosmetic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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14
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Liu H, Kuang H, Wang Y, Bao L, Cao W, Yu L, Qi M, Wang R, Yang X, Ye Q, Ding F, Ren L, Liu S, Ma F, Liu S. MSC-derived exosomes protect auditory hair cells from neomycin-induced damage via autophagy regulation. Biol Res 2024; 57:3. [PMID: 38217055 PMCID: PMC10787390 DOI: 10.1186/s40659-023-00475-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Accepted: 11/10/2023] [Indexed: 01/14/2024] Open
Abstract
BACKGROUND Sensorineural hearing loss (SNHL) poses a major threat to both physical and mental health; however, there is still a lack of effective drugs to treat the disease. Recently, novel biological therapies, such as mesenchymal stem cells (MSCs) and their products, namely, exosomes, are showing promising therapeutic potential due to their low immunogenicity, few ethical concerns, and easy accessibility. Nevertheless, the precise mechanisms underlying the therapeutic effects of MSC-derived exosomes remain unclear. RESULTS Exosomes derived from MSCs reduced hearing and hair cell loss caused by neomycin-induced damage in models in vivo and in vitro. In addition, MSC-derived exosomes modulated autophagy in hair cells to exert a protective effect. Mechanistically, exogenously administered exosomes were internalized by hair cells and subsequently upregulated endocytic gene expression and endosome formation, ultimately leading to autophagy activation. This increased autophagic activity promoted cell survival, decreased the mitochondrial oxidative stress level and the apoptosis rate in hair cells, and ameliorated neomycin-induced ototoxicity. CONCLUSIONS In summary, our findings reveal the otoprotective capacity of exogenous exosome-mediated autophagy activation in hair cells in an endocytosis-dependent manner, suggesting possibilities for deafness treatment.
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Affiliation(s)
- Huan Liu
- Department of Otolaryngology Head and Neck Surgery, Peking University Third Hospital, Beijing, China
| | - Huijuan Kuang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology,, The Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Yiru Wang
- Anesthesiology Department, Seventh Medical Center of PLA General Hospital, Beijing, China
| | - Lili Bao
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology,, The Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Wanxin Cao
- Department of Otolaryngology Head and Neck Surgery, Peking University Third Hospital, Beijing, China
| | - Lu Yu
- Department of Periodontology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University and Shandong Key Laboratory of Oral Tissue Regeneration and Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration and Shandong Provincial Clinical Research Center for Oral Diseases, Jinan, Shandong, China
| | - Meihao Qi
- Department of Otolaryngology-Head and Neck Surgery, Xijing Hospital, Air Force Military, Xi'an, Shaanxi, China
| | - Renfeng Wang
- Department of Otolaryngology-Head and Neck Surgery, Xijing Hospital, Air Force Military, Xi'an, Shaanxi, China
| | - Xiaoshan Yang
- School of Stomatology, Stomatological Hospital, Southern Medical University, Guangzhou, China
| | - Qingyuan Ye
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Key Laboratory of Stomatology, Digital Dentistry Center, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Feng Ding
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology,, The Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Lili Ren
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology,, The Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Siying Liu
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology,, The Fourth Military Medical University, Xi'an, Shaanxi, China.
| | - Furong Ma
- Department of Otolaryngology Head and Neck Surgery, Peking University Third Hospital, Beijing, China.
| | - Shiyu Liu
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology,, The Fourth Military Medical University, Xi'an, Shaanxi, China.
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15
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Tan F, Li X, Wang Z, Li J, Shahzad K, Zheng J. Clinical applications of stem cell-derived exosomes. Signal Transduct Target Ther 2024; 9:17. [PMID: 38212307 PMCID: PMC10784577 DOI: 10.1038/s41392-023-01704-0] [Citation(s) in RCA: 136] [Impact Index Per Article: 136.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2023] [Revised: 10/15/2023] [Accepted: 11/12/2023] [Indexed: 01/13/2024] Open
Abstract
Although stem cell-based therapy has demonstrated considerable potential to manage certain diseases more successfully than conventional surgery, it nevertheless comes with inescapable drawbacks that might limit its clinical translation. Compared to stem cells, stem cell-derived exosomes possess numerous advantages, such as non-immunogenicity, non-infusion toxicity, easy access, effortless preservation, and freedom from tumorigenic potential and ethical issues. Exosomes can inherit similar therapeutic effects from their parental cells such as embryonic stem cells and adult stem cells through vertical delivery of their pluripotency or multipotency. After a thorough search and meticulous dissection of relevant literature from the last five years, we present this comprehensive, up-to-date, specialty-specific and disease-oriented review to highlight the surgical application and potential of stem cell-derived exosomes. Exosomes derived from stem cells (e.g., embryonic, induced pluripotent, hematopoietic, mesenchymal, neural, and endothelial stem cells) are capable of treating numerous diseases encountered in orthopedic surgery, neurosurgery, plastic surgery, general surgery, cardiothoracic surgery, urology, head and neck surgery, ophthalmology, and obstetrics and gynecology. The diverse therapeutic effects of stem cells-derived exosomes are a hierarchical translation through tissue-specific responses, and cell-specific molecular signaling pathways. In this review, we highlight stem cell-derived exosomes as a viable and potent alternative to stem cell-based therapy in managing various surgical conditions. We recommend that future research combines wisdoms from surgeons, nanomedicine practitioners, and stem cell researchers in this relevant and intriguing research area.
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Affiliation(s)
- Fei Tan
- Department of ORL-HNS, Shanghai Fourth People's Hospital, and School of Medicine, Tongji University, Shanghai, China.
- Plasma Medicine and Surgical Implants Center, Tongji University, Shanghai, China.
- The Royal College of Surgeons in Ireland, Dublin, Ireland.
- The Royal College of Surgeons of England, London, UK.
| | - Xuran Li
- Department of ORL-HNS, Shanghai Fourth People's Hospital, and School of Medicine, Tongji University, Shanghai, China
- Plasma Medicine and Surgical Implants Center, Tongji University, Shanghai, China
| | - Zhao Wang
- Department of ORL-HNS, Shanghai Fourth People's Hospital, and School of Medicine, Tongji University, Shanghai, China
| | - Jiaojiao Li
- Department of ORL-HNS, Shanghai Fourth People's Hospital, and School of Medicine, Tongji University, Shanghai, China
- Plasma Medicine and Surgical Implants Center, Tongji University, Shanghai, China
| | - Khawar Shahzad
- Department of ORL-HNS, Shanghai Fourth People's Hospital, and School of Medicine, Tongji University, Shanghai, China
- Plasma Medicine and Surgical Implants Center, Tongji University, Shanghai, China
| | - Jialin Zheng
- Center for Translational Neurodegeneration and Regenerative Therapy, Tongji Hospital affiliated to Tongji University School of Medicine, Shanghai, China
- Shanghai Frontiers Science Center of Nanocatalytic Medicine, Tongji University, Shanghai, China
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16
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Lye J, Delaney DS, Leith FK, Sardesai VS, McLenachan S, Chen FK, Atlas MD, Wong EYM. Recent Therapeutic Progress and Future Perspectives for the Treatment of Hearing Loss. Biomedicines 2023; 11:3347. [PMID: 38137568 PMCID: PMC10741758 DOI: 10.3390/biomedicines11123347] [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: 11/16/2023] [Revised: 12/06/2023] [Accepted: 12/11/2023] [Indexed: 12/24/2023] Open
Abstract
Up to 1.5 billion people worldwide suffer from various forms of hearing loss, with an additional 1.1 billion people at risk from various insults such as increased consumption of recreational noise-emitting devices and ageing. The most common type of hearing impairment is sensorineural hearing loss caused by the degeneration or malfunction of cochlear hair cells or spiral ganglion nerves in the inner ear. There is currently no cure for hearing loss. However, emerging frontier technologies such as gene, drug or cell-based therapies offer hope for an effective cure. In this review, we discuss the current therapeutic progress for the treatment of hearing loss. We describe and evaluate the major therapeutic approaches being applied to hearing loss and summarize the key trials and studies.
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Affiliation(s)
- Joey Lye
- Hearing Therapeutics, Ear Science Institute Australia, Nedlands, WA 6009, Australia; (J.L.); (D.S.D.); (F.K.L.); (V.S.S.); (M.D.A.)
- Centre for Ear Sciences, Medical School, The University of Western Australia, Nedlands, WA 6009, Australia
| | - Derek S. Delaney
- Hearing Therapeutics, Ear Science Institute Australia, Nedlands, WA 6009, Australia; (J.L.); (D.S.D.); (F.K.L.); (V.S.S.); (M.D.A.)
- Faculty of Health Sciences, Curtin Health Innovation Research Institute, Curtin University, Bentley, WA 6102, Australia
| | - Fiona K. Leith
- Hearing Therapeutics, Ear Science Institute Australia, Nedlands, WA 6009, Australia; (J.L.); (D.S.D.); (F.K.L.); (V.S.S.); (M.D.A.)
- Centre for Ear Sciences, Medical School, The University of Western Australia, Nedlands, WA 6009, Australia
| | - Varda S. Sardesai
- Hearing Therapeutics, Ear Science Institute Australia, Nedlands, WA 6009, Australia; (J.L.); (D.S.D.); (F.K.L.); (V.S.S.); (M.D.A.)
| | - Samuel McLenachan
- Ocular Tissue Engineering Laboratory, Lions Eye Institute, Nedlands, WA 6009, Australia; (S.M.); (F.K.C.)
- Centre for Ophthalmology and Visual Sciences, The University of Western Australia, Nedlands, WA 6009, Australia
| | - Fred K. Chen
- Ocular Tissue Engineering Laboratory, Lions Eye Institute, Nedlands, WA 6009, Australia; (S.M.); (F.K.C.)
- Centre for Ophthalmology and Visual Sciences, The University of Western Australia, Nedlands, WA 6009, Australia
- Vitroretinal Surgery, Royal Perth Hospital, Perth, WA 6000, Australia
- Ophthalmology, Department of Surgery, University of Melbourne, East Melbourne, VIC 3002, Australia
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, VIC 3002, Australia
| | - Marcus D. Atlas
- Hearing Therapeutics, Ear Science Institute Australia, Nedlands, WA 6009, Australia; (J.L.); (D.S.D.); (F.K.L.); (V.S.S.); (M.D.A.)
- Centre for Ear Sciences, Medical School, The University of Western Australia, Nedlands, WA 6009, Australia
| | - Elaine Y. M. Wong
- Hearing Therapeutics, Ear Science Institute Australia, Nedlands, WA 6009, Australia; (J.L.); (D.S.D.); (F.K.L.); (V.S.S.); (M.D.A.)
- Centre for Ear Sciences, Medical School, The University of Western Australia, Nedlands, WA 6009, Australia
- Curtin Medical School, Faculty of Health Sciences, Curtin University, Bentley, WA 6102, Australia
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Min X, Deng XH, Lao H, Wu ZC, Chen Y, Luo Y, Wu H, Wang J, Fu QL, Xiong H. BDNF-enriched small extracellular vesicles protect against noise-induced hearing loss in mice. J Control Release 2023; 364:546-561. [PMID: 37939851 DOI: 10.1016/j.jconrel.2023.11.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2023] [Revised: 11/03/2023] [Accepted: 11/04/2023] [Indexed: 11/10/2023]
Abstract
Noise-induced hearing loss (NIHL) is one of the most prevalent acquired sensorineural hearing loss etiologies and is characterized by the loss of cochlear hair cells, synapses, and nerve terminals. Currently, there are no agents available for the treatment of NIHL because drug delivery to the inner ear is greatly limited by the blood-labyrinth barrier. In this study, we used mesenchymal stem cell-derived small extracellular vesicles (MSC-sEVs) as nanoscale vehicles to deliver brain-derived neurotrophic factor (BDNF) and evaluated their protective effects in a mouse model of NIHL. Following intravenous administration, BDNF-loaded sEVs (BDNF-sEVs) efficiently increased the expression of BDNF protein in the cochlea. Systemic application of sEVs and BDNF-sEVs significantly attenuated noise-induced cochlear hair cell loss and NIHL in CBA/J mice. BDNF-sEVs also alleviated noise-induced loss of inner hair cell ribbon synapses and cochlear nerve terminals. In cochlear explants, sEVs and BDNF-sEVs effectively protected hair cells against H2O2-induced cell loss. Additionally, BDNF-sEVs remarkably ameliorated H2O2-induced oxidative stress, cell apoptosis, and cochlear nerve terminal degeneration. Transcriptomic analysis revealed that many mRNAs and miRNAs were involved in the protective actions of BDNF-sEVs against oxidative stress. Collectively, our findings reveal a novel therapeutic strategy of MSC-sEVs-mediated BDNF delivery for the treatment of NIHL.
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Affiliation(s)
- Xin Min
- Department of Otolaryngology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, PR China; Institute of Hearing and Speech-Language Science, Sun Yat-sen University, Guangzhou 510120, PR China
| | - Xiao-Hui Deng
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, PR China; Extracellular Vesicle Research and Clinical Translational Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, PR China; Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, PR China
| | - Huilin Lao
- Department of Otolaryngology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, PR China; Institute of Hearing and Speech-Language Science, Sun Yat-sen University, Guangzhou 510120, PR China
| | - Zi-Cong Wu
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, PR China; Extracellular Vesicle Research and Clinical Translational Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, PR China
| | - Yi Chen
- Department of Otolaryngology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, PR China; Institute of Hearing and Speech-Language Science, Sun Yat-sen University, Guangzhou 510120, PR China
| | - Yuelian Luo
- Department of Otolaryngology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, PR China; Institute of Hearing and Speech-Language Science, Sun Yat-sen University, Guangzhou 510120, PR China
| | - Haoyang Wu
- Department of Otolaryngology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, PR China; Institute of Hearing and Speech-Language Science, Sun Yat-sen University, Guangzhou 510120, PR China
| | - Junbo Wang
- Department of Otolaryngology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, PR China; Institute of Hearing and Speech-Language Science, Sun Yat-sen University, Guangzhou 510120, PR China
| | - Qing-Ling Fu
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, PR China; Extracellular Vesicle Research and Clinical Translational Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, PR China.
| | - Hao Xiong
- Department of Otolaryngology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, PR China; Institute of Hearing and Speech-Language Science, Sun Yat-sen University, Guangzhou 510120, PR China.
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18
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Zhang S, Yahaya BH, Pan Y, Liu Y, Lin J. Menstrual blood-derived endometrial stem cell, a unique and promising alternative in the stem cell-based therapy for chemotherapy-induced premature ovarian insufficiency. Stem Cell Res Ther 2023; 14:327. [PMID: 37957675 PMCID: PMC10644549 DOI: 10.1186/s13287-023-03551-w] [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: 12/16/2022] [Accepted: 10/27/2023] [Indexed: 11/15/2023] Open
Abstract
Chemotherapy can cause ovarian dysfunction and infertility since the ovary is extremely sensitive to chemotherapeutic drugs. Apart from the indispensable role of the ovary in the overall hormonal milieu, ovarian dysfunction also affects many other organ systems and functions including sexuality, bones, the cardiovascular system, and neurocognitive function. Although conventional hormone replacement therapy can partly relieve the adverse symptoms of premature ovarian insufficiency (POI), the treatment cannot fundamentally prevent deterioration of POI. Therefore, effective treatments to improve chemotherapy-induced POI are urgently needed, especially for patients desiring fertility preservation. Recently, mesenchymal stem cell (MSC)-based therapies have resulted in promising improvements in chemotherapy-induced ovary dysfunction by enhancing the anti-apoptotic capacity of ovarian cells, preventing ovarian follicular atresia, promoting angiogenesis and improving injured ovarian structure and the pregnancy rate. These improvements are mainly attributed to MSC-derived biological factors, functional RNAs, and even mitochondria, which are directly secreted or indirectly translocated with extracellular vesicles (microvesicles and exosomes) to repair ovarian dysfunction. Additionally, as a novel source of MSCs, menstrual blood-derived endometrial stem cells (MenSCs) have exhibited promising therapeutic effects in various diseases due to their comprehensive advantages, such as periodic and non-invasive sample collection, abundant sources, regular donation and autologous transplantation. Therefore, this review summarizes the efficacy of MSCs transplantation in improving chemotherapy-induced POI and analyzes the underlying mechanism, and further discusses the benefit and existing challenges in promoting the clinical application of MenSCs in chemotherapy-induced POI.
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Affiliation(s)
- Shenghui Zhang
- Stem Cell and Biotherapy Technology Research Center, Henan Joint International Research Laboratory of Stem Cell Medicine, Xinxiang Medical University, East of JinSui Road, Xinxiang, Henan, China
- Lung Stem Cell and Gene Therapy Group, Regenerative Medicine Cluster, Advanced Medical and Dental Institute (IPPT), Universiti Sains Malaysia, Penang, Malaysia
| | - Badrul Hisham Yahaya
- Lung Stem Cell and Gene Therapy Group, Regenerative Medicine Cluster, Advanced Medical and Dental Institute (IPPT), Universiti Sains Malaysia, Penang, Malaysia
| | - Ying Pan
- The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, , China
| | - Yanli Liu
- Stem Cell and Biotherapy Technology Research Center, Henan Joint International Research Laboratory of Stem Cell Medicine, Xinxiang Medical University, East of JinSui Road, Xinxiang, Henan, China.
| | - Juntang Lin
- Stem Cell and Biotherapy Technology Research Center, Henan Joint International Research Laboratory of Stem Cell Medicine, Xinxiang Medical University, East of JinSui Road, Xinxiang, Henan, China.
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19
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Fang Q, Wei Y, Zhang Y, Cao W, Yan L, Kong M, Zhu Y, Xu Y, Guo L, Zhang L, Wang W, Yu Y, Sun J, Yang J. Stem cells as potential therapeutics for hearing loss. Front Neurosci 2023; 17:1259889. [PMID: 37746148 PMCID: PMC10512725 DOI: 10.3389/fnins.2023.1259889] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Accepted: 08/23/2023] [Indexed: 09/26/2023] Open
Abstract
Hearing impairment is a global health problem. Stem cell therapy has become a cutting-edge approach to tissue regeneration. In this review, the recent advances in stem cell therapy for hearing loss have been discussed. Nanomaterials can modulate the stem cell microenvironment to augment the therapeutic effects further. The potential of combining nanomaterials with stem cells for repairing and regenerating damaged inner ear hair cells (HCs) and spiral ganglion neurons (SGNs) has also been discussed. Stem cell-derived exosomes can contribute to the repair and regeneration of damaged tissue, and the research progress on exosome-based hearing loss treatment has been summarized as well. Despite stem cell therapy's technical and practical limitations, the findings reported so far are promising and warrant further investigation for eventual clinical translation.
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Affiliation(s)
- Qiaojun Fang
- Department of Otolaryngology-Head and Neck Surgery, the Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
- School of Life Sciences and Technology, Southeast University, Nanjing, China
| | - Yongjie Wei
- Department of Otolaryngology-Head and Neck Surgery, the Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Yuhua Zhang
- Department of Otolaryngology-Head and Neck Surgery, the Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Wei Cao
- Department of Otolaryngology-Head and Neck Surgery, the Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Lin Yan
- Department of Otolaryngology-Head and Neck Surgery, the Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Mengdie Kong
- School of Life Sciences and Technology, Southeast University, Nanjing, China
| | - Yongjun Zhu
- Department of Otolaryngology-Head and Neck Surgery, the Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Yan Xu
- Department of Otolaryngology-Head and Neck Surgery, the Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Lingna Guo
- Department of Otolaryngology-Head and Neck Surgery, the Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Lei Zhang
- Department of Otolaryngology-Head and Neck Surgery, the Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Weiqing Wang
- Department of Otolaryngology-Head and Neck Surgery, the Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Yafeng Yu
- Department of Otolaryngology-Head and Neck Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Jingwu Sun
- Department of Otolaryngology-Head and Neck Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Jianming Yang
- Department of Otolaryngology-Head and Neck Surgery, the Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
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20
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Chen CP, Chen PC, Pan YL, Hsu YC. Prenatal lipopolysaccharide exposure induces anxiety-like behaviour in male mouse offspring and aberrant glial differentiation of embryonic neural stem cells. Cell Mol Biol Lett 2023; 28:67. [PMID: 37592237 PMCID: PMC10436442 DOI: 10.1186/s11658-023-00480-7] [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: 03/09/2023] [Accepted: 07/26/2023] [Indexed: 08/19/2023] Open
Abstract
BACKGROUND Prenatal infection has been implicated in the development of neuropsychiatric disorders in children. We hypothesised that exposure to lipopolysaccharide during prenatal development could induce anxiety-like behaviour and sensorineural hearing loss in offspring, as well as disrupt neural differentiation during embryonic neural development. METHODS We simulated prenatal infection in FVB mice and mouse embryonic stem cell (ESC) lines, specifically 46C and E14Tg2a, through lipopolysaccharide treatment. Gene expression profiling analyses and behavioural tests were utilized to study the effects of lipopolysaccharide on the offspring and alterations in toll-like receptor (TLR) 2-positive and TLR4-positive cells during neural differentiation in the ESCs. RESULTS Exposure to lipopolysaccharide (25 µg/kg) on gestation day 9 resulted in anxiety-like behaviour specifically in male offspring, while no effects were detected in female offspring. We also found significant increases in the expression of GFAP and CNPase, as well as higher numbers of GFAP + astrocytes and O4+ oligodendrocytes in the prefrontal cortex of male offspring. Furthermore, increased scores for genes related to oligodendrocyte and lipid metabolism, particularly ApoE, were observed in the prefrontal cortex regions. Upon exposure to lipopolysaccharide during the ESC-to-neural stem cell (NSC) transition, Tuj1, Map2, Gfap, O4, and Oligo2 mRNA levels increased in the differentiated neural cells on day 14. In vitro experiments demonstrated that lipopolysaccharide exposure induced inflammatory responses, as evidenced by increased expression of IL1b and ApoB mRNA. CONCLUSIONS Our findings suggest that prenatal infection at different stages of neural differentiation may result in distinct disturbances in neural differentiation during ESC-NSC transitions. Furthermore, early prenatal challenges with lipopolysaccharide selectively induce anxiety-like behaviour in male offspring. This behaviour may be attributed to the abnormal differentiation of astrocytes and oligodendrocytes in the brain, potentially mediated by ApoB/E signalling pathways in response to inflammatory stimuli.
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Affiliation(s)
- Chie-Pein Chen
- Division of High Risk Pregnancy, Department of Obstetrics and Gynecology, MacKay Memorial Hospital, Taipei, Taiwan
- Department of Medical Research, MacKay Memorial Hospital, Taipei, Taiwan
| | - Pei-Chun Chen
- Department of Medical Research, MacKay Memorial Hospital, Taipei, Taiwan
| | - Yu-Ling Pan
- Department of Audiology and Speech-Language Pathology, MacKay Medical College, New Taipei City, Taiwan
| | - Yi-Chao Hsu
- Department of Audiology and Speech-Language Pathology, MacKay Medical College, New Taipei City, Taiwan.
- Institute of Biomedical Sciences, MacKay Medical College, New Taipei City, Taiwan.
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21
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Zhang J, Ma H, Yang G, Ke J, Sun W, Yang L, Kuang S, Li H, Yuan W. Differentially expressed miRNA profiles of serum-derived exosomes in patients with sudden sensorineural hearing loss. Front Neurol 2023; 14:1177988. [PMID: 37332997 PMCID: PMC10273844 DOI: 10.3389/fneur.2023.1177988] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Accepted: 05/10/2023] [Indexed: 06/20/2023] Open
Abstract
Objectives This study aimed to compare the expressed microRNA (miRNA) profiles of serum-derived exosomes of patients with sudden sensorineural hearing loss (SSNHL) and normal hearing controls to identify exosomal miRNAs that may be associated with SSNHL or serve as biomarkers for SSNHL. Methods Peripheral venous blood of patients with SSNHL and healthy controls was collected to isolate exosomes. Nanoparticle tracking analysis, transmission electron microscopy, and Western blotting were used to identify the isolated exosomes, after which total RNA was extracted and used for miRNA transcriptome sequencing. Differentially expressed miRNAs (DE-miRNAs) were identified based on the thresholds of P < 0.05 and |log2fold change| > 1 and subjected to functional analyses. Finally, four exosomal DE-miRNAs, including PC-5p-38556_39, PC-5p-29163_54, PC-5p-31742_49, and hsa-miR-93-3p_R+1, were chosen for validation using quantitative real-time polymerase chain reaction (RT-qPCR). Results Exosomes were isolated from serum and identified based on particle size, morphological examination, and expression of exosome-marker proteins. A total of 18 exosomal DE-miRNAs, including three upregulated and 15 downregulated miRNAs, were found in SSNHL cases. Gene ontology (GO) functional annotation analysis revealed that target genes in the top 20 terms were mainly related to "protein binding," "metal ion binding," "ATP binding," and "intracellular signal transduction." Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis revealed that these target genes were functionally enriched in the "Ras," "Hippo," "cGMP-PKG," and "AMPK signaling pathways." The expression levels of PC-5p-38556_39 and PC-5p-29163_54 were significantly downregulated and that of miR-93-3p_R+1 was highly upregulated in SSNHL. Consequently, the consistency rate between sequencing and RT-qPCR was 75% and sequencing results were highly reliable. Conclusion This study identified 18 exosomal DE-miRNAs, including PC-5p-38556_39, PC-5p-29163_54, and miR-93-3p, which may be closely related to SSNHL pathogenesis or serve as biomarkers for SSNHL.
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Affiliation(s)
- Juhong Zhang
- Department of Otorhinolaryngology Head and Neck Surgery, Chongqing General Hospital, Chongqing, China
- School of Basic Medicine, Chongqing Medical University, Chongqing, China
| | - Haizhu Ma
- Department of Otorhinolaryngology Head and Neck Surgery, Chongqing General Hospital, Chongqing, China
| | - Guijun Yang
- Department of Otorhinolaryngology Head and Neck Surgery, Chongqing General Hospital, Chongqing, China
| | - Jing Ke
- Department of Otorhinolaryngology Head and Neck Surgery, Chongqing General Hospital, Chongqing, China
- School of Basic Medicine, Chongqing Medical University, Chongqing, China
| | - Wenfang Sun
- Department of Otorhinolaryngology Head and Neck Surgery, Chongqing General Hospital, Chongqing, China
| | - Li Yang
- Department of Otorhinolaryngology Head and Neck Surgery, Chongqing General Hospital, Chongqing, China
| | - Shaojing Kuang
- Department of Otorhinolaryngology Head and Neck Surgery, Chongqing General Hospital, Chongqing, China
| | - Hai Li
- Department of Otorhinolaryngology Head and Neck Surgery, Xuanhan County People's Hospital, Dazhou, Sichuan, China
| | - Wei Yuan
- Department of Otorhinolaryngology Head and Neck Surgery, Chongqing General Hospital, Chongqing, China
- School of Basic Medicine, Chongqing Medical University, Chongqing, China
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22
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Oliva J. Role of Extracellular Vesicles Produced by Stem Cells in Tissue Repair. Int J Mol Sci 2023; 24:ijms24054798. [PMID: 36902229 PMCID: PMC10003566 DOI: 10.3390/ijms24054798] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Accepted: 02/21/2023] [Indexed: 03/06/2023] Open
Abstract
The purpose of this Special Issue is to emphasize the great potential of the translational applications of extracellular vesicles (EVs) produced by stem cells (mesenchymal stem cells, induced pluripotent stem cells, etc [...].
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Affiliation(s)
- Joan Oliva
- Emmaus Life Sciences, Inc., 21250 Hawthorne Blvd., Suite 800, Torrance, CA 90503, USA
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23
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Warnecke A, Staecker H, Rohde E, Gimona M, Giesemann A, Szczepek AJ, Di Stadio A, Hochmair I, Lenarz T. Extracellular Vesicles in Inner Ear Therapies-Pathophysiological, Manufacturing, and Clinical Considerations. J Clin Med 2022; 11:jcm11247455. [PMID: 36556073 PMCID: PMC9788356 DOI: 10.3390/jcm11247455] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Revised: 12/09/2022] [Accepted: 12/11/2022] [Indexed: 12/23/2022] Open
Abstract
(1) Background: Sensorineural hearing loss is a common and debilitating condition. To date, comprehensive pharmacologic interventions are not available. The complex and diverse molecular pathology that underlies hearing loss may limit our ability to intervene with small molecules. The current review foccusses on the potential for the use of extracellular vesicles in neurotology. (2) Methods: Narrative literature review. (3) Results: Extracellular vesicles provide an opportunity to modulate a wide range of pathologic and physiologic pathways and can be manufactured under GMP conditions allowing for their application in the human inner ear. The role of inflammation in hearing loss with a focus on cochlear implantation is shown. How extracellular vesicles may provide a therapeutic option for complex inflammatory disorders of the inner ear is discussed. Additionally, manufacturing and regulatory issues that need to be addressed to develop EVs as advanced therapy medicinal product for use in the inner ear are outlined. (4) Conclusion: Given the complexities of inner ear injury, novel therapeutics such as extracellular vesicles could provide a means to modulate inflammation, stress pathways and apoptosis in the inner ear.
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Affiliation(s)
- Athanasia Warnecke
- Department of Otolaryngology, Hannover Medical School, 30625 Hannover, Germany
- Cluster of Excellence of the German Research Foundation (DFG; “Deutsche Forschungsgemeinschaft”) “Hearing4all”, 30625 Hannover, Germany
- Correspondence:
| | - Hinrich Staecker
- Department of Otolaryngology Head and Neck Surgery, University of Kansas School of Medicine, Rainbow Blvd., Kansas City, KS 66160, USA
| | - Eva Rohde
- GMP Unit, Spinal Cord Injury & Tissue Regeneration Centre Salzburg (SCI-TReCS), Paracelsus Medical University, 5020 Salzburg, Austria
- Transfer Centre for Extracellular Vesicle Theralytic Technologies (EV-TT), 5020 Salzburg, Austria
- Department of Transfusion Medicine, University Hospital, Salzburger Landeskliniken GesmbH (SALK) Paracelsus Medical University, 5020 Salzburg, Austria
| | - Mario Gimona
- GMP Unit, Spinal Cord Injury & Tissue Regeneration Centre Salzburg (SCI-TReCS), Paracelsus Medical University, 5020 Salzburg, Austria
- Transfer Centre for Extracellular Vesicle Theralytic Technologies (EV-TT), 5020 Salzburg, Austria
- Research Program “Nanovesicular Therapies”, Paracelsus Medical University, 5020 Salzburg, Austria
| | - Anja Giesemann
- Department of Diagnostic and Interventional Neuroradiology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
| | - Agnieszka J. Szczepek
- Department of Otorhinolaryngology, Head and Neck Surgery, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany
- Faculty of Medicine and Health Sciences, University of Zielona Gora, 65-046 Zielona Gora, Poland
| | - Arianna Di Stadio
- Department GF Ingrassia, University of Catania, 95124 Catania, Italy
| | | | - Thomas Lenarz
- Department of Otolaryngology, Hannover Medical School, 30625 Hannover, Germany
- Cluster of Excellence of the German Research Foundation (DFG; “Deutsche Forschungsgemeinschaft”) “Hearing4all”, 30625 Hannover, Germany
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24
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Sun K, Zheng X, Jin H, Yu F, Zhao W. Exosomes as CNS Drug Delivery Tools and Their Applications. Pharmaceutics 2022; 14:pharmaceutics14102252. [PMID: 36297688 PMCID: PMC9609403 DOI: 10.3390/pharmaceutics14102252] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Revised: 10/13/2022] [Accepted: 10/19/2022] [Indexed: 11/05/2022] Open
Abstract
Central nervous system (CNS) diseases threaten the health of people all over the world. However, due to the structural and functional particularities of the brain and spinal cord, CNS-targeted drug development is rather challenging. Exosomes are small cellular vesicles with lipid bilayers that can be secreted by almost all cells and play important roles in intercellular communication. The advantages of low immunogenicity, the ability to cross the blood-brain barrier, and the flexibility of drug encapsulation make them stand out among CNS drug delivery tools. Herein, we reviewed the research on exosomes in CNS drug delivery over the past decade and outlined the impact of the drug loading mode, administration route, and engineered modification on CNS targeting. Finally, we highlighted the problems and prospects of exosomes as CNS drug delivery tools.
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Affiliation(s)
- Ke Sun
- College of Pharmacy, Nankai University, Tongyan Road, Haihe Education Park, Tianjin 300350, China
| | - Xue Zheng
- College of Pharmacy, Nankai University, Tongyan Road, Haihe Education Park, Tianjin 300350, China
| | - Hongzhen Jin
- College of Pharmacy, Nankai University, Tongyan Road, Haihe Education Park, Tianjin 300350, China
- Correspondence: (H.J.); (F.Y.)
| | - Fan Yu
- College of Life Sciences, Nankai University, Weijin Road, Nankai District, Tianjin 300350, China
- Correspondence: (H.J.); (F.Y.)
| | - Wei Zhao
- College of Pharmacy, Nankai University, Tongyan Road, Haihe Education Park, Tianjin 300350, China
- State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tongyan Road, Haihe Education Park, Tianjin 300350, China
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25
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The Augmented Cochlear Implant: a Convergence of Drugs and Cochlear Implantation for the Treatment of Hearing Loss. CURRENT OTORHINOLARYNGOLOGY REPORTS 2022. [DOI: 10.1007/s40136-022-00426-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/14/2022]
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26
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Lee S, Ko JH, Kim SN. The Extracellular MicroRNAs on Inflammation: A Literature Review of Rodent Studies. Biomedicines 2022; 10:1601. [PMID: 35884901 PMCID: PMC9312877 DOI: 10.3390/biomedicines10071601] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 07/03/2022] [Accepted: 07/03/2022] [Indexed: 11/17/2022] Open
Abstract
Inflammation is an indispensable biological process stimulated by infection and injuries. Inflammatory mechanisms related to extracellular vesicles (EVs), which are small membrane structures carrying various molecules, were summarized in this review. Emerging evidence from animal studies has highlighted the role of EVs in modulating inflammatory responses, by transporting various molecules involved in host defense. In this review, we have discussed the role of EV miRNAs in inflammation. Rodent studies associated with extracellular miRNAs in inflammatory diseases, published from 2012 to 2022, were explored from PUBMED, EMBASE, and MEDLINE. A total of 95 studies were reviewed. In summary, EV-associated miRNAs play a key role in various diseases, including organ injury, immune dysfunction, neurological disease, metabolic syndrome, vesicular disease, arthritis, cancer, and other inflammatory diseases. Diverse EV-associated miRNAs regulate inflammasome activation and pro- and anti-inflammatory cytokine levels by targeting genes.
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Affiliation(s)
- Seri Lee
- College of Korean Medicine, Dongguk University, Goyang 10326, Korea; (S.L.); (J.H.K.)
- Graduate School, Dongguk University, Seoul 04620, Korea
| | - Jade Heejae Ko
- College of Korean Medicine, Dongguk University, Goyang 10326, Korea; (S.L.); (J.H.K.)
| | - Seung-Nam Kim
- College of Korean Medicine, Dongguk University, Goyang 10326, Korea; (S.L.); (J.H.K.)
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27
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Zhu Z, Zhang X, Hao H, Xu H, Shu J, Hou Q, Wang M. Exosomes Derived From Umbilical Cord Mesenchymal Stem Cells Treat Cutaneous Nerve Damage and Promote Wound Healing. Front Cell Neurosci 2022; 16:913009. [PMID: 35846563 PMCID: PMC9279568 DOI: 10.3389/fncel.2022.913009] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Accepted: 06/02/2022] [Indexed: 11/13/2022] Open
Abstract
Wound repair is a key step in the treatment of skin injury caused by burn, surgery, and trauma. Various stem cells have been proven to promote wound healing and skin regeneration as candidate seed cells. Therefore, exosomes derived from stem cells are emerging as a promising method for wound repair. However, the mechanism by which exosomes promote wound repair is still unclear. In this study, we reported that exosomes derived from umbilical cord mesenchymal stem cells (UC-MSCs) promote wound healing and skin regeneration by treating cutaneous nerve damage. The results revealed that UC-MSCs exosomes (UC-MSC-Exo) promote the growth and migration of dermal fibroblast cells. In in vitro culture, dermal fibroblasts could promote to nerve cells and secrete nerve growth factors when stimulated by exosomes. During the repair process UC-MSC-Exo accelerated the recruitment of fibroblasts at the site of trauma and significantly enhanced cutaneous nerve regeneration in vivo. Interestingly, it was found that UC-MSC-Exo could promote wound healing and skin regeneration by recruiting fibroblasts, stimulating them to secrete nerve growth factors (NGFs) and promoting skin nerve regeneration. Therefore, we concluded that UC-MSC-Exo promote cutaneous nerve repair, which may play an important role in wound repair and skin regeneration.
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Affiliation(s)
- Ziying Zhu
- College of Chemistry and Materials Engineering, Beijing Technology and Business University, Beijing, China
- The First Medical Center, Chinese People’s Liberation Army General Hospital, Beijing, China
- *Correspondence: Ziying Zhu,
| | - Xiaona Zhang
- College of Chemistry and Materials Engineering, Beijing Technology and Business University, Beijing, China
| | - Haojie Hao
- The First Medical Center, Chinese People’s Liberation Army General Hospital, Beijing, China
| | - Heran Xu
- College of Chemistry and Materials Engineering, Beijing Technology and Business University, Beijing, China
| | - Jun Shu
- The First Medical Center, Chinese People’s Liberation Army General Hospital, Beijing, China
| | - Qian Hou
- The First Medical Center, Chinese People’s Liberation Army General Hospital, Beijing, China
- Medical Innovation Research Center, Chinese People’s Liberation Army General Hospital, Beijing, China
- Qian Hou,
| | - Min Wang
- College of Chemistry and Materials Engineering, Beijing Technology and Business University, Beijing, China
- Min Wang,
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28
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Costa A, Balbi C, Garbati P, Palamà MEF, Reverberi D, De Palma A, Rossi R, Paladini D, Coviello D, De Biasio P, Ceresa D, Malatesta P, Mauri P, Quarto R, Gentili C, Barile L, Bollini S. Investigating the Paracrine Role of Perinatal Derivatives: Human Amniotic Fluid Stem Cell-Extracellular Vesicles Show Promising Transient Potential for Cardiomyocyte Renewal. Front Bioeng Biotechnol 2022; 10:902038. [PMID: 35757808 PMCID: PMC9214211 DOI: 10.3389/fbioe.2022.902038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Accepted: 04/27/2022] [Indexed: 11/15/2022] Open
Abstract
Cardiomyocyte renewal represents an unmet clinical need for cardiac regeneration. Stem cell paracrine therapy has attracted increasing attention to resurge rescue mechanisms within the heart. We previously characterized the paracrine effects that human amniotic fluid–derived stem cells (hAFSC) can exert to provide cardioprotection and enhance cardiac repair in preclinical models of myocardial ischemia and cardiotoxicity. Here, we analyze whether hAFSC secretome formulations, namely, hAFSC conditioned medium (hAFSC-CM) over extracellular vesicles (hAFSC-EVs) separated from it, can induce cardiomyocyte renewal. c-KIT+ hAFSC were obtained by leftover samples of II trimester prenatal amniocentesis (fetal hAFSC) and from clinical waste III trimester amniotic fluid during scheduled C-section procedures (perinatal hAFSC). hAFSC were primed under 1% O2 to enrich hAFSC-CM and EVs with cardioactive factors. Neonatal mouse ventricular cardiomyocytes (mNVCM) were isolated from cardiac tissue of R26pFUCCI2 mice with cell cycle fluorescent tagging by mutually exclusive nuclear signal. mNVCM were stimulated by fetal versus perinatal hAFSC-CM and hAFSC-EVs to identify the most promising formulation for in vivo assessment in a R26pFUCCI2 neonatal mouse model of myocardial infarction (MI) via intraperitoneal delivery. While the perinatal hAFSC secretome did not provide any significant cardiogenic effect, fetal hAFSC-EVs significantly sustained mNVCM transition from S to M phase by 2-fold, while triggering cytokinesis by 4.5-fold over vehicle-treated cells. Treated mNVCM showed disorganized expression of cardiac alpha-actinin, suggesting cytoskeletal re-arrangements prior to cell renewal, with a 40% significant downregulation of Cofilin-2 and a positive trend of polymerized F-Actin. Fetal hAFSC-EVs increased cardiomyocyte cell cycle progression by 1.8-fold in the 4-day-old neonatal left ventricle myocardium short term after MI; however, such effect was lost at the later stage. Fetal hAFSC-EVs were enriched with a short isoform of Agrin, a mediator of neonatal heart regeneration acting by YAP-related signaling; yet in vitro application of YAP inhibitor verteporfin partially affected EV paracrine stimulation on mNVCM. EVs secreted by developmentally juvenile fetal hAFSC can support cardiomyocyte renewal to some extension, via intercellular conveyance of candidates possibly involving Agrin in combination with other factors. These perinatal derivative promising cardiogenic effects need further investigation to define their specific mechanism of action and enhance their potential translation into therapeutic opportunity.
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Affiliation(s)
- Ambra Costa
- Experimental Biology Unit, Department of Experimental Medicine (DIMES), University of Genova, Genova, Italy
| | - Carolina Balbi
- Laboratory of Cellular and Molecular Cardiology, Istituto Cardiocentro Ticino, Ente Ospedaliero Cantonale, Lugano, Switzerland.,Center for Molecular Cardiology, University of Zurich, Zurich, Switzerland.,Laboratories for Translational Research, Ente Ospedaliero Cantonale, Bellinzona, Switzerland
| | - Patrizia Garbati
- Experimental Biology Unit, Department of Experimental Medicine (DIMES), University of Genova, Genova, Italy
| | | | - Daniele Reverberi
- Molecular Pathology Unit, IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Antonella De Palma
- Proteomics and Metabolomics Unit, Institute for Biomedical Technologies (ITB-CNR), Milan, Italy
| | - Rossana Rossi
- Proteomics and Metabolomics Unit, Institute for Biomedical Technologies (ITB-CNR), Milan, Italy
| | - Dario Paladini
- Fetal Medicine and Surgery Unit, IRCCS Istituto Giannina Gaslini, Genova, Italy
| | - Domenico Coviello
- Laboratory of Human Genetics, IRCCS Istituto Giannina Gaslini, Genova, Italy
| | - Pierangela De Biasio
- Prenatal Diagnosis Perinatal Medicine Unit, IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Davide Ceresa
- Cellular Oncology Unit, IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Paolo Malatesta
- Experimental Biology Unit, Department of Experimental Medicine (DIMES), University of Genova, Genova, Italy.,Cellular Oncology Unit, IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Pierluigi Mauri
- Proteomics and Metabolomics Unit, Institute for Biomedical Technologies (ITB-CNR), Milan, Italy
| | - Rodolfo Quarto
- Experimental Biology Unit, Department of Experimental Medicine (DIMES), University of Genova, Genova, Italy.,Cellular Oncology Unit, IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Chiara Gentili
- Experimental Biology Unit, Department of Experimental Medicine (DIMES), University of Genova, Genova, Italy
| | - Lucio Barile
- Laboratories for Translational Research, Ente Ospedaliero Cantonale, Bellinzona, Switzerland.,Laboratory for Cardiovascular Theranostics, Istituto Cardiocentro Ticino, Ente Ospedaliero Cantonale, Lugano, Switzerland.,Faculty of Biomedical Sciences, Università Svizzera Italiana, Lugano, Switzerland
| | - Sveva Bollini
- Experimental Biology Unit, Department of Experimental Medicine (DIMES), University of Genova, Genova, Italy
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Du H, Li CH, Gao RB, Cen XQ, Li P. Ablation of GSDMD Attenuates Neurological Deficits and Neuropathological Alterations After Traumatic Brain Injury. Front Cell Neurosci 2022; 16:915969. [PMID: 35669106 PMCID: PMC9164823 DOI: 10.3389/fncel.2022.915969] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Accepted: 05/02/2022] [Indexed: 11/28/2022] Open
Abstract
Pyroptosis plays a significant role in neuroinflammation after traumatic brain injury (TBI). However, the role of pyroptosis executor Gasdermin D (GSDMD) in neurological deficits and neuropathological alterations after TBI have not been elucidated. Our results demonstrated that GSDMD-KO exerted striking neuroprotective effects on motor dysfunction and neuropathological alterations (loss of synaptic proteins, microglia activation, astrogliosis, dendrite injury, and neuron death) at 3 days after TBI. GSDMD-KO inhibited the expression and release of pro-inflammatory cytokine releases (IL-1β and TNF-α) while promoting those of anti-inflammatory cytokines (IL-10 and TGF-β1). The temporal pattern of diverse inflammasome signals showed long-lasting elevations of NLRP3, caspase 1, and caspase 1 p20 after TBI, rather than NLRP1, NLRC4 or AIM2, similar to the change in GSDMD postinjury; and NLRP3-KO not only inhibited the expression and cleavage of GSDMD but also attenuated the loss of synaptic proteins and neurological deficits. Notably, RNA sequencing showed both GSDMD-KO and NLRP3-KO reversed the global expression of neuroinflammation- and neuropathology-related genes after TBI. Our findings proved that the inhibition of GSDMD exerts neuroprotective effects after TBI and is mainly driven by the NLRP3 inflammasome. GSDMD serves as a potent therapeutic target for the treatment of TBI.
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Affiliation(s)
- Hao Du
- Department of Army Occupational Disease, State Key Laboratory of Trauma, Burns and Combined Injury, Research Institute of Surgery and Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Chang-Hong Li
- Department of Army Occupational Disease, State Key Laboratory of Trauma, Burns and Combined Injury, Research Institute of Surgery and Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Ruo-Bing Gao
- Department of Army Occupational Disease, State Key Laboratory of Trauma, Burns and Combined Injury, Research Institute of Surgery and Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Xiao-Qing Cen
- Department of Army Occupational Disease, State Key Laboratory of Trauma, Burns and Combined Injury, Research Institute of Surgery and Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China
- College of Bioengineering, Chongqing University, Chongqing, China
| | - Ping Li
- Department of Army Occupational Disease, State Key Laboratory of Trauma, Burns and Combined Injury, Research Institute of Surgery and Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China
- Institute of Brain and Intelligence, Army Medical University (Third Military Medical University), Chongqing, China
- *Correspondence: Ping Li
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