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Eerdekens H, Pirlet E, Willems S, Bronckaers A, Pincela Lins PM. Extracellular vesicles: innovative cell-free solutions for wound repair. Front Bioeng Biotechnol 2025; 13:1571461. [PMID: 40248643 PMCID: PMC12003306 DOI: 10.3389/fbioe.2025.1571461] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2025] [Accepted: 03/17/2025] [Indexed: 04/19/2025] Open
Abstract
Chronic non-healing wounds are often associated with conditions such as diabetes and peripheral vascular disease, pose significant medical and socioeconomic challenges. Cell-based therapies have shown promise in promoting wound healing but have major drawbacks such as immunogenicity and tumor formation. As a result, recent research has shifted to the potential of extracellular vesicles (EVs) derived from these cells. EVs are nanosized lipid bilayer vesicles, naturally produced by all cell types, which facilitate intercellular communication and carry bioactive molecules, offering advantages such as low immunogenicity, negligible toxicity and the potential to be re-engineered. Recent evidence recognizes that during wound healing EVs are released from a wide range of cells including immune cells, skin cells, epithelial cells and platelets and they actively participate in wound repair. This review comprehensively summarizes the latest research on the function of EVs from endogenous cell types during the different phases of wound healing, thereby presenting interesting therapeutic targets. Additionally, it gives a critical overview of the current status of mesenchymal stem cell-derived EVs in wound treatment highlighting their tremendous therapeutic potential as a non-cellular of-the-shelf alternative in wound care.
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Affiliation(s)
- Hanne Eerdekens
- Hasselt University, Faculty of Medicine and Life Sciences, Biomedical Research Institute (BIOMED), Diepenbeek, Belgium
| | - Elke Pirlet
- Hasselt University, Faculty of Medicine and Life Sciences, Biomedical Research Institute (BIOMED), Diepenbeek, Belgium
| | - Sarah Willems
- Hasselt University, Faculty of Medicine and Life Sciences, Biomedical Research Institute (BIOMED), Diepenbeek, Belgium
| | - Annelies Bronckaers
- Hasselt University, Faculty of Medicine and Life Sciences, Biomedical Research Institute (BIOMED), Diepenbeek, Belgium
| | - Paula M. Pincela Lins
- Hasselt University, Faculty of Medicine and Life Sciences, Biomedical Research Institute (BIOMED), Diepenbeek, Belgium
- Flemish Institute for Technological Research (VITO), Environmental Intelligence Unit, Mol, Belgium
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Budayr OM, Miller BC, Nguyen J. Harnessing extracellular vesicle-mediated crosstalk between T cells and cancer cells for therapeutic applications. J Control Release 2025; 378:266-280. [PMID: 39657892 PMCID: PMC11830559 DOI: 10.1016/j.jconrel.2024.12.011] [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: 07/17/2024] [Revised: 11/23/2024] [Accepted: 12/05/2024] [Indexed: 12/12/2024]
Abstract
Small extracellular vesicles (EVs) are a diverse group of lipid-based particles that are ≤200 nm in diameter and contain an aqueous core. EVs have been shown to mediate intercellular communications between a wide array of immune cells; the downstream effects are diverse and have potential implications for the development of novel immunotherapeutic treatments. Despite a high volume of studies addressing the role EVs play in the immune system, our understanding of the crosstalk between T cells and cancer cells remains limited. Here, we discuss how EVs derived from cancer cells modulate T cell functions and conversely, how T cell derived EVs are crucial in modulating adaptive immune functions. In the context of cancer, tumor derived EVs (TD-EVs) halt T cell-mediated immunity by interfering with effector functions and enhancing regulatory T cell (Treg) functions. In contrast, EVs derived from effector T cells can serve to stimulate anticancer immunity, curbing metastasis and tumor growth. These findings highlight important aspects of how EVs can both mediate the therapeutic effects of T cells as well as impair T cell-mediated immunity. This calls for a deeper understanding of EV-mediated effects in order to advance them as next-generation therapeutics and nanocarriers.
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Affiliation(s)
- Omar M Budayr
- Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Brian C Miller
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Medicine, Division of Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA; Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
| | - Juliane Nguyen
- Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
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Wei B, Wei M, Huang H, Fan T, Zhang Z, Song X. Mesenchymal Stem Cell-Derived Exosomes: A Promising Therapeutic Strategy for Age-Related Diseases. Cell Prolif 2024:e13795. [PMID: 39704104 DOI: 10.1111/cpr.13795] [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: 08/28/2024] [Revised: 11/09/2024] [Accepted: 12/04/2024] [Indexed: 12/21/2024] Open
Abstract
The global increase in the aging population has led to a concurrent rise in the incidence of age-related diseases, posing substantial challenges to healthcare systems and affecting the well-being of the elderly. Identifying and securing effective treatments has become an urgent priority. In this context, mesenchymal stem cell-derived exosomes (MSC-Exos) have emerged as a promising and innovative modality in the field of anti-aging medicine, offering a multifaceted therapeutic approach. MSC-Exos demonstrate significant potential due to their immunomodulatory and anti-inflammatory properties, their ability to inhibit oxidative stress, and their reparative effects on senescent tissues. These attributes make them valuable in combating a range of conditions associated with aging, such as cardiovascular diseases, neurodegeneration, skin aging, and osteoarthritis. The integration of exosomes with membrane-penetrating peptides introduces a novel strategy for the delivery of biomolecules, surmounting traditional cellular barriers and enhancing therapeutic efficacy. This review provides a comprehensive synthesis of the current understanding of MSC-Exos, underscoring their role as a novel and potent therapeutic strategy against the intricate challenges of age-related diseases.
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Affiliation(s)
- Bohua Wei
- School of Pharmacy, China Medical University, Shenyang, Liaoning Province, China
| | - Mengting Wei
- School of Stomatology, China Medical University, Shenyang, Liaoning Province, China
| | - Haonan Huang
- China Medical University, Shenyang, Liaoning Province, China
| | - Ting Fan
- Department of Computer, School of Intelligent Medicine, China Medical University, Shenyang, Liaoning Province, China
| | - Zhichang Zhang
- Department of Computer, School of Intelligent Medicine, China Medical University, Shenyang, Liaoning Province, China
| | - Xiaoyu Song
- The College of Basic Medical Science, Health Sciences Institute, China Medical University, Shenyang, Liaoning Province, China
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Lu J, Zhang W, Zhu Y, Luo P, Tong X, Xie S, Jiang L, Guo X, Huang J, Gu M, Ding X, Xian S, Huang R, Ji S, Xia Z. Revealing the Therapeutic Potential of Stem Cells in Burn Healing: A Deeper Understanding of the Therapeutic Mechanisms of Epidermal Stem Cells and Mesenchymal Stem Cells. Stem Cells Int 2024; 2024:1914585. [PMID: 39717868 PMCID: PMC11666318 DOI: 10.1155/2024/1914585] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Revised: 07/20/2024] [Accepted: 08/19/2024] [Indexed: 12/25/2024] Open
Abstract
Background: Burns are a global public health issue and a major cause of disability and death around the world. Stem cells, which are the undifferentiated cells with the potential for indefinite proliferation and multilineage differentiation, have the ability to replace injured skin and facilitate the wound repair process through paracrine mechanisms. In light of this, the present study aims to conduct a bibliometric analysis in order to identify research hotspots of stem cell-related burns and assess global research tendencies. Methods: To achieve this objective, we retrieved scientific publications on burns associated with stem cells covering the period from January 1, 1978, to October 13, 2022, from the Web of Science Core Collection (WoSCC). Bibliometric analyses, including production and collaboration analyses between countries, institutions, authors, and journals, as well as keyword and topic analyses, were conducted using the bibliometrix R package, CiteSpace, and VOSviewer. Results: A total of 1648 burns associated with stem cell documents were published and listed on WOSCC. The most contributive country, institution, journal, and author were the United States, LV Prasad Eye Institute, Burns, and Scheffer C.G. Tseng, respectively. More importantly, combined with historical direct citation network, trend topic analysis, keyword co-occurrence network, and substantial literature analysis, we eventually summarized the research hotspots and frontiers on burns associated stem cell reasearch. Conclusion: The present study obtained deep insight into the developing trends and research hotspots on burns associated with stem cells, which arouses growing concerns and implies increasing clinical implications. The mechanism and therapeutics of epidermal stem cells (ESCs) for burn wounds and the mechanism of mesenchymal stem cells (MSCs) and MSC-derived exosomes for burns wounds are two research hotspots in this field.
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Affiliation(s)
- Jianyu Lu
- Department of Burn Surgery, The First Affiliated Hospital of Naval Medical University, Shanghai 200433, China
| | - Wei Zhang
- Department of Burn Surgery, The First Affiliated Hospital of Naval Medical University, Shanghai 200433, China
| | - Yushu Zhu
- Department of Burn Surgery, The First Affiliated Hospital of Naval Medical University, Shanghai 200433, China
| | - Pengfei Luo
- Department of Burn Surgery, The First Affiliated Hospital of Naval Medical University, Shanghai 200433, China
| | - Xirui Tong
- Department of Burn Surgery, The First Affiliated Hospital of Naval Medical University, Shanghai 200433, China
| | - Sujie Xie
- Department of Burn Surgery, The First Affiliated Hospital of Naval Medical University, Shanghai 200433, China
| | - Luofeng Jiang
- Department of Burn Surgery, The First Affiliated Hospital of Naval Medical University, Shanghai 200433, China
| | - Xinya Guo
- Department of Burn Surgery, The First Affiliated Hospital of Naval Medical University, Shanghai 200433, China
| | - Jie Huang
- Department of Burn Surgery, The First Affiliated Hospital of Naval Medical University, Shanghai 200433, China
| | - Minyi Gu
- Department of Burn Surgery, The First Affiliated Hospital of Naval Medical University, Shanghai 200433, China
| | - Xinran Ding
- Department of Burn Surgery, The First Affiliated Hospital of Naval Medical University, Shanghai 200433, China
| | - Shuyuan Xian
- Department of Burn Surgery, The First Affiliated Hospital of Naval Medical University, Shanghai 200433, China
| | - Runzhi Huang
- Department of Burn Surgery, The First Affiliated Hospital of Naval Medical University, Shanghai 200433, China
| | - Shizhao Ji
- Department of Burn Surgery, The First Affiliated Hospital of Naval Medical University, Shanghai 200433, China
| | - Zhaofan Xia
- Department of Burn Surgery, The First Affiliated Hospital of Naval Medical University, Shanghai 200433, China
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Abd-Allah SH, Khamis T, Samy W, Alsemeh AE, Abdullah DM, Hussein S. Mesenchymal Stem Cells and Their Derived Exosomes Mitigated Hepatic Cirrhosis in Rats by Altering the Expression of miR-23b and miR-221. IRANIAN JOURNAL OF MEDICAL SCIENCES 2024; 49:724-740. [PMID: 39678523 PMCID: PMC11645418 DOI: 10.30476/ijms.2023.99524.3159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Revised: 10/18/2023] [Accepted: 11/19/2023] [Indexed: 12/17/2024]
Abstract
Background The therapeutic effect of mesenchymal stem cells (MSCs) in liver cirrhosis is limited by their entrapment in the pulmonary vessels. Thus, the use of MSC-derived exosomes has become a promising strategy. The current work aimed to compare the role of human umbilical cord blood-MSCs (hUCB-MSCs) and their derived exosomes in the alleviation of liver cirrhosis focusing on the role of miR-23b and miR-221 and their direct effectors in inflammatory and autophagic pathways. Methods Rats were divided into six groups normal controls (negative control), liver cirrhosis group (positive control), liver cirrhotic rats that received conditioned media, liver cirrhotic rats that received hUCB-MSCs, cirrhotic rats that received exosomes, and cirrhotic rats that received both hUCB-MSCs and exosomes. The messenger RNA expression of transforming growth factor-β (TGF-β), Matrix metalloproteinase 9 (MMP 9), fibronectin, collagen type-1 (col1), alpha-smooth muscle actin (α-SMA), Suppressor of Mothers Against Decapentaplegic (SMAD) 2 and 7, Beclin, P62, and light chain 3 (LC3) were evaluated by quantitative real-time polymerase chain reaction. Immunohistochemical staining for Beclin, P62, and LC3 was performed. Results The treatment of cirrhotic rats with hUCB-MSCs, exosomes, or the combination of them significantly downregulated miRNA-221, fibronectin, collagen I, α-SMA, Smad2 (P<0.001, for each), and P62 (P=0.032, P<0.001, P<0.001, respectively). Additionally, the treatment of cirrhotic rats with hUCB-MSCs, exosomes, or the combination of them significantly upregulated mTOR, Beclin, LC3, and Smad7 (P<0.001, for each) and miRNA-23 (P=0.021, P<0.001, P<0.001, respectively). Conclusion hUCB-MSCs and their derived exosomes ameliorated liver cirrhosis by anti-inflammatory and anti-fibrotic effects besides modulation of autophagy. The exosomes had a better improvement effect either alone or combined with hUCB-MSCs, as proved by improvement in liver function tests, and molecular, histopathological, and immunohistochemical profiles.
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Affiliation(s)
- Somia H. Abd-Allah
- Department of Medical Biochemistry and Molecular Biology, School of Medicine, Zagazig University, Zagazig, Egypt
| | - Tarek Khamis
- Department of Pharmacology, Faculty of Veterinary Medicine, Zagazig University, Zagazig, Egypt
| | - Walaa Samy
- Department of Medical Biochemistry and Molecular Biology, School of Medicine, Zagazig University, Zagazig, Egypt
| | | | - Doaa M. Abdullah
- Department of Clinical Pharmacology, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Samia Hussein
- Department of Medical Biochemistry and Molecular Biology, School of Medicine, Zagazig University, Zagazig, Egypt
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Zhang Y, Wu D, Zhou C, Bai M, Wan Y, Zheng Q, Fan Z, Wang X, Yang C. Engineered extracellular vesicles for tissue repair and regeneration. BURNS & TRAUMA 2024; 12:tkae062. [PMID: 39439545 PMCID: PMC11495891 DOI: 10.1093/burnst/tkae062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Revised: 09/12/2024] [Accepted: 09/21/2024] [Indexed: 10/25/2024]
Abstract
Extracellular vesicles (EVs) are heterogeneous membrane-like vesicles secreted by living cells that are involved in many physiological and pathological processes and act as intermediaries of intercellular communication and molecular transfer. Recent studies have shown that EVs from specific sources regulate tissue repair and regeneration by delivering proteins, lipids, and nucleic acids to target cells as signaling molecules. Nanotechnology breakthroughs have facilitated the development and exploration of engineered EVs for tissue repair. Enhancements through gene editing, surface modification, and content modification have further improved their therapeutic efficacy. This review summarizes the potential of EVs in tissue repair and regeneration, their mechanisms of action, and their research progress in regenerative medicine. This review highlights their design logic through typical examples and explores the development prospects of EVs in tissue repair. The aim of this review is to provide new insights into the design of EVs for tissue repair and regeneration applications, thereby expanding their use in regenerative medicine.
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Affiliation(s)
- Yan Zhang
- College of Basic Medicin, Beihua University, No. 3999 Binjiang East Road, Fengman District, Jilin City, Jilin Province, China
- School of Public Health, Beihua University, No. 3999 Binjiang East Road, Fengman District, Jilin City, Jilin Province, China
| | - Dan Wu
- College of Basic Medicin, Beihua University, No. 3999 Binjiang East Road, Fengman District, Jilin City, Jilin Province, China
| | - Chen Zhou
- Department of Laboratory Medicine, The Eighth Affiliated Hospital, Sun Yat-Sen University, No. 3025 Shennan Middle Road, Futian District, Shenzhen, China
| | - Muran Bai
- College of Basic Medicin, Beihua University, No. 3999 Binjiang East Road, Fengman District, Jilin City, Jilin Province, China
| | - Yucheng Wan
- Hospital of Stomatology, Zunyi Medical University, No. 89, Wujiang East Road, Xinpu New District, Zunyi City, Guizhou Province, China
| | - Qing Zheng
- College of Basic Medicin, Beihua University, No. 3999 Binjiang East Road, Fengman District, Jilin City, Jilin Province, China
| | - Zhijin Fan
- Institute for Engineering Medicine, Kunming Medical University, No. 1168 Chunrong West Road, Yuhua Street, Chenggong District, Kunming City, Yunnan Province China
| | - Xianwen Wang
- School of Biomedical Engineering, Research and Engineering Center of Biomedical Materials, Anhui Medical University, No.81 Meishan Road, Shushan District, Hefei 230032, China
| | - Chun Yang
- College of Basic Medicin, Beihua University, No. 3999 Binjiang East Road, Fengman District, Jilin City, Jilin Province, China
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7
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Tang S, Cai P, He H, Tian Y, Hao R, Liu X, Jing T, Xu Y, Li X. Global trends in the clinical utilization of exosomes in dermatology: a bibliometric analysis. Front Med (Lausanne) 2024; 11:1462085. [PMID: 39450105 PMCID: PMC11500466 DOI: 10.3389/fmed.2024.1462085] [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: 07/09/2024] [Accepted: 09/11/2024] [Indexed: 10/26/2024] Open
Abstract
The arena of exosomal research presents substantial emerging prospects for clinical dermatology applications. This investigation conducts a thorough analysis of the contemporary global research landscape regarding exosomes and their implications for dermatological applications over the preceding decade. Employing bibliometric methodologies, this study meticulously dissects the knowledge framework and identifies dynamic trends within this specialized field. Contemporary scholarly literature spanning the last decade was sourced from the Web of Science Core Collection (WoSCC) database. Subsequent to retrieval, both quantitative and visual analyses of the pertinent publications were performed utilizing the analytical software tools VOSviewer and Citespace. A comprehensive retrieval yielded 545 scholarly articles dated from January 1, 2014, to December 31, 2023. Leading the research forefront are institutions such as Shanghai Jiao Tong University, The Fourth Military Medical University, and Sun Yat-sen University. The most prolific contributors on a national scale are China, the United States, and South Korea. Among the authors, Zhang Bin, Zhang Wei, and Zhang Yan emerge as the most published, with Zhang Bin also achieving the distinction of being the most cited. The International Journal of Molecular Sciences leads in article publications, whereas Stem Cell Research & Therapy holds the pinnacle in citation rankings. Theranostics boasts the highest impact factor among the periodicals. Current research hotspots in this area include Adipose mesenchymal stem cell-derived exosomes(ADSC-Exos), diabetic skin wounds, cutaneous angiogenesis, and the combination of biomaterials and exosomes. This manuscript constitutes the inaugural comprehensive bibliometric analysis that delineates the prevailing research trends and advancements in the clinical application of exosomes in dermatology. These analyses illuminate the contemporary research focal points and trajectories, providing invaluable insights that will inform further exploration within this domain.
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Affiliation(s)
- Shiqin Tang
- School of Clinical Medicine, Hebei University of Engineering, Handan, Hebei, China
| | - Pai Cai
- School of Information Engineering, Suihua University, Suihua, Heilongjiang, China
| | - Huina He
- School of Clinical Medicine, Hebei University of Engineering, Handan, Hebei, China
| | - Yanan Tian
- School of Clinical Medicine, Hebei University of Engineering, Handan, Hebei, China
| | - Ruiying Hao
- Affiliated Hospital of Hebei University of Engineering, Handan, Hebei, China
| | - Xin Liu
- Handan Stomatological Hospital, Endodontics, Handan, Hebei, China
| | - Tingting Jing
- Affiliated Hospital of Hebei University of Engineering, Handan, Hebei, China
- Hebei Key Laboratory of Immunological Dermatology, Handan, Hebei, China
| | - Yanyan Xu
- Affiliated Hospital of Hebei University of Engineering, Handan, Hebei, China
- Hebei Key Laboratory of Immunological Dermatology, Handan, Hebei, China
| | - Xiaojing Li
- School of Clinical Medicine, Hebei University of Engineering, Handan, Hebei, China
- Affiliated Hospital of Hebei University of Engineering, Handan, Hebei, China
- Hebei Key Laboratory of Immunological Dermatology, Handan, Hebei, China
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Peng C, Xu H, Zhuang Q, Liu J, Ding Y, Tang Q, Wang Z, Yao K. Placenta-derived mesenchymal stem cells promote diabetic wound healing via exosomal protein interaction networks. Wound Repair Regen 2024; 32:638-651. [PMID: 39022990 DOI: 10.1111/wrr.13199] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Revised: 04/17/2024] [Accepted: 05/29/2024] [Indexed: 07/20/2024]
Abstract
There is a lack of effective treatment options for diabetic refractory wounds, which presents a critical clinical issue that needs to be addressed urgently. Our research has demonstrated that human placenta-derived mesenchymal stem cells (plaMSCs) facilitate the migration and proliferation of HaCat cells, thereby enhancing diabetic wound healing primarily via the exosomes derived from plaMSCs (plaMSCs-Ex). Using label-free proteomics, plaMSCs and their exosomes were analysed for proteome taxonomic content in order to explore the underlying effective components mechanism of plaMSCs-Ex in diabetic wound healing. Differentially expressed proteins enriched in plaMSCs-Ex were identified and underwent bioinformatics analysis including GO annotation, KEGG pathway enrichment, gene set enrichment analysis (GSEA) and protein-protein interaction analysis (PPI). Results showed that the proteins enriched in plaMSCs-Ex are significantly involved in extracellular matrix organisation, epithelium morphogenesis, cell growth, adhesion, proliferation and angiogenesis. PPI analysis filtered 2 wound healing-related clusters characterised by hub proteins such as POSTN, FN1, SPARC, TIMP1, SERPINE1, LRP1 and multiple collagens. In brief, the exosomal proteins derived from plaMSCs reveal diverse functions of regeneration and tissue remodelling based on proteomics analysis and potentially play a role in diabetic wound healing.
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Affiliation(s)
- Cheng Peng
- Department of Burns and Plastic Surgery, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Hongbo Xu
- Department of Vascular Surgery, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Quan Zhuang
- Transplantation Center, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Jinya Liu
- Department of Burns and Plastic Surgery, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Yinhe Ding
- Department of Spine Surgery, The Xiangya Hospital of Central South University, Changsha, China
| | - Qiyu Tang
- Department of Burns and Plastic Surgery, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Zheng Wang
- Department of Vascular Surgery, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Kai Yao
- Department of Vascular Surgery, The Third Xiangya Hospital of Central South University, Changsha, China
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Sędzik M, Rakoczy K, Sleziak J, Kisiel M, Kraska K, Rubin J, Łuniewska W, Choromańska A. Comparative Analysis of Exosomes and Extracellular Microvesicles in Healing Pathways: Insights for Advancing Regenerative Therapies. Molecules 2024; 29:3681. [PMID: 39125084 PMCID: PMC11314465 DOI: 10.3390/molecules29153681] [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: 06/22/2024] [Revised: 07/30/2024] [Accepted: 07/31/2024] [Indexed: 08/12/2024] Open
Abstract
Exosomes and microvesicles bear great potential to broaden therapeutic options in the clinical context. They differ in genesis, size, cargo, and composition despite their similarities. They were identified as participating in various processes such as angiogenesis, cell migration, and intracellular communication. Additionally, they are characterized by their natural biocompatibility. Therefore, researchers concluded that they could serve as a novel curative method capable of achieving unprecedented results. Indeed, in experiments, they proved remarkably efficient in enhancing wound regeneration and mitigating inflammation. Despite immense advancements in research on exosomes and microvesicles, the time for their large-scale application is yet to come. This article aims to gather and analyze current knowledge on those promising particles, their characteristics, and their potential clinical implementations.
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Affiliation(s)
- Mikołaj Sędzik
- Faculty of Medicine, Wroclaw Medical University, 50-367 Wroclaw, Poland; (M.S.); (K.R.); (J.S.); (M.K.); (K.K.); (J.R.); (W.Ł.)
| | - Katarzyna Rakoczy
- Faculty of Medicine, Wroclaw Medical University, 50-367 Wroclaw, Poland; (M.S.); (K.R.); (J.S.); (M.K.); (K.K.); (J.R.); (W.Ł.)
| | - Jakub Sleziak
- Faculty of Medicine, Wroclaw Medical University, 50-367 Wroclaw, Poland; (M.S.); (K.R.); (J.S.); (M.K.); (K.K.); (J.R.); (W.Ł.)
| | - Michał Kisiel
- Faculty of Medicine, Wroclaw Medical University, 50-367 Wroclaw, Poland; (M.S.); (K.R.); (J.S.); (M.K.); (K.K.); (J.R.); (W.Ł.)
| | - Karolina Kraska
- Faculty of Medicine, Wroclaw Medical University, 50-367 Wroclaw, Poland; (M.S.); (K.R.); (J.S.); (M.K.); (K.K.); (J.R.); (W.Ł.)
| | - Jakub Rubin
- Faculty of Medicine, Wroclaw Medical University, 50-367 Wroclaw, Poland; (M.S.); (K.R.); (J.S.); (M.K.); (K.K.); (J.R.); (W.Ł.)
| | - Wiktoria Łuniewska
- Faculty of Medicine, Wroclaw Medical University, 50-367 Wroclaw, Poland; (M.S.); (K.R.); (J.S.); (M.K.); (K.K.); (J.R.); (W.Ł.)
| | - Anna Choromańska
- Department of Molecular and Cellular Biology, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland
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10
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Li X, Zhang D, Yu Y, Wang L, Zhao M. Umbilical cord-derived mesenchymal stem cell secretome promotes skin regeneration and rejuvenation: From mechanism to therapeutics. Cell Prolif 2024; 57:e13586. [PMID: 38148579 PMCID: PMC10984109 DOI: 10.1111/cpr.13586] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Revised: 10/31/2023] [Accepted: 11/22/2023] [Indexed: 12/28/2023] Open
Abstract
How to effectively repair cutaneous wounds and promote skin rejuvenation has always been a challenging issue for clinical medicine and medical aesthetics. Current conventional medicines exhibit several drawbacks, including limited therapeutic effects, prolonged treatment periods, and high costs. As a novel cell-free therapy, the umbilical cord-derived mesenchymal stem cell (UCMSC) secretome may offer a promising approach for skin regeneration and rejuvenation. The UCMSC secretome is a collection of all proteins secreted by mesenchymal stem cells, including conditioned media, exosomes, and other substances. The UCMSC secretome has numerous abilities to accelerate acute wound healing, including high fibroblast and keratinocyte proliferative activity, pro-angiogenesis, anti-inflammation, anti-fibrosis, and anti-oxidative stress. Its impact on the four stages of wound healing is manifested by inducing the haemostasis phase, inhibiting the inflammation phase, promoting the proliferation phase, and regulating the remodelling phase. Furthermore, it is highly effective in the treatment of chronic wounds, alopecia, aging, and skin homeostasis disturbance. This review focuses on the clinical therapies and application prospects of the UCMSC secretome, encompassing its source, culture, separation, identification, storage, and pretreatment. Additionally, a discussion on the dosage, administration route, efficacy, and biosafety in the clinical situation is presented. This review aims to provide scientific support for the mechanistic investigation and clinical utilisation of the UCMSC secretome in wound healing and skin rejuvenation.
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Affiliation(s)
- Xixian Li
- Department of Plastic SurgeryThe Second Hospital of Dalian Medical UniversityDalianLiaoningChina
- CAS Key Laboratory of Separation Science for Analytical ChemistryDalian Institute of Chemical Physics, Chinese Academy of SciencesDalianLiaoningChina
| | - Dan Zhang
- Department of Plastic SurgeryThe Second Hospital of Dalian Medical UniversityDalianLiaoningChina
| | - Yang Yu
- CAS Key Laboratory of Separation Science for Analytical ChemistryDalian Institute of Chemical Physics, Chinese Academy of SciencesDalianLiaoningChina
| | - Liang Wang
- Research and Teaching Department of Comparative MedicineDalian Medical UniversityDalianLiaoningChina
| | - Muxin Zhao
- Department of Plastic SurgeryThe Second Hospital of Dalian Medical UniversityDalianLiaoningChina
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11
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van Griensven M, Balmayor ER. Extracellular vesicles are key players in mesenchymal stem cells' dual potential to regenerate and modulate the immune system. Adv Drug Deliv Rev 2024; 207:115203. [PMID: 38342242 DOI: 10.1016/j.addr.2024.115203] [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: 06/01/2023] [Revised: 10/15/2023] [Accepted: 02/05/2024] [Indexed: 02/13/2024]
Abstract
MSCs are used for treatment of inflammatory conditions or for regenerative purposes. MSCs are complete cells and allogenic transplantation is in principle possible, but mostly autologous use is preferred. In recent years, it was discovered that cells secrete extracellular vesicles. These are active budded off vesicles that carry a cargo. The cargo can be miRNA, protein, lipids etc. The extracellular vesicles can be transported through the body and fuse with target cells. Thereby, they influence the phenotype and modulate the disease. The extracellular vesicles have, like the MSCs, immunomodulatory or regenerative capacities. This review will focus on those features of extracellular vesicles and discuss their dual role. Besides the immunomodulation, the regeneration will concentrate on bone, cartilage, tendon, vessels and nerves. Current clinical trials with extracellular vesicles for immunomodulation and regeneration that started in the last five years are highlighted as well. In summary, extracellular vesicles have a great potential as disease modulating entity and treatment. Their dual characteristics need to be taken into account and often are both important for having the best effect.
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Affiliation(s)
- Martijn van Griensven
- Department of Cell Biology-Inspired Tissue Engineering, MERLN Institute for Technology-Inspired Regenerative Medicine, 6229 ER Maastricht, the Netherlands; Musculoskeletal Gene Therapy Laboratory, Rehabilitation Medicine Research Center, Mayo Clinic, Rochester, MN 55905, USA.
| | - Elizabeth R Balmayor
- Musculoskeletal Gene Therapy Laboratory, Rehabilitation Medicine Research Center, Mayo Clinic, Rochester, MN 55905, USA; Experimental Orthopaedics and Trauma Surgery, Department of Orthopaedic, Trauma, and Reconstructive Surgery, RWTH Aachen University Hospital, 52074 Aachen, Germany
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12
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Wang M, Yang D, Li L, Wu P, Sun Y, Zhang X, Ji C, Xu W, Qian H, Shi H. A Dual Role of Mesenchymal Stem Cell Derived Small Extracellular Vesicles on TRPC6 Protein and Mitochondria to Promote Diabetic Wound Healing. ACS NANO 2024; 18:4871-4885. [PMID: 38290527 PMCID: PMC10867885 DOI: 10.1021/acsnano.3c09814] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Revised: 01/24/2024] [Accepted: 01/25/2024] [Indexed: 02/01/2024]
Abstract
Diabetic wounds exhibit delayed and incomplete healing, usually due to vascular and nerve damage. Dysregulation of cellular Ca2+ homeostasis has recently been shown to be closely related to insulin resistance and type 2 diabetes mellitus. However, the involvement of this dysregulation in diabetic wound complications remains unknown. In this study, we found calcium dysregulation in patients with diabetic ulcers via tissue protein profiling. High glucose and glucometabolic toxicant stimulation considerably impaired the function of TRPC6, a pore subunit of transient receptor potential channels mediating Ca2+ influx, and mitochondria, which regulate calcium cycling and metabolism. Furthermore, we found that mesenchymal stem cell (MSC)-derived small extracellular vesicles (MSC-sEVs) could play a dual role in restoring the function of TRPC6 and mitochondria by delivering transcription factor SP2 and deubiquitinating enzyme USP9, respectively. MSC-sEVs could transfer SP2 that activated TRPC6 expression by binding to its specific promoter regions (-1519 to -1725 bp), thus recovering Ca2+ influx and downstream pathways. MSC-sEVs also promoted mitophagy to restore mitochondrial function by transporting USP9 that stabilized the expression of Parkin, a major player in mitophagy, thereby guaranteeing Ca2+ efflux and avoidance of Ca2+ overload. Targeting the regulation of calcium homeostasis provides a perspective for understanding diabetic wound healing, and the corresponding design of MSC-sEVs could be a potential therapeutic strategy.
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Affiliation(s)
- Min Wang
- Jiangsu
Key Laboratory of Medical Science and Laboratory Medicine, Department
of Clinical Laboratory, School of Medicine, Jiangsu University, Zhenjiang 212000, China
- School
of Biomedical Engineering, Research and Engineering Center of Biomedical
Materials, Anhui Medical University, Hefei 230000, China
| | - Dakai Yang
- Jiangsu
Key Laboratory of Medical Science and Laboratory Medicine, Department
of Clinical Laboratory, School of Medicine, Jiangsu University, Zhenjiang 212000, China
| | - Linli Li
- Department
of Clinical Laboratory, Changzhou Second
Hospital, Changzhou 213000, China
| | - Peipei Wu
- Department
of Clinical Laboratory, The First Affiliated Hospital of USTC, Division
of Life Sciences and Medicine, University
of Science and Technology of China, 17 Lujiang Road, Hefei 230000, China
| | - Yaoxiang Sun
- Department
of Clinical Laboratory, The Affiliated Yixing
Hospital of Jiangsu University, Yixing 214200, China
| | - Xu Zhang
- Jiangsu
Key Laboratory of Medical Science and Laboratory Medicine, Department
of Clinical Laboratory, School of Medicine, Jiangsu University, Zhenjiang 212000, China
| | - Cheng Ji
- Jiangsu
Key Laboratory of Medical Science and Laboratory Medicine, Department
of Clinical Laboratory, School of Medicine, Jiangsu University, Zhenjiang 212000, China
| | - Wenrong Xu
- Jiangsu
Key Laboratory of Medical Science and Laboratory Medicine, Department
of Clinical Laboratory, School of Medicine, Jiangsu University, Zhenjiang 212000, China
| | - Hui Qian
- Jiangsu
Key Laboratory of Medical Science and Laboratory Medicine, Department
of Clinical Laboratory, School of Medicine, Jiangsu University, Zhenjiang 212000, China
| | - Hui Shi
- Jiangsu
Key Laboratory of Medical Science and Laboratory Medicine, Department
of Clinical Laboratory, School of Medicine, Jiangsu University, Zhenjiang 212000, China
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13
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Dolatshahi M, Bahrami AR, Sheikh QI, Ghanbari M, Matin MM. Gastric cancer and mesenchymal stem cell-derived exosomes: from pro-tumorigenic effects to anti-cancer vehicles. Arch Pharm Res 2024; 47:1-19. [PMID: 38151649 DOI: 10.1007/s12272-023-01477-8] [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: 06/27/2023] [Accepted: 12/15/2023] [Indexed: 12/29/2023]
Abstract
Gastric cancer (GC) is one of the most prevalent malignancies in the world, with a high mortality rate in both women and men. Conventional treatments, like chemotherapy, radiotherapy and surgery, are facing some drawbacks like acquired drug resistance and various side effects, leading to cancer recurrence and increased morbidity; thus, development of novel approaches in targeted therapy would be very beneficial. Exosomes, extracellular vesicles with a size distribution of sub-150 nm, interplay in physiological and pathophysiological cell-cell communications and can pave the way for targeted cancer therapy. Accumulating pieces of evidence have indicated that exosomes derived from mesenchymal stem cells (MSC-EXs) can act as a double-edged sword in some cancers. The purpose of this review is to assess the differences between stem cell therapy and exosome therapy. Moreover, our aim is to demonstrate how naïve MSCs transform into GC-MSCs in the tumor microenvironment. Additionally, the tumorigenic and anti-proliferation effects of MSC-EXs derived from different origins were investigated. Finally, we suggest potential modifications and combination options that involve utilizing MSC-EXs from the foreskin and umbilical cord as promising sources to enhance the efficacy of gastric cancer treatment. This approach is presented in contrast to bone marrow cells, which are more heterogeneous, age-related, and are also easily affected by the patient's circulation system.
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Affiliation(s)
- Maryam Dolatshahi
- Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Ahmad Reza Bahrami
- Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran
- Industrial Biotechnology Research Group, Institute of Biotechnology, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Qaiser Iftikhar Sheikh
- School of Biosciences, Western Bank, Firth Court, University of Sheffield, Sheffield, S10 2TN, England, UK
| | - Mohsen Ghanbari
- Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Maryam M Matin
- Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran.
- Novel Diagnostics and Therapeutics Research Group, Institute of Biotechnology, Ferdowsi University of Mashhad, Mashhad, Iran.
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14
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Zhang T, Li D, Wang Y, Zhang C, Yang W, Gao G. Delivering umbilical cord mesenchymal stem cell exosomes through hydrogel ameliorates vaginal atrophy in ovariectomized rats. Aging (Albany NY) 2023; 15:14292-14305. [PMID: 38059876 PMCID: PMC10756086 DOI: 10.18632/aging.205302] [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: 08/09/2023] [Accepted: 11/06/2023] [Indexed: 12/08/2023]
Abstract
BACKGROUND Menopausal and postmenopausal women often experience vaginal atrophy due to estrogen deficiency. Mesenchymal stem cell exosomes have emerged as potential therapeutic agents, capable of promoting tissue regeneration and repair. OBJECTIVE This study aimed to explore the benefits of exosomes on VK2 cells and the therapeutic effect of topical exosomal hydrogel on atrophic vaginas. METHODS Exosomes were extracted using the high-speed centrifugation method, and their effects on VK2 cell proliferation, migration, and differentiation were observed through co-culture. The menopause model was induced by ovariectomy in rats, followed by the injection of exosome-loaded hydrogel into their vaginas. The treatment's effectiveness was evaluated by measuring vaginal epithelium thickness using HE staining, and assessing vaginal mucosa proliferation and lamina propria angiogenesis using Ki67 and anti-CD31 staining, respectively. RESULTS Exosomes significantly promoted VK2 cell proliferation and migration, but had no significant effect on differentiation. The exosome hydrogel increased the expression of Ki67 and CD31, leading to a significant improvement in epithelial thickness. CONCLUSIONS UcMSC- ex can stimulate the proliferation and migration of VK2 cells, but do not appear to promote differentiation. Topical application of exosome hydrogel enhances vaginal epithelium thickness to a certain degree, offering a promising non-hormonal therapeutic strategy to alleviate vaginal atrophy in postmenopausal women.
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Affiliation(s)
- Tao Zhang
- Gannan Medical University, Ganzhou 341000, Jiangxi, China
| | - Dandan Li
- Savaid Medical School, University of Chinese Academy of Sciences, Huairou 101400, Beijing, China
| | - Yanting Wang
- Gannan Medical University, Ganzhou 341000, Jiangxi, China
| | - Chi Zhang
- Department of Orthopedics, Peking University International Hospital, Changping 102206, Beijing, China
| | - Wenlan Yang
- Department of Orthopedics, Peking University International Hospital, Changping 102206, Beijing, China
| | - Guolan Gao
- Savaid Medical School, University of Chinese Academy of Sciences, Huairou 101400, Beijing, China
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15
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Yang B, Lin Y, Huang Y, Zhu N, Shen YQ. Extracellular vesicles modulate key signalling pathways in refractory wound healing. BURNS & TRAUMA 2023; 11:tkad039. [PMID: 38026441 PMCID: PMC10654481 DOI: 10.1093/burnst/tkad039] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/22/2023] [Revised: 05/10/2023] [Accepted: 06/22/2023] [Indexed: 12/01/2023]
Abstract
Chronic wounds are wounds that cannot heal properly due to various factors, such as underlying diseases, infection or reinjury, and improper healing of skin wounds and ulcers can cause a serious economic burden. Numerous studies have shown that extracellular vesicles (EVs) derived from stem/progenitor cells promote wound healing, reduce scar formation and have significant advantages over traditional treatment methods. EVs are membranous particles that carry various bioactive molecules from their cellular origins, such as cytokines, nucleic acids, enzymes, lipids and proteins. EVs can mediate cell-to-cell communication and modulate various physiological processes, such as cell differentiation, angiogenesis, immune response and tissue remodelling. In this review, we summarize the recent advances in EV-based wound healing, focusing on the signalling pathways that are regulated by EVs and their cargos. We discuss how EVs derived from different types of stem/progenitor cells can promote wound healing and reduce scar formation by modulating the Wnt/β-catenin, phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin, vascular endothelial growth factor, transforming growth factor β and JAK-STAT pathways. Moreover, we also highlight the challenges and opportunities for engineering or modifying EVs to enhance their efficacy and specificity for wound healing.
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Affiliation(s)
- Bowen Yang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, No. 14, Section 3, Renmin South Road, Wuhou District, Chengdu 610041, China
| | - Yumeng Lin
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, No. 14, Section 3, Renmin South Road, Wuhou District, Chengdu 610041, China
| | - Yibo Huang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, No. 14, Section 3, Renmin South Road, Wuhou District, Chengdu 610041, China
| | - Nanxi Zhu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, No. 14, Section 3, Renmin South Road, Wuhou District, Chengdu 610041, China
| | - Ying-Qiang Shen
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, No. 14, Section 3, Renmin South Road, Wuhou District, Chengdu 610041, China
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16
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Sun Z, Ning Y, Wu H, Guo S, Jiao X, Ji J, Ding X, Yu X. 14-3-3ζ targets β-catenin nuclear translocation to maintain mitochondrial homeostasis and promote the balance between proliferation and apoptosis in cisplatin-induced acute kidney injury. Cell Signal 2023; 111:110878. [PMID: 37657586 DOI: 10.1016/j.cellsig.2023.110878] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 08/14/2023] [Accepted: 08/29/2023] [Indexed: 09/03/2023]
Abstract
Cisplatin is a chemotherapeutic agent that is used extensively to treat solid tumors; however, its clinical application is limited by side effects, especially nephrotoxicity. Cisplatin-induced acute kidney injury (AKI) is characterized by DNA damage, cell-cycle arrest, and mitochondrial oxidative stress. Recent research demonstrated that 14-3-3ζ plays an important role in cancers, nerve disease, and kidney disease, although the regulatory mechanisms underlying cisplatin-induced AKI have yet to be fully elucidated. In the present study, we found that 14-3-3ζ mRNA was upregulated in human kidney organoids (GSE145085) when treated with cisplatin; subsequently, this was confirmed in experimental mice. The application of a protein interaction inhibitor for 14-3-3 (BV02) resulted in a decline in renal function, along with apoptosis, mitochondrial dysfunction, and oxidative stress in cisplatin-induced AKI. Accordingly, the knockdown of 14-3-3ζ in cisplatin-treated NRK-52E cells led to increased apoptosis, cell-cycle arrest, the production of reactive oxygen species (ROS), and lipid dysbolism. Furthermore, the blockade of 14-3-3ζ, both in vivo and in vitro, suppressed β-catenin and its nuclear translocation, thus downregulating expression of the downstream gene cyclin D1 in cisplatin-induced damage. In contrast, the overexpression of 14-3-3ζ alleviated the injury caused by cisplatin both in vivo and in vitro. Furthermore, a non-specific agonist of β-catenin, BIO, reversed the effects of 14-3-3ζ knockdown in terms of cisplatin-induced damage in NRK-52E cells by activating β-catenin. Next, we verified the direct interaction between 14 - 3-3ζ and β-catenin by CO-IP and immunofluorescence. Collectively, these findings indicate that 14-3-3ζ protects against cisplatin-induced AKI by improving mitochondrial function and the balance between proliferation and apoptosis by facilitating the nuclear translocation of β-catenin.
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Affiliation(s)
- Zhaoxing Sun
- Department of Nephrology, Zhongshan Hospital, Fudan University, China.
| | - Yichun Ning
- Department of Nephrology, Zhongshan Hospital, Fudan University, China; Shanghai Medical Center for Kidney, China; Shanghai Key Laboratory of Kidney and Blood Purification, Shanghai, China; Shanghai Institute of Kidney and Dialysis, Shanghai, China; Hemodialysis Quality Control Center of Shanghai, Shanghai, China.
| | - Huan Wu
- Department of Nephrology, Zhongshan Hospital, Fudan University, China.
| | - Shulan Guo
- Department of Nephrology, Zhongshan Hospital, Fudan University, China.
| | - Xiaoyan Jiao
- Department of Nephrology, Zhongshan Hospital, Fudan University, China; Shanghai Medical Center for Kidney, China; Shanghai Key Laboratory of Kidney and Blood Purification, Shanghai, China; Shanghai Institute of Kidney and Dialysis, Shanghai, China; Hemodialysis Quality Control Center of Shanghai, Shanghai, China.
| | - Ji Ji
- Department of Nephrology, Zhongshan Hospital, Fudan University, China.
| | - Xiaoqiang Ding
- Department of Nephrology, Zhongshan Hospital, Fudan University, China; Shanghai Medical Center for Kidney, China; Shanghai Key Laboratory of Kidney and Blood Purification, Shanghai, China; Shanghai Institute of Kidney and Dialysis, Shanghai, China; Hemodialysis Quality Control Center of Shanghai, Shanghai, China.
| | - Xiaofang Yu
- Department of Nephrology, Zhongshan Hospital, Fudan University, China; Shanghai Medical Center for Kidney, China; Shanghai Key Laboratory of Kidney and Blood Purification, Shanghai, China; Shanghai Institute of Kidney and Dialysis, Shanghai, China; Hemodialysis Quality Control Center of Shanghai, Shanghai, China.
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17
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Feng J, Yao Y, Wang Q, Han X, Deng X, Cao Y, Chen X, Zhou M, Zhao C. Exosomes: Potential key players towards novel therapeutic options in diabetic wounds. Biomed Pharmacother 2023; 166:115297. [PMID: 37562235 DOI: 10.1016/j.biopha.2023.115297] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Revised: 07/31/2023] [Accepted: 08/05/2023] [Indexed: 08/12/2023] Open
Abstract
Diabetic wounds are usually difficult to heal, and wounds in foot in particular are often aggravated by infection, trauma, diabetic neuropathy, peripheral vascular disease and other factors, resulting in serious foot ulcers. The pathogenesis and clinical manifestations of diabetic wounds are complicated, and there is still a lack of objective and in-depth laboratory diagnosis and classification standards. Exosomes are nanoscale vesicles containing DNA, mRNA, microRNA, cyclic RNA, metabolites, lipids, cytoplasm and cell surface proteins, etc., which are involved in intercellular communication and play a crucial role in vascular regeneration, tissue repair and inflammation regulation in the process of diabetic wound healing. Here, we discussed exosomes of different cellular origins, such as diabetic wound-related fibroblasts (DWAF), adipose stem cells (ASCs), mesenchymal stem cells (MSCs), immune cells, platelets, human amniotic epithelial cells (hAECs), epidermal stem cells (ESCs), and their various molecular components. They exhibit multiple therapeutic effects during diabetic wound healing, including promoting cell proliferation and migration associated with wound healing, regulating macrophage polarization to inhibit inflammatory responses, promoting nerve repair, and promoting vascular renewal and accelerating wound vascularization. In addition, exosomes can be designed to deliver different therapeutic loads and have the ability to deliver them to the desired target. Therefore, exosomes may become an innovative target for precision therapeutics in diabetic wounds. In this review, we summarize the latest research on the role of exosomes in the healing of diabetic wound by regulating the pathogenesis of diabetic wounds, and discuss their potential applications in the precision treatment of diabetic wounds.
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Affiliation(s)
- Jiawei Feng
- Shanghai Traditional Chinese Medicine Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200082, China
| | - Yichen Yao
- Institute for Interdisciplinary Medicine Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Qixue Wang
- Institute for Interdisciplinary Medicine Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Xiaozhou Han
- Shanghai Traditional Chinese Medicine Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200082, China
| | - Xiaofei Deng
- Shanghai Traditional Chinese Medicine Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200082, China
| | - Yemin Cao
- Shanghai Traditional Chinese Medicine Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200082, China
| | - Xinghua Chen
- Jinshan Hospital Afflicted to Fudan University, Shanghai, China.
| | - Mingmei Zhou
- Institute for Interdisciplinary Medicine Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
| | - Cheng Zhao
- Shanghai Traditional Chinese Medicine Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200082, China.
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18
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Ding JY, Chen MJ, Wu LF, Shu GF, Fang SJ, Li ZY, Chu XR, Li XK, Wang ZG, Ji JS. Mesenchymal stem cell-derived extracellular vesicles in skin wound healing: roles, opportunities and challenges. Mil Med Res 2023; 10:36. [PMID: 37587531 PMCID: PMC10433599 DOI: 10.1186/s40779-023-00472-w] [Citation(s) in RCA: 51] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Accepted: 07/24/2023] [Indexed: 08/18/2023] Open
Abstract
Skin wounds are characterized by injury to the skin due to trauma, tearing, cuts, or contusions. As such injuries are common to all human groups, they may at times represent a serious socioeconomic burden. Currently, increasing numbers of studies have focused on the role of mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) in skin wound repair. As a cell-free therapy, MSC-derived EVs have shown significant application potential in the field of wound repair as a more stable and safer option than conventional cell therapy. Treatment based on MSC-derived EVs can significantly promote the repair of damaged substructures, including the regeneration of vessels, nerves, and hair follicles. In addition, MSC-derived EVs can inhibit scar formation by affecting angiogenesis-related and antifibrotic pathways in promoting macrophage polarization, wound angiogenesis, cell proliferation, and cell migration, and by inhibiting excessive extracellular matrix production. Additionally, these structures can serve as a scaffold for components used in wound repair, and they can be developed into bioengineered EVs to support trauma repair. Through the formulation of standardized culture, isolation, purification, and drug delivery strategies, exploration of the detailed mechanism of EVs will allow them to be used as clinical treatments for wound repair. In conclusion, MSC-derived EVs-based therapies have important application prospects in wound repair. Here we provide a comprehensive overview of their current status, application potential, and associated drawbacks.
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Affiliation(s)
- Jia-Yi Ding
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Institute of Imaging Diagnosis and Minimally Invasive Intervention Research, the Fifth Affiliated Hospital of Wenzhou Medical University, Zhejiang, 323000, Lishui, China
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - Min-Jiang Chen
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Institute of Imaging Diagnosis and Minimally Invasive Intervention Research, the Fifth Affiliated Hospital of Wenzhou Medical University, Zhejiang, 323000, Lishui, China
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - Ling-Feng Wu
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
- Clinical College of the Affiliated Central Hospital, School of Medicine, Lishui University, Lishui, 323000, Zhejiang, China
| | - Gao-Feng Shu
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Institute of Imaging Diagnosis and Minimally Invasive Intervention Research, the Fifth Affiliated Hospital of Wenzhou Medical University, Zhejiang, 323000, Lishui, China
- Clinical College of the Affiliated Central Hospital, School of Medicine, Lishui University, Lishui, 323000, Zhejiang, China
| | - Shi-Ji Fang
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Institute of Imaging Diagnosis and Minimally Invasive Intervention Research, the Fifth Affiliated Hospital of Wenzhou Medical University, Zhejiang, 323000, Lishui, China
- Clinical College of the Affiliated Central Hospital, School of Medicine, Lishui University, Lishui, 323000, Zhejiang, China
| | - Zhao-Yu Li
- Department of Overseas Education College, Jimei University, Xiamen, 361021, Fujian, China
| | - Xu-Ran Chu
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
- Department of Medicine II, Internal Medicine, Cardio-Pulmonary Institute (CPI), Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Justus-Liebig University Giessen, 35392, Giessen, Germany
- Pulmonary and Critical Care, Department of Medicine V, Internal Medicine, Infectious Diseases and Infection Control, Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Justus-Liebig University Giessen, 35392, Giessen, Germany
| | - Xiao-Kun Li
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China.
| | - Zhou-Guang Wang
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Institute of Imaging Diagnosis and Minimally Invasive Intervention Research, the Fifth Affiliated Hospital of Wenzhou Medical University, Zhejiang, 323000, Lishui, China.
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China.
| | - Jian-Song Ji
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Institute of Imaging Diagnosis and Minimally Invasive Intervention Research, the Fifth Affiliated Hospital of Wenzhou Medical University, Zhejiang, 323000, Lishui, China.
- Clinical College of the Affiliated Central Hospital, School of Medicine, Lishui University, Lishui, 323000, Zhejiang, China.
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19
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Ju C, Liu D. Exosomal microRNAs from Mesenchymal Stem Cells: Novel Therapeutic Effect in Wound Healing. Tissue Eng Regen Med 2023; 20:647-660. [PMID: 37131016 PMCID: PMC10352215 DOI: 10.1007/s13770-023-00542-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2023] [Revised: 03/23/2023] [Accepted: 03/27/2023] [Indexed: 05/04/2023] Open
Abstract
BACKGROUND Wound healing is a complicated biological process that leads to the regeneration of damaged skin tissue. Determining the methods to promote wound healing has become a hot topic in medical cosmetology and tissue repair research. Mesenchymal stem cells (MSCs) are a group of stem cells with the potential of self-renewal and multi-differentiation. MSCs transplantation has a broad application prospect in wound healing therapy. Many studies have demonstrated that the therapeutic capacity of MSCs is mainly mediated by paracrine actions. Exosomes (EXOs), which are nanosized vesicles carrying a variety of nucleic acids, proteins and lipids, are an important component of paracrine secretion. It has been demonstrated that exosomal microRNAs (EXO-miRNAs) play a key role in the function of exosomes. METHODS In this review, we focus on current research on miRNAs from MSC-derived exosomes (MSC-EXO miRNAs) in terms of sorting, releasing and function and their effects on inflammation regulation, epidermal cell function, fibroblast function, and extracellular matrix formation. At last, we discuss the current attempts to improve the treatment of MSC-EXO-miRNAs. RESULTS Many studies have demonstrated that MSC-EXO miRNAs play a key role in promoting wound healing. They have been shown to regulate inflammation response, enhance epidermal cell proliferation and migration, stimulate fibroblast proliferation and collagen synthesis, and regulate extracellular matrix formation. Besides, there have been a number of strategies developed to promote MSC-EXO and MSC-EXO miRNAs for wound healing treatment. CONCLUSION Utilizing the association of exosomes from MSCs with miRNAs may be a promising strategy to promote trauma healing. MSC-EXO miRNAs may provide a new approach to promote wound healing and improve the quality of life for patients with skin injuries.
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Affiliation(s)
- Congcong Ju
- Medical Center of Burn Plastic and Wound Repair, The First Affiliated Hospital of Nanchang University, 17 Yongwai Street, Nanchang, 330006, Jiangxi, People's Republic of China
- Huankui Academy, Nanchang University, Nanchang, Jiangxi, People's Republic of China
| | - Dewu Liu
- Medical Center of Burn Plastic and Wound Repair, The First Affiliated Hospital of Nanchang University, 17 Yongwai Street, Nanchang, 330006, Jiangxi, People's Republic of China.
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Zheng D, Ruan H, Chen W, Zhang Y, Cui W, Chen H, Shen H. Advances in extracellular vesicle functionalization strategies for tissue regeneration. Bioact Mater 2023; 25:500-526. [PMID: 37056271 PMCID: PMC10087114 DOI: 10.1016/j.bioactmat.2022.07.022] [Citation(s) in RCA: 33] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2022] [Revised: 07/06/2022] [Accepted: 07/19/2022] [Indexed: 11/02/2022] Open
Abstract
Extracellular vesicles (EVs) are nano-scale vesicles derived by cell secretion with unique advantages such as promoting cell proliferation, anti-inflammation, promoting blood vessels and regulating cell differentiation, which benefit their wide applications in regenerative medicine. However, the in vivo therapeutic effect of EVs still greatly restricted by several obstacles, including the off-targetability, rapid blood clearance, and undesired release. To address these issues, biomedical engineering techniques are vastly explored. This review summarizes different strategies to enhance EV functions from the perspective of drug loading, modification, and combination of biomaterials, and emphatically introduces the latest developments of functionalized EV-loaded biomaterials in different diseases, including cardio-vascular system diseases, osteochondral disorders, wound healing, nerve injuries. Challenges and future directions of EVs are also discussed.
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Affiliation(s)
- Dandan Zheng
- Department of Spine Surgery, Renji Hospital, Shanghai JiaoTong University School of Medicine, 160 Pujian Road, Shanghai, 200127, PR China
| | - Huitong Ruan
- Department of Orthopaedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai, 200025, China
| | - Wei Chen
- Department of Orthopaedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai, 200025, China
| | - Yuhui Zhang
- Department of Spine Surgery, Renji Hospital, Shanghai JiaoTong University School of Medicine, 160 Pujian Road, Shanghai, 200127, PR China
| | - Wenguo Cui
- Department of Orthopaedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai, 200025, China
| | - Hao Chen
- Department of Spine Surgery, Renji Hospital, Shanghai JiaoTong University School of Medicine, 160 Pujian Road, Shanghai, 200127, PR China
| | - Hongxing Shen
- Department of Spine Surgery, Renji Hospital, Shanghai JiaoTong University School of Medicine, 160 Pujian Road, Shanghai, 200127, PR China
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21
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Yin S, Zhou Z, Fu P, Jin C, Wu P, Ji C, Shan Y, Shi L, Xu M, Qian H. Roles of extracellular vesicles in ageing-related chronic kidney disease: demon or angel. Pharmacol Res 2023:106795. [PMID: 37211241 DOI: 10.1016/j.phrs.2023.106795] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Revised: 05/02/2023] [Accepted: 05/16/2023] [Indexed: 05/23/2023]
Abstract
Ageing is a universal and unavoidable phenomenon that significantly increases the risk of developing chronic kidney disease (CKD). It has been reported that ageing is associated with functional disruption and structural damage to the kidneys. Extracellular vesicles (EVs), which are nanoscale membranous vesicles containing lipids, proteins, and nucleic acids, are secreted by cells into the extracellular spaces. They have diverse functions such as repairing and regenerating different forms of ageing-related CKD and playing a crucial role in intercellular communication. This paper reviews the etiology of ageing in CKD, with particular attention paid to the roles of EVs as carriers of ageing signals and anti-ageing therapeutic strategies in CKD. In this regard, the double-edged role of EVs in ageing-related CKD is examined, along with the potential for their application in clinical settings.
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Affiliation(s)
- Siqi Yin
- Institute of Translational Medicine of Jiangsu University, Affiliated Hospital of Jiangsu University, Zhenjiang 212001, Jiangsu, China; Key Laboratory of Laboratory Medicine of Jiangsu Province, Department of laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang 212013, Jiangsu, China
| | - Zixuan Zhou
- Institute of Translational Medicine of Jiangsu University, Affiliated Hospital of Jiangsu University, Zhenjiang 212001, Jiangsu, China; Key Laboratory of Laboratory Medicine of Jiangsu Province, Department of laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang 212013, Jiangsu, China
| | - Peiwen Fu
- Key Laboratory of Laboratory Medicine of Jiangsu Province, Department of laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang 212013, Jiangsu, China
| | - Chaoying Jin
- Department of Plastic and Aesthetic Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang, China
| | - Peipei Wu
- Department of Clinical Laboratory, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230001, China
| | - Cheng Ji
- Institute of Translational Medicine of Jiangsu University, Affiliated Hospital of Jiangsu University, Zhenjiang 212001, Jiangsu, China; Key Laboratory of Laboratory Medicine of Jiangsu Province, Department of laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang 212013, Jiangsu, China
| | - Yunjie Shan
- Key Laboratory of Laboratory Medicine of Jiangsu Province, Department of laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang 212013, Jiangsu, China
| | - Linru Shi
- Key Laboratory of Laboratory Medicine of Jiangsu Province, Department of laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang 212013, Jiangsu, China
| | - Min Xu
- Institute of Translational Medicine of Jiangsu University, Affiliated Hospital of Jiangsu University, Zhenjiang 212001, Jiangsu, China.
| | - Hui Qian
- Institute of Translational Medicine of Jiangsu University, Affiliated Hospital of Jiangsu University, Zhenjiang 212001, Jiangsu, China; Key Laboratory of Laboratory Medicine of Jiangsu Province, Department of laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang 212013, Jiangsu, China.
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22
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Xu L, Sima Y, Xiao C, Chen Y. Exosomes derived from mesenchymal stromal cells: a promising treatment for pelvic floor dysfunction. Hum Cell 2023; 36:937-949. [PMID: 36940057 DOI: 10.1007/s13577-023-00887-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Accepted: 02/25/2023] [Indexed: 03/21/2023]
Abstract
Pelvic floor dysfunction (PFDs), which include pelvic organ prolapse (POP), stress urinary incontinence (SUI) and anal incontinence (AI), are common degenerative diseases in women that have dramatic effects on quality of life. The pathology of PFDs is based on impaired pelvic connective tissue supportive strength due to an imbalance in extracellular matrix (ECM) metabolism, the loss of a variety of cell types, such as fibroblasts, muscle cells, peripheral nerve cells, and oxidative stress and inflammation in the pelvic environment. Fortunately, exosomes, which are one of the major secretions of mesenchymal stromal cells (MSCs), are involved in intercellular communication and the modulation of molecular activities in recipient cells via their contents, which are bioactive proteins and genetic factors such as mRNAs and miRNAs. These components modify fibroblast activation and secretion, facilitate ECM modelling, and promote cell proliferation to enhance pelvic tissue regeneration. In this review, we focus on the molecular mechanisms and future directions of exosomes derived from MSCs that are of great value in the treatment of PFD.
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Affiliation(s)
- Leimei Xu
- Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, 128 ShenYang Road, Shanghai, 200011, People's Republic of China.,Shanghai Key Laboratory of Female Reproductive Endocrine-Related Diseases, Shanghai, China
| | - Yizhen Sima
- Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, 128 ShenYang Road, Shanghai, 200011, People's Republic of China.,Shanghai Key Laboratory of Female Reproductive Endocrine-Related Diseases, Shanghai, China
| | - Chengzhen Xiao
- Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, 128 ShenYang Road, Shanghai, 200011, People's Republic of China
| | - Yisong Chen
- Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, 128 ShenYang Road, Shanghai, 200011, People's Republic of China. .,Shanghai Key Laboratory of Female Reproductive Endocrine-Related Diseases, Shanghai, China.
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23
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Wang TT, Wu LL, Wu J, Zhang LS, Shen WJ, Zhao YH, Liu JN, Fu B, Wang X, Li QG, Bai XY, Wang LQ, Chen XM. 14-3-3ζ inhibits maladaptive repair in renal tubules by regulating YAP and reduces renal interstitial fibrosis. Acta Pharmacol Sin 2023; 44:381-392. [PMID: 35840657 PMCID: PMC9889378 DOI: 10.1038/s41401-022-00946-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Accepted: 05/30/2022] [Indexed: 02/04/2023]
Abstract
Acute kidney injury (AKI) refers to a group of common clinical syndromes characterized by acute renal dysfunction, which may lead to chronic kidney disease (CKD), and this process is called the AKI-CKD transition. The transcriptional coactivator YAP can promote the AKI-CKD transition by regulating the expression of profibrotic factors, and 14-3-3 protein zeta (14-3-3ζ), an important regulatory protein of YAP, may prevent the AKI-CKD transition. We established an AKI-CKD model in mice by unilateral renal ischemia-reperfusion injury and overexpressed 14-3-3ζ in mice using a fluid dynamics-based gene transfection technique. We also overexpressed and knocked down 14-3-3ζ in vitro. In AKI-CKD model mice, 14-3-3ζ expression was significantly increased at the AKI stage. During the development of chronic disease, the expression of 14-3-3ζ tended to decrease, whereas active YAP was consistently overexpressed. In vitro, we found that 14-3-3ζ can combine with YAP, promote the phosphorylation of YAP, inhibit YAP nuclear translocation, and reduce the expression of fibrosis-related proteins. In an in vivo intervention experiment, we found that the overexpression of 14-3-3ζ slowed the process of renal fibrosis in a mouse model of AKI-CKD. These findings suggest that 14-3-3ζ can affect the expression of fibrosis-related proteins by regulating YAP, inhibit the maladaptive repair of renal tubular epithelial cells, and prevent the AKI-CKD transition.
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Affiliation(s)
- Tian-Tian Wang
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Nephrology Institute of the Chinese People's Liberation Army, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Disease Research, Beijing, 100853, China
| | - Ling-Ling Wu
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Nephrology Institute of the Chinese People's Liberation Army, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Disease Research, Beijing, 100853, China
| | - Jie Wu
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Nephrology Institute of the Chinese People's Liberation Army, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Disease Research, Beijing, 100853, China
| | - Li-Sheng Zhang
- College of Veterinary Medicine/College of Biomedicine and Health, Huazhong Agricultural University, Wuhan, 430070, China
| | - Wan-Jun Shen
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Nephrology Institute of the Chinese People's Liberation Army, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Disease Research, Beijing, 100853, China
| | - Ying-Hua Zhao
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Nephrology Institute of the Chinese People's Liberation Army, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Disease Research, Beijing, 100853, China
| | - Jiao-Na Liu
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Nephrology Institute of the Chinese People's Liberation Army, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Disease Research, Beijing, 100853, China
| | - Bo Fu
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Nephrology Institute of the Chinese People's Liberation Army, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Disease Research, Beijing, 100853, China
| | - Xu Wang
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Nephrology Institute of the Chinese People's Liberation Army, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Disease Research, Beijing, 100853, China
| | - Qing-Gang Li
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Nephrology Institute of the Chinese People's Liberation Army, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Disease Research, Beijing, 100853, China
| | - Xue-Yuan Bai
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Nephrology Institute of the Chinese People's Liberation Army, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Disease Research, Beijing, 100853, China
| | - Li-Qiang Wang
- Department of Ophthalmology, Chinese PLA General Hospital, Beijing, 100853, China.
| | - Xiang-Mei Chen
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Nephrology Institute of the Chinese People's Liberation Army, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Disease Research, Beijing, 100853, China.
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Deng C, Hu Y, Conceição M, Wood MJA, Zhong H, Wang Y, Shao P, Chen J, Qiu L. Oral delivery of layer-by-layer coated exosomes for colitis therapy. J Control Release 2023; 354:635-650. [PMID: 36634710 DOI: 10.1016/j.jconrel.2023.01.017] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 01/05/2023] [Accepted: 01/06/2023] [Indexed: 01/14/2023]
Abstract
Mesenchymal stem cell-derived exosomes (MSC-Exos) have attracted much attention as a potential cell-free therapy for ulcerative colitis (UC), mainly due to their anti-inflammatory, tissue repair, and immunomodulatory properties. Although intravenous injection of MSC-Exos is able to improve UC to a certain extent, oral administration of exosomes is the preferred method to treat gastrointestinal diseases such as UC. However, exosomes contain proteins and nucleic acids that are vulnerable to degradation by the gastrointestinal environment, making oral administration difficult to implement. Layer-by-layer (LbL) self-assembly technology provides a promising strategy for the oral delivery of exosomes. Therefore, an efficient LbL-Exos self-assembly system was constructed in this study for the oral delivery of exosomes targeted to the colon to improve UC treatment. Biocompatible and biodegradable N-(2-hydroxyl) propyl-3-trimethyl ammonium chitosan chloride (HTCC) and oxidized konjac glucomannan (OKGM) polysaccharides were used as the outer layers to provide colon targeting and to protect exosomes from degradation. Similar to plain exosomes, LbL-Exos had a similar structure and features, but LbL provided controlled release of exosomes in the inflammatory colon. Compared with intravenous administration, oral administration of LbL-Exos could effectively alleviate UC using half the number of exosomes. Mechanistic studies showed that LbL-Exos were internalized by macrophages and intestinal epithelial cells to exert anti-inflammatory and tissue repair effects and therefore alleviate UC. Furthermore, the LbL-Exos system was able to improve UC via MAPK/NF-κB signaling pathway inhibition. Overall, our data show that LbL-MSC-Exos can alleviate UC after oral administration and therefore may constitute a new strategy for UC treatment in the future.
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Affiliation(s)
- Chao Deng
- Wuxi School of Medicine, Jiangnan University, Wuxi 214122, China
| | - Yiwei Hu
- Wuxi School of Medicine, Jiangnan University, Wuxi 214122, China; Jiangyin Center for Disease Control and Prevention, Jiangyin 214434, China
| | | | - Matthew J A Wood
- Department of Paediatrics, University of Oxford, Oxford OX1 3QX, UK; MDUK Oxford Neuromuscular Centre, University of Oxford, Oxford, UK
| | - Hongyao Zhong
- Wuxi School of Medicine, Jiangnan University, Wuxi 214122, China
| | - Yan Wang
- Yixing Hospital of Traditional Chinese Medicine, Wuxi 214200, China
| | - Ping Shao
- Yixing Hospital of Traditional Chinese Medicine, Wuxi 214200, China.
| | - Jinghua Chen
- School of Life Sciences and Health Engineering, Jiangnan University, Wuxi 214122, China.
| | - Lipeng Qiu
- Department of Paediatrics, University of Oxford, Oxford OX1 3QX, UK; School of Life Sciences and Health Engineering, Jiangnan University, Wuxi 214122, China.
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25
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Zakeri A, Khaseb S, Akhavan Rahnama M, Hajaliaskari A, Soufi Zomorrod M. Exosomes derived from mesenchymal stem cells: A promising cell-free therapeutic tool for cutaneous wound healing. Biochimie 2023; 209:73-84. [PMID: 36681232 DOI: 10.1016/j.biochi.2023.01.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Revised: 01/15/2023] [Accepted: 01/17/2023] [Indexed: 01/20/2023]
Abstract
Skin wound healing is a multifaceted process involving a cascade of molecular and cellular procedures that occur in four different phases: (a) hemostasis, (b) inflammation, (c) proliferation, and (d) tissue remodeling. Prolonged wound healing in skin is still a major challenge in treatment of wounds. Mesenchymal stem cells (MSCs) accelerate cutaneous wound healing through their paracrine activity. Exosomes are one of the key secretory products of MSCs, mimicking the effects of parental MSCs in skin wound healing process. Exosomes are small membrane vesicles (30-150 nm in diameter) that originate from endosomal pathways and transport numerous biomolecules, including DNAs, messenger RNAs, microRNAs, lipids, and proteins. They can be taken up by target cells and release their contents to modulate the activity of recipient cells. Exosomes derived from mesenchymal stem cells (MSC-Exo) reduce inflammation, promote proliferation, inhibit apoptosis, and enhance angiogenesis in skin wound healing process. Therefore, exosomes are emerging as novel cell-cell communication mediators and have opened a novel viewpoint for developing cell-free therapies. This review aims to demonstrate the roles of exosomes in each step of skin wound healing through a comprehensive literature search.
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Affiliation(s)
- Armin Zakeri
- Department of Hematology and Cell Therapy, Faculty of Medical Sciences, Tarbiat Modares University (TMU), Tehran, Iran.
| | - Sanaz Khaseb
- Department of Hematology and Cell Therapy, Faculty of Medical Sciences, Tarbiat Modares University (TMU), Tehran, Iran.
| | - Mahshid Akhavan Rahnama
- Department of Hematology and Cell Therapy, Faculty of Medical Sciences, Tarbiat Modares University (TMU), Tehran, Iran.
| | - Akram Hajaliaskari
- Department of Hematology and Cell Therapy, Faculty of Medical Sciences, Tarbiat Modares University (TMU), Tehran, Iran.
| | - Mina Soufi Zomorrod
- Department of Hematology and Cell Therapy, Faculty of Medical Sciences, Tarbiat Modares University (TMU), Tehran, Iran.
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26
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Wei Q, Liu X, Su JL, Wang YX, Chu ZQ, Ma K, Huang QL, Li HH, Fu XB, Zhang CP. Small extracellular vesicles from mesenchymal stem cells: A potential Weapon for chronic non-healing wound treatment. Front Bioeng Biotechnol 2023; 10:1083459. [PMID: 36704302 PMCID: PMC9872203 DOI: 10.3389/fbioe.2022.1083459] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Accepted: 12/28/2022] [Indexed: 01/11/2023] Open
Abstract
Chronic non-healing wounds have posed a severe threat to patients mentally and physically. Behavior dysregulation of remaining cells at wound sites is recognized as the chief culprit to destroy healing process and hinders wound healing. Therefore, regulating and restoring normal cellular behavior is the core of chronic non-healing wound treatment. In recent years, the therapy with mesenchymal stem cells (MSCs) has become a promising option for chronic wound healing and the efficacy has increasingly been attributed to their exocrine functions. Small extracellular vesicles derived from MSCs (MSC-sEVs) are reported to benefit almost all stages of wound healing by regulating the cellular behavior to participate in the process of inflammatory response, angiogenesis, re-epithelization, and scarless healing. Here, we describe the characteristics of MSC-sEVs and discuss their therapeutic potential in chronic wound treatment. Additionally, we also provide an overview of the application avenues of MSC-sEVs in wound treatment. Finally, we summarize strategies for large-scale production and engineering of MSC-sEVs. This review may possibly provide meaningful guidance for chronic wound treatment with MSC-sEVs.
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Affiliation(s)
- Qian Wei
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Division and the 4th Medical Center of Chinese, PLA General Hospital, Beijing, China
| | - Xi Liu
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Division and the 4th Medical Center of Chinese, PLA General Hospital, Beijing, China
| | - Jian-Long Su
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Division and the 4th Medical Center of Chinese, PLA General Hospital, Beijing, China
| | - Ya-Xi Wang
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Division and the 4th Medical Center of Chinese, PLA General Hospital, Beijing, China
| | - Zi-Qiang Chu
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Division and the 4th Medical Center of Chinese, PLA General Hospital, Beijing, China
| | - Kui Ma
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Division and the 4th Medical Center of Chinese, PLA General Hospital, Beijing, China
- Tissue Repair and Regeneration, Chinese Academy of Medical Sciences, Research Unit of Trauma Care, Beijing, China
- PLA Key Laboratory of Tissue Repair and Regenerative Medicine and Beijing Key Research Laboratory of Skin Injury, Repair and Regeneration, Beijing, China
| | - Qi-Lin Huang
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Division and the 4th Medical Center of Chinese, PLA General Hospital, Beijing, China
| | - Hai-Hong Li
- Department of Wound Repair, Institute of Wound Repair and Regeneration Medicine, Southern University of Science and Technology Hospital, Southern University of Science and Technology School of Medicine, Shenzhen, China
| | - Xiao-Bing Fu
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Division and the 4th Medical Center of Chinese, PLA General Hospital, Beijing, China
- Tissue Repair and Regeneration, Chinese Academy of Medical Sciences, Research Unit of Trauma Care, Beijing, China
- PLA Key Laboratory of Tissue Repair and Regenerative Medicine and Beijing Key Research Laboratory of Skin Injury, Repair and Regeneration, Beijing, China
| | - Cui-Ping Zhang
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Division and the 4th Medical Center of Chinese, PLA General Hospital, Beijing, China
- Tissue Repair and Regeneration, Chinese Academy of Medical Sciences, Research Unit of Trauma Care, Beijing, China
- PLA Key Laboratory of Tissue Repair and Regenerative Medicine and Beijing Key Research Laboratory of Skin Injury, Repair and Regeneration, Beijing, China
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27
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Anwar I, Ashfaq UA. Impact of Nanotechnology on Differentiation and Augmentation of Stem Cells for Liver Therapy. Crit Rev Ther Drug Carrier Syst 2023; 40:89-116. [PMID: 37585310 DOI: 10.1615/critrevtherdrugcarriersyst.2023042400] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/18/2023]
Abstract
The liver is one of the crucial organs of the body that performs hundreds of chemical reactions needed by the body to survive. It is also the largest gland of the body. The liver has multiple functions, including the synthesis of chemicals, metabolism of nutrients, and removal of toxins. It also acts as a storage unit. The liver has a unique ability to regenerate itself, but it can lead to permanent damage if the injury is beyond recovery. The only possible treatment of severe liver damage is liver transplant which is a costly procedure and has several other drawbacks. Therefore, attention has been shifted towards the use of stem cells that have shown the ability to differentiate into hepatocytes. Among the numerous kinds of stem cells (SCs), the mesenchymal stem cells (MSCs) are the most famous. Various studies suggest that an MSC transplant can repair liver function, improve the signs and symptoms, and increase the chances of survival. This review discusses the impact of combining stem cell therapy with nanotechnology. By integrating stem cell science and nanotechnology, the information about stem cell differentiation and regulation will increase, resulting in a better comprehension of stem cell-based treatment strategies. The augmentation of SCs with nanoparticles has been shown to boost the effect of stem cell-based therapy. Also, the function of green nanoparticles in liver therapies is discussed.
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Affiliation(s)
- Ifrah Anwar
- Department of Bioinformatics and Biotechnology, Government College University Faisalabad, Faisalabad, Pakistan
| | - Usman Ali Ashfaq
- Department of Bioinformatics and Biotechnology, Government College University Faisalabad, Faisalabad, Pakistan
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28
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Zhang B, Gong J, He L, Khan A, Xiong T, Shen H, Li Z. Exosomes based advancements for application in medical aesthetics. Front Bioeng Biotechnol 2022; 10:1083640. [PMID: 36605254 PMCID: PMC9810265 DOI: 10.3389/fbioe.2022.1083640] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2022] [Accepted: 12/05/2022] [Indexed: 01/07/2023] Open
Abstract
Beauty is an eternal pursuit of all people. Wound repair, anti-aging, inhibiting hyperpigmentation and hair loss are the main demands for medical aesthetics. At present, the repair and remodeling of human body shape and function in medical aesthetics are often achieved by injection of antioxidants, hyaluronic acid and botulinum toxin, stem cell therapy. However, there are some challenges, such as difficulty controlling the injection dose, abnormal local contour, increased foreign body sensation, and the risk of tumor occurrence and deformity induced by stem cell therapy. Exosomes are tiny vesicles secreted by cells, which are rich in proteins, nucleic acids and other bioactive molecules. They have the characteristics of low immunogenicity and strong tissue penetration, making them ideal for applications in medical aesthetics. However, their low yield, strong heterogeneity, and long-term preservation still hinder their application in medical aesthetics. In this review, we summarize the mechanism of action, administration methods, engineered production and preservation technologies for exosomes in medical aesthetics in recent years to further promote their research and industrialization in the field of medical aesthetics.
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Affiliation(s)
- Bin Zhang
- College of Life Science, Yangtze University, Jingzhou, China
- Department of Clinical Laboratory, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Jianmin Gong
- College of Life Science, Yangtze University, Jingzhou, China
- Department of Clinical Laboratory, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Lei He
- Department of Clinical Laboratory, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Adeel Khan
- State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, National Demonstration Center for Experimental Biomedical Engineering Education, Southeast University, Nanjing, China
| | - Tao Xiong
- College of Life Science, Yangtze University, Jingzhou, China
| | - Han Shen
- Department of Clinical Laboratory, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Zhiyang Li
- Department of Clinical Laboratory, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
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Wu J, Chen LH, Sun SY, Li Y, Ran XW. Mesenchymal stem cell-derived exosomes: The dawn of diabetic wound healing. World J Diabetes 2022; 13:1066-1095. [PMID: 36578867 PMCID: PMC9791572 DOI: 10.4239/wjd.v13.i12.1066] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 11/04/2022] [Accepted: 11/23/2022] [Indexed: 12/15/2022] Open
Abstract
Chronic wound healing has long been an unmet medical need in the field of wound repair, with diabetes being one of the major etiologies. Diabetic chronic wounds (DCWs), especially diabetic foot ulcers, are one of the most threatening chronic complications of diabetes. Although the treatment strategies, drugs, and dressings for DCWs have made great progress, they remain ineffective in some patients with refractory wounds. Stem cell-based therapies have achieved specific efficacy in various fields, with mesenchymal stem cells (MSCs) being the most widely used. Although MSCs have achieved good feedback in preclinical studies and clinical trials in the treatment of cutaneous wounds or other situations, the potential safety concerns associated with allogeneic/autologous stem cells and unknown long-term health effects need further attention and supervision. Recent studies have reported that stem cells mainly exert their trauma repair effects through paracrine secretion, and exosomes play an important role in intercellular communication as their main bioactive component. MSC-derived exosomes (MSC-Exos) inherit the powerful inflammation and immune modulation, angiogenesis, cell proliferation and migration promotion, oxidative stress alleviation, collagen remodeling imbalances regulation of their parental cells, and can avoid the potential risks of direct stem cell transplantation to a large extent, thus demonstrating promising performance as novel "cell-free" therapies in chronic wounds. This review aimed to elucidate the potential mechanism and update the progress of MSC-Exos in DCW healing, thereby providing new therapeutic directions for DCWs that are difficult to be cured using conventional therapy.
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Affiliation(s)
- Jing Wu
- Innovation Center for Wound Repair, Diabetic Foot Care Center, Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Li-Hong Chen
- Innovation Center for Wound Repair, Diabetic Foot Care Center, Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Shi-Yi Sun
- Innovation Center for Wound Repair, Diabetic Foot Care Center, Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Yan Li
- Innovation Center for Wound Repair, Diabetic Foot Care Center, Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Xing-Wu Ran
- Innovation Center for Wound Repair, Diabetic Foot Care Center, Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
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Lu S, Lu L, Liu Y, Li Z, Fang Y, Chen Z, Zhou J. Native and engineered extracellular vesicles for wound healing. Front Bioeng Biotechnol 2022; 10:1053217. [PMID: 36568307 PMCID: PMC9780283 DOI: 10.3389/fbioe.2022.1053217] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2022] [Accepted: 11/28/2022] [Indexed: 12/14/2022] Open
Abstract
Extracellular vesicles (EVs) that act as messengers mediate communication between parent and recipient cells through their contents, including nucleic acids, proteins, and lipids. These endogenous vesicles have emerged as a novel cell-free strategy for the treatment of diseases. EVs can be released by various types of cells with unique biological properties. Recent studies have shown that native EVs are used as therapeutic agents to promote tissue repair by delivering various growth factors and trophic factors including VEGF, EGF, TFN-α, IL-1β, and TGF-β to participate in all physiological processes of wound healing. Furthermore, to improve their specificity, safety, and efficiency for wound healing, the content and surface of EVs can be designed, modified, and engineered. The engineering strategies of EVs are divided into parent cell modification and indirect modification of EVs. The therapeutic potential of current EVs and engineered EVs for wound healing still requires the exploration of their large-scale clinical applications through innovative approaches. Herein, we provide an overview of the current biological knowledge about wound healing and EVs, as well as the application of native EVs in promoting wound healing. We also outline recent advances in engineering EV methodologies to achieve ideal therapeutic potential. Finally, the therapeutic applications of engineered EVs in wound healing are reviewed, and the challenges and prospects for the translation of engineered EVs to clinical applications are discussed.
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Affiliation(s)
- Shengli Lu
- Department of Plastic Surgery, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Liping Lu
- Department of Pediatrics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yang Liu
- Department of Plastic Surgery, The Third Xiangya Hospital, Central South University, Changsha, China
- Department of Dermatology, Leiden University Medical Center, Leiden, Netherland
| | - Zenan Li
- Department of Plastic Surgery, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Yuan Fang
- Department of Plastic Surgery, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Zhizhao Chen
- Department of Plastic Surgery, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Jianda Zhou
- Department of Plastic Surgery, The Third Xiangya Hospital, Central South University, Changsha, China
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Almeria C, Kreß S, Weber V, Egger D, Kasper C. Heterogeneity of mesenchymal stem cell-derived extracellular vesicles is highly impacted by the tissue/cell source and culture conditions. Cell Biosci 2022; 12:51. [PMID: 35501833 PMCID: PMC9063275 DOI: 10.1186/s13578-022-00786-7] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Accepted: 04/10/2022] [Indexed: 12/19/2022] Open
Abstract
AbstractExtracellular vesicles (EVs) are cell-derived membrane structures exerting major effects in physiological as well as pathological processes by functioning as vehicles for the delivery of biomolecules to their target cells. An increasing number of effects previously attributed to cell-based therapies have been recognized to be actually mediated by EVs derived from the respective cells, suggesting the administration of purified EVs instead of living cells for cell-based therapies. In this review, we focus on the heterogeneity of EVs derived from mesenchymal stem/stromal cells (MSC) and summarize upstream process parameters that crucially affect the resulting therapeutic properties and biological functions. Hereby, we discuss the effects of the cell source, medium composition, 3D culture, bioreactor culture and hypoxia. Furthermore, aspects of the isolation and storage strategies influences EVs are described. Conclusively, optimization of upstream process parameters should focus on controlling MSC-derived EV heterogeneity for specific therapeutic applications.
Graphical Abstract
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Shimizu Y, Ntege EH, Sunami H. Current regenerative medicine-based approaches for skin regeneration: A review of literature and a report on clinical applications in Japan. Regen Ther 2022; 21:73-80. [PMID: 35785041 PMCID: PMC9213559 DOI: 10.1016/j.reth.2022.05.008] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Revised: 05/11/2022] [Accepted: 05/25/2022] [Indexed: 11/18/2022] Open
Abstract
Current trends indicate a growing interest among healthcare specialists and the public in the use of regenerative medicine-based approaches for skin regeneration. The approaches are categorised in either cell-based or cell-free therapies and are reportedly safe and effective. Cell-based therapies include mesenchymal stem cells (MSCs), tissue induced pluripotent stem cells (iPSCs), fibroblast-based products, and blood-derived therapies, such as those employing platelet-rich plasma (PRP) products. Cell-free therapies primarily involve the use of MSC-derived extracellular vesicles/exosomes. MSCs are isolated from various tissues, such as fat, bone marrow, umbilical cord, menstrual blood, and foetal skin, and expanded ex vivo before transplantation. In cell-free therapies, MSC exosomes, MSC-derived cultured media, and MSC-derived extracellular vesicles are collected from MSC-conditioned media or supernatant. In this review, a literature search of the Cochrane Library, MEDLINE (PubMed), EMBASE, and Scopus was conducted using several combinations of terms, such as ‘stem’, ‘cell’, ‘aging’, ‘wrinkles’, ‘nasolabial folds’, ‘therapy’, ‘mesenchymal stem cells’, and ‘skin’, to identify relevant articles providing a comprehensive update on the different regenerative medicine-based therapies and their application to skin regeneration. In addition, the regulatory perspectives on the clinical application of some of these therapies in Japan are highlighted.
The use of regenerative medicine-based therapy for skin rejuvenation is expanding. Therapies can be categorised as either cell-based or cell-free therapies. MSCs can be isolated from various tissues for cosmetic applications. MSC-derived exosomes increase skin cell proliferation and migration. In Japan, most cell-based treatments carry class II/III regenerative medicine risks.
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Affiliation(s)
- Yusuke Shimizu
- Department of Plastic and Reconstructive Surgery, Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Nakagami, 903-0215 Okinawa, Japan
- Corresponding author. Department of Plastic and Reconstructive Surgery Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan
| | - Edward Hosea Ntege
- Department of Plastic and Reconstructive Surgery, Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Nakagami, 903-0215 Okinawa, Japan
| | - Hiroshi Sunami
- Center for Advanced Medical Research, School of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Nakagami, 903-0215 Okinawa, Japan
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Nallakumarasamy A, Jeyaraman M, Maffulli N, Jeyaraman N, Suresh V, Ravichandran S, Gupta M, Potty AG, El-Amin SF, Khanna M, Gupta A. Mesenchymal Stromal Cell-Derived Extracellular Vesicles in Wound Healing. Life (Basel) 2022; 12:1733. [PMID: 36362890 PMCID: PMC9699035 DOI: 10.3390/life12111733] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2022] [Accepted: 10/24/2022] [Indexed: 07/26/2023] Open
Abstract
The well-orchestrated process of wound healing may be negatively impacted from interrupted or incomplete tissue regenerative processes. The healing potential is further compromised in patients with diabetes mellitus, chronic venous insufficiency, critical limb ischemia, and immunocompromised conditions, with a high health care burden and expenditure. Stem cell-based therapy has shown promising results in clinical studies. Mesenchymal stem cell-derived exosomes (MSC Exos) may favorably impact intercellular signaling and immunomodulation, promoting neoangiogenesis, collagen synthesis, and neoepithelization. This article gives an outline of the biogenesis and mechanism of extracellular vesicles (EVs), particularly exosomes, in the process of tissue regeneration and discusses the use of preconditioned exosomes, platelet-rich plasma-derived exosomes, and engineered exosomes in three-dimensional bioscaffolds such as hydrogels (collagen and chitosan) to prolong the contact time of exosomes at the recipient site within the target tissue. An appropriate antibiotic therapy based on culture-specific guidance coupled with the knowledge of biopolymers helps to fabricate nanotherapeutic materials loaded with MSC Exos to effectively deliver drugs locally and promote novel approaches for the management of chronic wounds.
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Affiliation(s)
- Arulkumar Nallakumarasamy
- Department of Orthopaedics, All India Institute of Medical Sciences, Bhubaneswar 751019, Odissa, India
- Fellow in Orthopaedic Rheumatology, Dr. RML National Law University, Lucknow 226010, Uttar Pradesh, India
- Indian Stem Cell Study Group (ISCSG) Association, Lucknow 226010, Uttar Pradesh, India
| | - Madhan Jeyaraman
- Indian Stem Cell Study Group (ISCSG) Association, Lucknow 226010, Uttar Pradesh, India
- Department of Orthopaedics, Faculty of Medicine—Sri Lalithambigai Medical College and Hospital, Dr. MGR Educational and Research Institute, Chennai 600095, Tamil Nadu, India
- Department of Medical Research and Translational Medicine, Faculty of Medicine—Sri Lalithambigai Medical College and Hospital, Dr. MGR Educational and Research Institute, Chennai 600095, Tamil Nadu, India
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida 201310, Uttar Pradesh, India
- South Texas Orthopaedic Research Institute (STORI Inc.), Laredo, TX 78045, USA
| | - Nicola Maffulli
- Department of Musculoskeletal Disorders, School of Medicine and Surgery, University of Salerno, 84084 Fisciano, Italy
- San Giovanni di Dio e Ruggi D’Aragona Hospital “Clinica Ortopedica” Department, Hospital of Salerno, 84124 Salerno, Italy
- Barts and the London School of Medicine and Dentistry, Centre for Sports and Exercise Medicine, Queen Mary University of London, London E1 4DG, UK
- School of Pharmacy and Bioengineering, Keele University School of Medicine, Stoke on Trent ST5 5BG, UK
| | - Naveen Jeyaraman
- Indian Stem Cell Study Group (ISCSG) Association, Lucknow 226010, Uttar Pradesh, India
- Fellow in Joint Replacement, Department of Orthopaedics, Atlas Hospitals, Tiruchirappalli 620002, Tamil Nadu, India
| | - Veerasivabalan Suresh
- Department of Obstetrics-Gynecology, Madras Medical College and Hospital, Chennai 600003, Tamil Nadu, India
| | - Srinath Ravichandran
- Department of General and GI Surgery, Stepping Hill Hospital, Stockport NHS Foundation Trust, Stockport SK27JE, UK
| | - Manu Gupta
- Polar Aesthetics Dental & Cosmetic Centre, Noida 201301, Uttar Pradesh, India
| | - Anish G. Potty
- South Texas Orthopaedic Research Institute (STORI Inc.), Laredo, TX 78045, USA
| | - Saadiq F. El-Amin
- El-Amin Orthopaedic & Sports Medicine Institute, Lawrenceville, GA 30043, USA
- Regenerative Sports Medicine, Lawrenceville, GA 30043, USA
- BioIntegrate, Lawrenceville, GA 30043, USA
| | - Manish Khanna
- Indian Stem Cell Study Group (ISCSG) Association, Lucknow 226010, Uttar Pradesh, India
- Department of Orthopaedics, Autonomous State Medical College, Ayodhya 224135, Uttar Pradesh, India
| | - Ashim Gupta
- Indian Stem Cell Study Group (ISCSG) Association, Lucknow 226010, Uttar Pradesh, India
- South Texas Orthopaedic Research Institute (STORI Inc.), Laredo, TX 78045, USA
- BioIntegrate, Lawrenceville, GA 30043, USA
- Regenerative Orthopaedics, Noida 201301, Uttar Pradesh, India
- Future Biologics, Lawrenceville, GA 30043, USA
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hucMSC-sEVs-Derived 14-3-3ζ Serves as a Bridge between YAP and Autophagy in Diabetic Kidney Disease. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:3281896. [PMID: 36199425 PMCID: PMC9527117 DOI: 10.1155/2022/3281896] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/28/2022] [Revised: 08/06/2022] [Accepted: 08/26/2022] [Indexed: 12/29/2022]
Abstract
As nanoscale membranous vesicles, human umbilical cord mesenchymal stem cell-derived small extracellular vesicles (hucMSC-sEVs) have attracted extensive attention in the field of tissue regeneration. Under the premise that the mechanisms of hucMSC-sEVs on the treatment of diabetic kidney disease (DKD) have not been revealed clearly, we constructed DKD rat model with success. After tail vein injection, hucMSC-sEVs effectively reduced blood glucose, maintained body weight and improved renal function in DKD rats. Notably, we found that hucMSC-sEVs suppressed YAP expression in renal cortical regions. Further in vitro experiments, we confirmed that the expression of YAP in the nucleus of renal podocytes was increased, and the level of autophagy was inhibited in the high-glucose environment, which could be reversed by intervention with hucMSC-sEVs. We screened out the key protein 14-3-3ζ, which could not only promote YAP cytoplasmic retention instead of entering the nucleus, but also enhance the level of autophagy in the cytoplasm. Ultimately, excessive YAP protein was removed by autophagy, a classic way of protein degradation. In conclusion, our study provides new strategies for the prevention of DKD and proposes the possibility of hucMSC-sEVs becoming a new treatment for DKD in the future.
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Hao X, Zhang Y, Shi X, Liu H, Zheng Z, Han G, Rong D, Zhang C, Tang W, Wang X. CircPAK1 promotes the progression of hepatocellular carcinoma via modulation of YAP nucleus localization by interacting with 14-3-3ζ. J Exp Clin Cancer Res 2022; 41:281. [PMID: 36131287 PMCID: PMC9494907 DOI: 10.1186/s13046-022-02494-z] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Accepted: 08/23/2022] [Indexed: 12/24/2022] Open
Abstract
Abstract
Background
Circular RNA (circRNA), a new class of non-coding RNA, has obvious correlations with the occurrence and development of many diseases, including tumors. This study aimed to investigate the potential roles of circPAK1 in hepatocellular carcinoma (HCC).
Methods
High-throughput sequencing was performed on 3 pairs of HCC and matched normal tissues to determine the upregulated circRNAs. The expression level of circPAK1 was detected by qRT-PCR in HCC and paired with normal liver tissue samples. The effects of circPAK1 on proliferation, invasion, metastasis and apoptosis of HCC cells were evaluated by in vitro and in vivo experiments. We also constructed Chitosan/si-circPAK1 (CS/si-circPAK1) nanocomplexes using Chitosan material to evaluate its in vivo therapeutic effect on HCC. High-throughput sequencing, RNA-sequencing, RNA probe pull-down, RNA immunoprecipitation and Co-Immunoprecipitation assays were performed to explore the relationship between circPAK1, 14–3-3ζ, p-LATS1 and YAP. Exosomes isolated from lenvatinib-resistant HCC cell lines were used to evaluate the relationship between exosomal circPAK1 and lenvatinib resistance.
Results
CircPAK1, a novel circRNA, is highly expressed in HCC tumor tissues and cell lines as well as correlated with poor outcomes in HCC patients. Functionally, circPAK1 knockdown inhibited HCC cell proliferation, migration, invasion and angiogenesis while circPAK1 overexpression promoted HCC progression. The tumor-promoting phenotypes of circPAK1 on HCC were also confirmed by animal experiments. Importantly, the application of CS/si-circPAK1 nanocomplexes showed a better therapeutic effect on tumor growth and metastasis. Mechanistically, circPAK1 enhanced HCC progression by inactivating the Hippo signaling pathway, and this kind of inactivation is based on its competitively binding of 14–3-3 ζ with YAP, which weakens the recruitment and cytoplasmic fixation of 14–3-3 ζ to YAP, thus promoting YAP nucleus localization. Additionally, circPAK1 could be transported by exosomes from lenvatinib-resistant cells to sensitive cells and induce lenvatinib resistance of receipt cells.
Conclusion
CircPAK1 exerts its oncogenic function by competitively binding 14–3-3 ζ with YAP, thus promoting YAP nucleus localization, leading to the inactivation of a Hippo signaling pathway. Exosomal circPAK1 may drive resistance to lenvatinib, providing a potential therapeutic target for HCC patients.
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Sun Q, Lin S, Zhang M, Gong Y, Ma H, Tran NT, Zhang Y, Li S. SpRab11a-Regulated Exosomes Inhibit Bacterial Infection through the Activation of Antilipopolysaccharide Factors in Crustaceans. THE JOURNAL OF IMMUNOLOGY 2022; 209:710-722. [DOI: 10.4049/jimmunol.2200094] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Accepted: 05/19/2022] [Indexed: 01/04/2023]
Abstract
Abstract
Exosomes, secreted by most cells, are critical antimicrobial immune factors in animals. Recent studies of certain key regulators of vesicular transport, the Rab GTPases, have linked Rab dysfunction to regulation of innate immune signaling. However, the relationship between exosomes and Rab GTPases, resulting in antimicrobial activity in vertebrates and invertebrates during pathogenic infection, has not been addressed. In this study, SpRab11a was reported to have a protective effect on the survival rate of mud crabs Scylla paramamosain after Vibrio parahaemolyticus challenge through the stimulation of exosome secretion and modulation of anti-LPS factor (ALF) expression. Furthermore, Sp14-3-3 was confirmed to be densely packaged in exosomes after V. parahaemolyticus infection, which could recruit the MyD88 and TLR by binding the Toll/IL-1R domain to the plasma membrane, promoting the translocation of Dorsal from the cytoplasm into the nucleus, and thereby regulating ALFs expression in the hemocytes of mud crab in response to the bacterial infection. The findings therefore provide, to our knowledge, a novel mechanism that underlies the cross-talk between SpRab11a-regulated exosome formation and ALFs expression in innate immune response in invertebrates, with a crustacean species, mud crab S. paramamosain, as a model study.
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Affiliation(s)
- Qian Sun
- *Southern Marine Science and Engineering Guangdong Laboratory (Guangzhou), Guangzhou, China
- †Guangdong Provincial Key Laboratory of Marine Biology, Shantou University, Shantou, China; and
- ‡Marine Biology Institute, Shantou University, Shantou, China
| | - Shanmeng Lin
- †Guangdong Provincial Key Laboratory of Marine Biology, Shantou University, Shantou, China; and
- ‡Marine Biology Institute, Shantou University, Shantou, China
| | - Ming Zhang
- †Guangdong Provincial Key Laboratory of Marine Biology, Shantou University, Shantou, China; and
- ‡Marine Biology Institute, Shantou University, Shantou, China
| | - Yi Gong
- *Southern Marine Science and Engineering Guangdong Laboratory (Guangzhou), Guangzhou, China
- †Guangdong Provincial Key Laboratory of Marine Biology, Shantou University, Shantou, China; and
- ‡Marine Biology Institute, Shantou University, Shantou, China
| | - Hongyu Ma
- *Southern Marine Science and Engineering Guangdong Laboratory (Guangzhou), Guangzhou, China
- †Guangdong Provincial Key Laboratory of Marine Biology, Shantou University, Shantou, China; and
- ‡Marine Biology Institute, Shantou University, Shantou, China
| | - Ngoc Tuan Tran
- *Southern Marine Science and Engineering Guangdong Laboratory (Guangzhou), Guangzhou, China
- †Guangdong Provincial Key Laboratory of Marine Biology, Shantou University, Shantou, China; and
- ‡Marine Biology Institute, Shantou University, Shantou, China
| | - Yueling Zhang
- *Southern Marine Science and Engineering Guangdong Laboratory (Guangzhou), Guangzhou, China
- †Guangdong Provincial Key Laboratory of Marine Biology, Shantou University, Shantou, China; and
- ‡Marine Biology Institute, Shantou University, Shantou, China
| | - Shengkang Li
- *Southern Marine Science and Engineering Guangdong Laboratory (Guangzhou), Guangzhou, China
- †Guangdong Provincial Key Laboratory of Marine Biology, Shantou University, Shantou, China; and
- ‡Marine Biology Institute, Shantou University, Shantou, China
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Flores AI, Pipino C, Jerman UD, Liarte S, Gindraux F, Kreft ME, Nicolas FJ, Pandolfi A, Tratnjek L, Giebel B, Pozzobon M, Silini AR, Parolini O, Eissner G, Lang-Olip I. Perinatal derivatives: How to best characterize their multimodal functions in vitro. Part C: Inflammation, angiogenesis, and wound healing. Front Bioeng Biotechnol 2022; 10:965006. [PMID: 35992360 PMCID: PMC9386263 DOI: 10.3389/fbioe.2022.965006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Accepted: 07/07/2022] [Indexed: 11/13/2022] Open
Abstract
Perinatal derivatives (PnD) are birth-associated tissues, such as placenta, umbilical cord, amniotic and chorionic membrane, and thereof-derived cells as well as secretomes. PnD play an increasing therapeutic role with beneficial effects on the treatment of various diseases. The aim of this review is to elucidate the modes of action of non-hematopoietic PnD on inflammation, angiogenesis and wound healing. We describe the source and type of PnD with a special focus on their effects on inflammation and immune response, on vascular function as well as on cutaneous and oral wound healing, which is a complex process that comprises hemostasis, inflammation, proliferation (including epithelialization, angiogenesis), and remodeling. We further evaluate the different in vitro assays currently used for assessing selected functional and therapeutic PnD properties. This review is a joint effort from the COST SPRINT Action (CA17116) with the intention to promote PnD into the clinics. It is part of a quadrinomial series on functional assays for validation of PnD, spanning biological functions, such as immunomodulation, anti-microbial/anti-cancer activities, anti-inflammation, wound healing, angiogenesis, and regeneration.
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Affiliation(s)
- Ana I. Flores
- Regenerative Medicine Group, Research Institute Hospital 12 de Octubre (imas12), Madrid, Spain
| | - Caterina Pipino
- Center for Advanced Studies and Technology (CAST), Department of Medical, Oral and Biotechnological Sciences, University G. d’Annunzio Chieti-Pescara, StemTech Group, Chieti, Italy
| | - Urška Dragin Jerman
- University of Ljubljana, Faculty of Medicine, Institute of Cell Biology, Ljubljana, Slovenia
| | - Sergio Liarte
- Laboratorio de Regeneración, Oncología Molecular y TGF-β, IMIB-Arrixaca, Murcia, Spain
| | - Florelle Gindraux
- Service de Chirurgie Maxillo-Faciale, Stomatologie et Odontologie Hospitalière, CHU Besançon, Besançon, France
- Laboratoire de Nanomédecine, Imagerie, Thérapeutique EA 466, Université Bourgogne Franche-Comté, Besançon, France
| | - Mateja Erdani Kreft
- University of Ljubljana, Faculty of Medicine, Institute of Cell Biology, Ljubljana, Slovenia
| | - Francisco J. Nicolas
- Laboratorio de Regeneración, Oncología Molecular y TGF-β, IMIB-Arrixaca, Murcia, Spain
| | - Assunta Pandolfi
- Center for Advanced Studies and Technology (CAST), Department of Medical, Oral and Biotechnological Sciences, University G. d’Annunzio Chieti-Pescara, StemTech Group, Chieti, Italy
| | - Larisa Tratnjek
- University of Ljubljana, Faculty of Medicine, Institute of Cell Biology, Ljubljana, Slovenia
| | - Bernd Giebel
- Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Michela Pozzobon
- Department of Women’s and Children’s Health, University of Padova, Padova, Italy and Foundation Institute of Pediatric Research Fondazione Città Della Speranza, Padova, Italy
| | | | - Ornella Parolini
- Department of Life Science and Public Health, Università Cattolica del Sacro Cuore, Rome, Italy
- Fondazione Policlinico Universitario “Agostino Gemelli” IRCCS, Rome, Italy
| | - Günther Eissner
- Systems Biology Ireland, School of Medicine, Conway Institute, University College Dublin, Dublin, Ireland
| | - Ingrid Lang-Olip
- Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center, Medical University of Graz, Graz, Austria
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Xu Q, Sigen A, Wang W. Injectable Hydrogels as a Stem Cell Delivery Platform for Wound Healing. MULTIFUNCTIONAL HYDROGELS FOR BIOMEDICAL APPLICATIONS 2022:323-355. [DOI: 10.1002/9783527825820.ch14] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Role of Yes-Associated Protein in Psoriasis and Skin Tumor Pathogenesis. J Pers Med 2022; 12:jpm12060978. [PMID: 35743763 PMCID: PMC9225571 DOI: 10.3390/jpm12060978] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 06/13/2022] [Accepted: 06/14/2022] [Indexed: 11/16/2022] Open
Abstract
Psoriasis and skin tumors (such as basal cell carcinoma, squamous cell carcinoma, and melanoma) are chronic diseases that endanger physical and mental health, and yet the causes are largely unknown and treatment options limited. The development of targeted drugs requires a better understanding of the exact pathogenesis of these diseases, and Yes-associated protein (YAP), a member of the Hippo signaling pathway, is believed to play an important role. Psoriasis and skin tumors are characterized by excessive cell proliferation, abnormal differentiation, vasodilation, and proliferation. Here, we review the literature related to YAP-associated disease mechanisms and discuss the latest research. YAP regulates cell apoptosis, proliferation, and differentiation; inhibits cell density and intercellular contacts and angiogenesis; and maintains the three-dimensional structure of the skin. These mechanisms may be associated with the occurrence and development of psoriasis and skin tumors. The results of recent studies have shown that YAP expression is increased in psoriasis and skin tumors. High expression of YAP in psoriasis and skin tumors may indicate its positive functions in skin inflammation and malignancies and may play an important role in disease pathogenesis. The study of new drugs targeting YAP can provide novel approaches for the treatment of skin diseases.
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Preconditioning and Engineering Strategies for Improving the Efficacy of Mesenchymal Stem Cell-Derived Exosomes in Cell-Free Therapy. Stem Cells Int 2022; 2022:1779346. [PMID: 35607400 PMCID: PMC9124131 DOI: 10.1155/2022/1779346] [Citation(s) in RCA: 52] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Revised: 04/07/2022] [Accepted: 04/23/2022] [Indexed: 12/13/2022] Open
Abstract
Mesenchymal stem cells (MSCs) have been widely applied to regenerative medicine owing to their multiple differentiation, self-renewal, and immunomodulatory abilities. Exosomes are cell-secreted natural nanovesicles and thought to be mediators of intercellular communication and material transport. The therapeutic potential of MSCs can be largely attributed to MSC-derived exosomes (MSC-exosomes). Emerging evidence suggests that the therapeutic efficacy of MSC-exosomes is highly dependent on the status of MSCs, and optimization of the extracellular environment affects the exosomal content. Pretreatment methods including three-dimensional cultures, hypoxia, and other biochemical cues have been shown to potentially enhance the biological activity of MSC-exosomes while maintaining or enhancing their production. On the other hand, engineering means to enhance the desired function of MSC-exosomes has been rapidly gaining attention. In particular, biologically active molecule encapsulation and membrane modification can alter or enhance biological functions and targeting of MSC-exosomes. In this review, we summarize two possible strategies to improve the therapeutic activity of MSC-exosomes: preconditioning approaches and engineering exosomes. We also explore the underlying mechanisms of different strategies and discuss their advantages and limitations of the upcoming clinical applications.
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Li J, Komatsu H, Poku EK, Olafsen T, Huang KX, Huang LA, Chea J, Bowles N, Chang B, Rawson J, Peng J, Wu AM, Shively JE, Kandeel FR. Biodistribution of Intra-Arterial and Intravenous Delivery of Human Umbilical Cord Mesenchymal Stem Cell-Derived Extracellular Vesicles in a Rat Model to Guide Delivery Strategies for Diabetes Therapies. Pharmaceuticals (Basel) 2022; 15:595. [PMID: 35631421 PMCID: PMC9143655 DOI: 10.3390/ph15050595] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Revised: 05/06/2022] [Accepted: 05/10/2022] [Indexed: 02/04/2023] Open
Abstract
Umbilical cord mesenchymal stem cell-derived extracellular vesicles (UC-MSC-EVs) have become an emerging strategy for treating various autoimmune and metabolic disorders, particularly diabetes. Delivery of UC-MSC-EVs is essential to ensure optimal efficacy of UC-MSC-EVs. To develop safe and superior EVs-based delivery strategies, we explored nuclear techniques including positron emission tomography (PET) to evaluate the delivery of UC-MSC-EVs in vivo. In this study, human UC-MSC-EVs were first successfully tagged with I-124 to permit PET determination. Intravenous (I.V.) and intra-arterial (I.A.) administration routes of [124I]I-UC-MSC-EVs were compared and evaluated by in vivo PET-CT imaging and ex vivo biodistribution in a non-diabetic Lewis (LEW) rat model. For I.A. administration, [124I]I-UC-MSC-EVs were directly infused into the pancreatic parenchyma via the celiac artery. PET imaging revealed that the predominant uptake occurred in the liver for both injection routes, and further imaging characterized clearance patterns of [124I]I-UC-MSC-EVs. For biodistribution, the uptake (%ID/gram) in the spleen was significantly higher for I.V. administration compared to I.A. administration (1.95 ± 0.03 and 0.43 ± 0.07, respectively). Importantly, the pancreas displayed similar uptake levels between the two modalities (0.20 ± 0.06 for I.V. and 0.24 ± 0.03 for I.A.). Therefore, our initial data revealed that both routes had similar delivery efficiency for [124I]I-UC-MSC-EVs except in the spleen and liver, considering that higher spleen uptake could enhance immunomodulatory application of UC-MSC-EVs. These findings could guide the development of safe and efficacious delivery strategies for UC-MSC-EVs in diabetes therapies, in which a minimally invasive I.V. approach would serve as a better delivery strategy. Further confirmation studies are ongoing.
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Affiliation(s)
- Junfeng Li
- Department of Translational Research & Cellular Therapeutics, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA; (H.K.); (K.X.H.); (L.A.H.); (J.R.); (J.P.)
| | - Hirotake Komatsu
- Department of Translational Research & Cellular Therapeutics, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA; (H.K.); (K.X.H.); (L.A.H.); (J.R.); (J.P.)
| | - Erasmus K. Poku
- Department of Radiopharmacy, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA; (E.K.P.); (J.C.); (N.B.)
| | - Tove Olafsen
- Department of Cancer Molecular Imaging and Therapy, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA; (T.O.); (B.C.); (A.M.W.); (J.E.S.)
| | - Kelly X. Huang
- Department of Translational Research & Cellular Therapeutics, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA; (H.K.); (K.X.H.); (L.A.H.); (J.R.); (J.P.)
| | - Lina A. Huang
- Department of Translational Research & Cellular Therapeutics, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA; (H.K.); (K.X.H.); (L.A.H.); (J.R.); (J.P.)
| | - Junie Chea
- Department of Radiopharmacy, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA; (E.K.P.); (J.C.); (N.B.)
| | - Nicole Bowles
- Department of Radiopharmacy, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA; (E.K.P.); (J.C.); (N.B.)
| | - Betty Chang
- Department of Cancer Molecular Imaging and Therapy, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA; (T.O.); (B.C.); (A.M.W.); (J.E.S.)
| | - Jeffrey Rawson
- Department of Translational Research & Cellular Therapeutics, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA; (H.K.); (K.X.H.); (L.A.H.); (J.R.); (J.P.)
| | - Jiangling Peng
- Department of Translational Research & Cellular Therapeutics, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA; (H.K.); (K.X.H.); (L.A.H.); (J.R.); (J.P.)
| | - Anna M. Wu
- Department of Cancer Molecular Imaging and Therapy, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA; (T.O.); (B.C.); (A.M.W.); (J.E.S.)
| | - John E. Shively
- Department of Cancer Molecular Imaging and Therapy, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA; (T.O.); (B.C.); (A.M.W.); (J.E.S.)
| | - Fouad R. Kandeel
- Department of Translational Research & Cellular Therapeutics, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA; (H.K.); (K.X.H.); (L.A.H.); (J.R.); (J.P.)
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Zeng X, Yi X, Chen L, Zhang H, Zhou R, Wu J, Chen Y, Huang W, Zhang L, Zheng J, Xiao Y, Yang F. Characterization and bioassays of extracellular vesicles extracted by tangential flow filtration. Regen Med 2022; 17:141-154. [PMID: 35073731 DOI: 10.2217/rme-2021-0038] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Aim: To evaluate the efficiency of tangential flow filtration (TFF) in improving the yield of human umbilical cord mesenchymal stem cell (MSC)-derived extracellular vesicles (hucMSC-EVs) while promoting cell regeneration under oxidative stress. Methods: HucMSC-EVs were extracted from supernatants by ultracentrifugation (UC-EVs) and TFF (TFF-EVs), followed by feature characterization and bioactivity assays. Results: The yield of TFF-EVs increased 18-times compared with that of UC-EVs. TFF-EVs displayed proliferation-promoting ability similar to that of UC-EVs in the damaged HaCaT cell model with ultraviolet radiation B (UVB) and H2O2. Furthermore, the antiapoptotic effects of TFF-EVs were improved, whereby the apoptosis rate exhibited a 3.7-fold decrease. Conclusion: HucMSC-EVs extracted by TFF show a higher yield and rejuvenate the damaged HaCaT cells induced by oxidative stress.
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Affiliation(s)
- Xiaoli Zeng
- Translational Medicine Research Laboratory, PLA Air Force Hospital of Southern Theatre Command, Guangzhou, 510602, China.,Guangzhou Dude Biotechnology Co., Ltd., Guangzhou, 510320, China
| | - Xuerui Yi
- Central Research Laboratory, PLA Air Force Hospital of Southern Theatre Command, Guangzhou, 510602, China
| | - Lixuan Chen
- Guangzhou Dude Biotechnology Co., Ltd., Guangzhou, 510320, China
| | - Haisong Zhang
- Central Research Laboratory, PLA Air Force Hospital of Southern Theatre Command, Guangzhou, 510602, China
| | - Rongcheng Zhou
- Guangzhou Dude Biotechnology Co., Ltd., Guangzhou, 510320, China
| | - Jiwei Wu
- Guangzhou Dude Biotechnology Co., Ltd., Guangzhou, 510320, China
| | - Yuguang Chen
- Guangzhou Dude Biotechnology Co., Ltd., Guangzhou, 510320, China
| | - Wanyi Huang
- Guangzhou Dude Biotechnology Co., Ltd., Guangzhou, 510320, China
| | - Linyan Zhang
- Guangzhou Dude Biotechnology Co., Ltd., Guangzhou, 510320, China
| | - Jie Zheng
- Guangzhou Dude Biotechnology Co., Ltd., Guangzhou, 510320, China
| | - Yang Xiao
- Guangzhou Dude Biotechnology Co., Ltd., Guangzhou, 510320, China.,Stem Cell Translational Medicine Center, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510260, China
| | - Fuqiang Yang
- Translational Medicine Research Laboratory, PLA Air Force Hospital of Southern Theatre Command, Guangzhou, 510602, China
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Zhao B, Tang M, Lv Y. Shear stress regulates the migration of suspended breast cancer cells by nuclear lamina protein A/C and large tumor suppressor through yes-associated protein. Hum Cell 2022; 35:583-598. [PMID: 34984662 DOI: 10.1007/s13577-021-00666-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Accepted: 12/22/2021] [Indexed: 12/30/2022]
Abstract
Breast cancer is life threatening among women because its migration by hematogenous metastasis, where, besides biochemical cues, breast circulating tumor cells (CTCs) expose to suspension state and shear stress. However, the combined effects of these mechanical factors on CTCs migration were unclear. Here, suspension state and shear stress were loaded to breast tumor cells (BTCs) to mimic two mechanical cues in the mechanical environment of breast CTCs and the mechanobiological mechanism of suspension state and shear stress regulating the migration of (BTCs) was investigated. The migration and nuclear lamina protein A/C (Lamin A/C) accumulation were enhanced in MDA-MB-231 and SK-BR-3 BTCs exposed to shear stress though lower than that of suspended cells with different yes-associated protein (YAP) subcellular localization. Knockdown of LMNA downregulated and upregulated YAP targets in suspended BTCs and BTCs exposed to shear stress, respectively, which inhibited MDA-MB-231 BTCs migration in vitro and in vivo. Large tumor suppressor (LATS) responded to suspension state and shear stress, knockdown of which decreased the migration of MDA-MB-231 BTCs. These findings uncover the mechanobiological mechanism that suspension state and shear stress antagonistically promote BTCs migration by Lamin A/C and LATS through YAP and the potential for targeting YAP in CTCs prognosis. Shear stress regulates suspended breast cancer cells migration by Lamin A/C and LATS through YAP.
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Affiliation(s)
- Boyuan Zhao
- Mechanobiology and Regenerative Medicine Laboratory, Bioengineering College, Chongqing University, Chongqing, 400044, People's Republic of China
| | - Mei Tang
- Mechanobiology and Regenerative Medicine Laboratory, Bioengineering College, Chongqing University, Chongqing, 400044, People's Republic of China
| | - Yonggang Lv
- State Key Laboratory of New Textile Materials and Advanced Processing Technologies, Wuhan Textile University, Jiangxia District, No. 1 Sunshine Avenue, Wuhan, 430200, Hubei Province, People's Republic of China.
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44
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Mao GC, Gong CC, Wang Z, Sun MX, Pei ZP, Meng WQ, Cen JF, He XW, Lu Y, Xu QQ, Xiao K. BMSC-derived exosomes ameliorate sulfur mustard-induced acute lung injury by regulating the GPRC5A-YAP axis. Acta Pharmacol Sin 2021; 42:2082-2093. [PMID: 33654219 PMCID: PMC8633287 DOI: 10.1038/s41401-021-00625-4] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2020] [Accepted: 02/09/2021] [Indexed: 12/12/2022]
Abstract
Sulfur mustard (SM) is a highly toxic chemical warfare agent that causes acute lung injury (ALI) and/or acute respiratory distress syndrome (ARDS). There are no effective therapeutic treatments or antidotes available currently to counteract its toxic effects. Our previous study shows that bone marrow-derived mesenchymal stromal cells (BMSCs) could exert therapeutic effects against SM-induced lung injury. In this study, we explored the therapeutic potential of BMSC-derived exosomes (BMSC-Exs) against ALI and the underlying mechanisms. ALI was induced in mice by injection of SM (30 mg/kg, sc) at their medial and dorsal surfaces. BMSC-Exs (20 μg/kg in 200 μL PBS, iv) were injected for a 5-day period after SM exposure. We showed that BMSC-Exs administration caused a protective effect against pulmonary edema. Using a lung epithelial cell barrier model, BMSC-Exs (10, 20, 40 μg) dose-dependently inhibited SM-induced cell apoptosis and promoted the recovery of epithelial barrier function by facilitating the expression and relocalization of junction proteins (E-cadherin, claudin-1, occludin, and ZO-1). We further demonstrated that BMSC-Exs protected against apoptosis and promoted the restoration of barrier function against SM through upregulating G protein-coupled receptor family C group 5 type A (GPRC5A), a retinoic acid target gene predominately expressed in the epithelial cells of the lung. Knockdown of GPRC5A reduced the antiapoptotic and barrier regeneration abilities of BMSC-Exs and diminished their therapeutic effects in vitro and in vivo. BMSC-Exs-caused upregulation of GPRC5A promoted the expression of Bcl-2 and junction proteins via regulating the YAP pathway. In summary, BMSC-Exs treatment exerts protective effects against SM-induced ALI by promoting alveolar epithelial barrier repair and may be an alternative approach to stem cell-based therapy.
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Affiliation(s)
- Guan-Chao Mao
- Lab of Toxicology and Pharmacology, Faculty of Naval Medicine, Naval Medical University, Shanghai, 200433, China
| | - Chu-Chu Gong
- Lab of Toxicology and Pharmacology, Faculty of Naval Medicine, Naval Medical University, Shanghai, 200433, China
| | - Zhen Wang
- Lab of Toxicology and Pharmacology, Faculty of Naval Medicine, Naval Medical University, Shanghai, 200433, China
- Department of Preventive Medicinne, School of Medicine, Hunan Normal University, Changsha, China
| | - Ming-Xue Sun
- Lab of Toxicology and Pharmacology, Faculty of Naval Medicine, Naval Medical University, Shanghai, 200433, China
| | - Zhi-Peng Pei
- Lab of Toxicology and Pharmacology, Faculty of Naval Medicine, Naval Medical University, Shanghai, 200433, China
| | - Wen-Qi Meng
- Lab of Toxicology and Pharmacology, Faculty of Naval Medicine, Naval Medical University, Shanghai, 200433, China
| | - Jin-Feng Cen
- Lab of Toxicology and Pharmacology, Faculty of Naval Medicine, Naval Medical University, Shanghai, 200433, China
| | - Xiao-Wen He
- Origincell Technology Group Co., Ltd., Shanghai, 201203, China
| | - Ying Lu
- Department of Pharmaceutical Science, School of Pharmacy, Naval Medical University, Shanghai, 200433, China.
| | - Qing-Qiang Xu
- Lab of Toxicology and Pharmacology, Faculty of Naval Medicine, Naval Medical University, Shanghai, 200433, China.
| | - Kai Xiao
- Lab of Toxicology and Pharmacology, Faculty of Naval Medicine, Naval Medical University, Shanghai, 200433, China.
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45
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Bie Q, Zhai R, Chen Y, Li Y, Xie N, Wang B, Yuan P, Zhou X, Cong H, Chang X, Xiong H, Zhang B. Sox9 Is Crucial for Mesenchymal Stem Cells to Enhance Cutaneous Wound Healing. Int J Stem Cells 2021; 14:465-474. [PMID: 34456192 PMCID: PMC8611311 DOI: 10.15283/ijsc21078] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 06/09/2021] [Accepted: 07/08/2021] [Indexed: 11/09/2022] Open
Abstract
BACKGROUND AND OBJECTIVES Human umbilical cord mesenchymal stem cells (HUC-MSCs) are promising candidates for cell-based therapy in regenerative medicine or other diseases due to their superior characteristics, including higher proliferation, faster self-renewal ability, lower immunogenicity, a noninvasive harvest procedure, easy expansion in vitro, and ethical access, compared with stem cells from other sources. METHODS AND RESULTS In the present study, we knocked down the expression of SOX9 in HUC-MSCs by lentivirus interference and found that knockdown of SOX9 inhibited the proliferation and migration of HUC-MSCs and influenced the expression of cytokines (IL-6 and IL-8), growth factors (GM-CSF and VEGF) and stemness-related genes (OCT4 and SALL4). In addition, the repair effect of skin with burn injury in rats treated with HUC-MSCs transfected with sh-control was better than that rats treated with HUC-MSCs transfected with shSOX9 or PBS, and the accessory structures of the skin, including hair follicles and glands, were greater than those in the other groups. We found that knockdown of the expression of SOX9 obviously inhibited the expression of Ki67, CK14 and CK18. CONCLUSIONS In conclusion, this study will provide a guide for modifying HUC-MSCs by bioengineering technology in the future.
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Affiliation(s)
- Qingli Bie
- Department of Laboratory Medicine, Affiliated Hospital of
Jining Medical University, Jining Medical University, Jining,
China
- Institute of Forensic Medicine and Laboratory Medicine,
Jining Medical University, Jining, China
| | - Ruixia Zhai
- Department of Obstetric, Affiliated Hospital of Jining
Medical University, Jining Medical University, Jining,
China
| | - Yanrong Chen
- Department of Laboratory Medicine, Affiliated Hospital of
Jining Medical University, Jining Medical University, Jining,
China
| | - Yingao Li
- Department of Laboratory Medicine, Affiliated Hospital of
Jining Medical University, Jining Medical University, Jining,
China
| | - Na Xie
- Department of Laboratory Medicine, Affiliated Hospital of
Jining Medical University, Jining Medical University, Jining,
China
| | - Baoyi Wang
- Institute of Forensic Medicine and Laboratory Medicine,
Jining Medical University, Jining, China
| | - Poyun Yuan
- Institute of Forensic Medicine and Laboratory Medicine,
Jining Medical University, Jining, China
| | - Xinjie Zhou
- Institute of Forensic Medicine and Laboratory Medicine,
Jining Medical University, Jining, China
| | - Haiyan Cong
- Department of Central Lab, Weihai Municipal Hospital,
Cheeloo College of Medicine, Weihai, China
| | - Xin Chang
- Department of Central Lab, Weihai Municipal Hospital,
Cheeloo College of Medicine, Weihai, China
| | - Huabao Xiong
- Institute of Immunology and Molecular Medicine, Jining
Medical University, Jining, China
| | - Bin Zhang
- Department of Laboratory Medicine, Affiliated Hospital of
Jining Medical University, Jining Medical University, Jining,
China
- Institute of Forensic Medicine and Laboratory Medicine,
Jining Medical University, Jining, China
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Shi H, Wang M, Sun Y, Yang D, Xu W, Qian H. Exosomes: Emerging Cell-Free Based Therapeutics in Dermatologic Diseases. Front Cell Dev Biol 2021; 9:736022. [PMID: 34722517 PMCID: PMC8553038 DOI: 10.3389/fcell.2021.736022] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Accepted: 08/20/2021] [Indexed: 12/17/2022] Open
Abstract
Exosomes are lipid bilayer vesicles released by multiple cell types. These bioactive vesicles are gradually becoming a leading star in intercellular communication involving in various pathological and physiological process. Exosomes convey specific and bioactive transporting cargos, including lipids, nucleic acids and proteins which can be reflective of their parent cells, rendering them attractive in cell-free therapeutics. Numerous findings have confirmed the crucial role of exosomes in restraining scars, burning, senescence and wound recovery. Moreover, the biology research of exosomes in cutting-edge studies are emerging, allowing for the development of particular guidelines and quality control methodology, which favor their possible application in the future. In this review, we discussed therapeutic potential of exosomes in different relevant mode of dermatologic diseases, as well as the various molecular mechanisms. Furthermore, given the advantages of favorable biocompatibility and transporting capacity, the bioengineering modification of exosomes is also involved.
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Affiliation(s)
- Hui Shi
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Institute of Stem Cell, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Min Wang
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Institute of Stem Cell, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Yaoxiang Sun
- Department of Clinical Laboratory, The Affiliated Yixing Hospital of Jiangsu University, Yixing, China
| | - Dakai Yang
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Institute of Stem Cell, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Wenrong Xu
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Institute of Stem Cell, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Hui Qian
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Institute of Stem Cell, School of Medicine, Jiangsu University, Zhenjiang, China
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Amadeo F, Trivino Cepeda K, Littlewood J, Wilm B, Taylor A, Murray P. Mesenchymal stromal cells: what have we learned so far about their therapeutic potential and mechanisms of action? Emerg Top Life Sci 2021; 5:549-562. [PMID: 34495324 PMCID: PMC8589440 DOI: 10.1042/etls20210013] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 08/11/2021] [Accepted: 08/27/2021] [Indexed: 01/10/2023]
Abstract
Mesenchymal stromal cells (MSCs) have been found to be safe and effective in a wide range of animal models of human disease. MSCs have been tested in thousands of clinical trials, but results show that while these cells appear to be safe, they tend to lack efficacy. This has raised questions about whether animal models are useful for predicting efficacy in patients. However, a problem with animal studies is that there is a lack of standardisation in the models and MSC therapy regimes used; there appears to be publication bias towards studies reporting positive outcomes; and the reproducibility of results from animal experiments tends not to be confirmed prior to clinical translation. A further problem is that while some progress has been made towards investigating the mechanisms of action (MoA) of MSCs, we still fail to understand how they work. To make progress, it is important to ensure that prior to clinical translation, the beneficial effects of MSCs in animal studies are real and can be repeated by independent research groups. We also need to understand the MoA of MSCs to assess whether their effects are likely to be beneficial across different species. In this review, we give an overview of the current clinical picture of MSC therapies and discuss what we have learned from animal studies. We also give a comprehensive update of what we know about the MoA of MSCs, particularly in relation to their role in immunomodulation.
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Affiliation(s)
- Francesco Amadeo
- Department of Molecular Physiology and Cell Signalling, Integrative Biology, University of Liverpool, Crown Street, L69 3GE Liverpool, U.K
- Centre for Pre-clinical Imaging, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Crown Street, L69 3GE Liverpool, U.K
| | - Katherine Trivino Cepeda
- Department of Molecular Physiology and Cell Signalling, Integrative Biology, University of Liverpool, Crown Street, L69 3GE Liverpool, U.K
- Centre for Pre-clinical Imaging, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Crown Street, L69 3GE Liverpool, U.K
| | - James Littlewood
- Department of Molecular Physiology and Cell Signalling, Integrative Biology, University of Liverpool, Crown Street, L69 3GE Liverpool, U.K
- Centre for Pre-clinical Imaging, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Crown Street, L69 3GE Liverpool, U.K
| | - Bettina Wilm
- Department of Molecular Physiology and Cell Signalling, Integrative Biology, University of Liverpool, Crown Street, L69 3GE Liverpool, U.K
- Centre for Pre-clinical Imaging, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Crown Street, L69 3GE Liverpool, U.K
| | - Arthur Taylor
- Department of Molecular Physiology and Cell Signalling, Integrative Biology, University of Liverpool, Crown Street, L69 3GE Liverpool, U.K
- Centre for Pre-clinical Imaging, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Crown Street, L69 3GE Liverpool, U.K
| | - Patricia Murray
- Department of Molecular Physiology and Cell Signalling, Integrative Biology, University of Liverpool, Crown Street, L69 3GE Liverpool, U.K
- Centre for Pre-clinical Imaging, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Crown Street, L69 3GE Liverpool, U.K
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Pichlsberger M, Jerman UD, Obradović H, Tratnjek L, Macedo AS, Mendes F, Fonte P, Hoegler A, Sundl M, Fuchs J, Schoeberlein A, Kreft ME, Mojsilović S, Lang-Olip I. Systematic Review of the Application of Perinatal Derivatives in Animal Models on Cutaneous Wound Healing. Front Bioeng Biotechnol 2021; 9:742858. [PMID: 34631683 PMCID: PMC8498585 DOI: 10.3389/fbioe.2021.742858] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Accepted: 09/06/2021] [Indexed: 12/21/2022] Open
Abstract
Knowledge of the beneficial effects of perinatal derivatives (PnD) in wound healing goes back to the early 1900s when the human fetal amniotic membrane served as a biological dressing to treat burns and skin ulcerations. Since the twenty-first century, isolated cells from perinatal tissues and their secretomes have gained increasing scientific interest, as they can be obtained non-invasively, have anti-inflammatory, anti-cancer, and anti-fibrotic characteristics, and are immunologically tolerated in vivo. Many studies that apply PnD in pre-clinical cutaneous wound healing models show large variations in the choice of the animal species (e.g., large animals, rodents), the choice of diabetic or non-diabetic animals, the type of injury (full-thickness wounds, burns, radiation-induced wounds, skin flaps), the source and type of PnD (placenta, umbilical cord, fetal membranes, cells, secretomes, tissue extracts), the method of administration (topical application, intradermal/subcutaneous injection, intravenous or intraperitoneal injection, subcutaneous implantation), and the type of delivery systems (e.g., hydrogels, synthetic or natural biomaterials as carriers for transplanted cells, extracts or secretomes). This review provides a comprehensive and integrative overview of the application of PnD in wound healing to assess its efficacy in preclinical animal models. We highlight the advantages and limitations of the most commonly used animal models and evaluate the impact of the type of PnD, the route of administration, and the dose of cells/secretome application in correlation with the wound healing outcome. This review is a collaborative effort from the COST SPRINT Action (CA17116), which broadly aims at approaching consensus for different aspects of PnD research, such as providing inputs for future standards for the preclinical application of PnD in wound healing.
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Affiliation(s)
- Melanie Pichlsberger
- Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center, Medical University of Graz, Graz, Austria
| | - Urška Dragin Jerman
- Institute of Cell Biology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Hristina Obradović
- Group for Hematology and Stem Cells, Institute for Medical Research, University of Belgrade, Belgrade, Serbia
| | - Larisa Tratnjek
- Institute of Cell Biology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Ana Sofia Macedo
- LAQV, REQUIMTE, Department of Chemical Sciences-Applied Chemistry Lab, Faculty of Pharmacy, University of Porto, Porto, Portugal
| | - Francisca Mendes
- iBB-Institute for Bioengineering and Biosciences, Department of Bioengineering, Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal.,Associate Laboratory i4HB-Institute for Health and Bioeconomy at Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal
| | - Pedro Fonte
- iBB-Institute for Bioengineering and Biosciences, Department of Bioengineering, Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal.,Associate Laboratory i4HB-Institute for Health and Bioeconomy at Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal.,Center for Marine Sciences (CCMar), Faculty of Sciences and Technology, University of Algarve, Faro, Portugal.,Department of Chemistry and Pharmacy, Faculty of Sciences and Technology, University of Algarve, Faro, Portugal
| | - Anja Hoegler
- Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center, Medical University of Graz, Graz, Austria
| | - Monika Sundl
- Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center, Medical University of Graz, Graz, Austria
| | - Julia Fuchs
- Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center, Medical University of Graz, Graz, Austria
| | - Andreina Schoeberlein
- Department of Obstetrics and Feto-maternal Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.,Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
| | - Mateja Erdani Kreft
- Institute of Cell Biology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Slavko Mojsilović
- Group for Hematology and Stem Cells, Institute for Medical Research, University of Belgrade, Belgrade, Serbia
| | - Ingrid Lang-Olip
- Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center, Medical University of Graz, Graz, Austria
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Guo Y, Wu D, Zhang X, Zhang K, Luo Y. Biomolecules in cell-derived extracellular vesicle chariots as warriors to repair damaged tissues. NANOSCALE 2021; 13:16017-16033. [PMID: 34570853 DOI: 10.1039/d1nr04999b] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
In this review, we highlight the innovative applications of biomolecules from parent cell-derived extracellular vesicles (EVs) for tissue repair that have been developed in recent years. We evaluate the underlying mechanisms and therapeutic efficacy of each therapy. In previous literature reviews, it was most common to classify the use of EVs in tissue repair by disease type. This article reviews the role of three biomolecules in EVs in tissue repair. This review first summarizes the definitions and classifications of EVs. Then, the importance and significance of treating tissue damage with EVs are discussed. In particular, EV contents for tissue repair are three main types of biomolecules: proteins, RNAs and cell growth factors. The therapeutic and repair mechanisms of the biomolecules are discussed respectively. Finally, the development prospect and potential challenges of EV contents from highly differentiated cells as specific agents for tissue repair are summarized. When EVs are used to treat diseases such as tissue or organ damage, EVs play a role in delivery, and the real repair effect is effected by the various biomolecules carried by EVs. We believe that EV biomolecules have unparalleled advantages and clinical transformation potential for tissue repair and expect this review to inspire more intensive research work in this field.
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Affiliation(s)
- Yingshu Guo
- Shandong Provincial Key Laboratory of Molecular Engineering, School of Chemistry and Chemical Engineering, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250353, China.
| | - Di Wu
- School of Chemistry and Chemical Engineering, Linyi University, Linyi 276005, China
| | - Xu Zhang
- Shandong Provincial Key Laboratory of Molecular Engineering, School of Chemistry and Chemical Engineering, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250353, China.
| | - Kaixiang Zhang
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China.
| | - Yang Luo
- Center of Smart Laboratory and Molecular Medicine, School of Medicine, Chongqing University, Chongqing 400044, P.R. China.
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50
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Stem Cell-Derived Nanovesicles: A Novel Cell-Free Therapy for Wound Healing. Stem Cells Int 2021; 2021:1285087. [PMID: 34567129 PMCID: PMC8457964 DOI: 10.1155/2021/1285087] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Accepted: 08/10/2021] [Indexed: 12/15/2022] Open
Abstract
Wound healing and regeneration are a dynamic and complex process that requires a collaborative effort between growth factors, epidermal cells, dermal cells, extracellular matrix, and vessels local to the wound area. Mesenchymal stem cells participate in the recruitment site, mainly by releasing secretory factors and matrix proteins to promote wound healing. Stem cell-derived nanovesicles (CDNs), including microvesicles, exosomes, and exosome mimetics, contain most of the biologically active substances of their parent cells and have similar effects. CDNs can shuttle various proteins, messenger RNAs, and microRNAs to regulate the activity of receptor cells, and they play important roles in skin wound healing. This article reviews recent research progress on CDNs for wound repair. We summarize current knowledge on how CDNs regulate immunity, fibroblast activity, angiogenesis, and scar formation in the wound healing process. This review can help researchers explore new treatment strategies to enhance the therapeutic efficacy of CDNs, which have a promising future as naturally cell-free therapies.
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