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Large extracellular vesicles secreted by human iPSC-derived MSCs ameliorate tendinopathy via regulating macrophage heterogeneity

Tendinopathy is a common musculoskeletal disorder which results in chronic pain and reduced performance. The therapeutic effect of stem cell derived-small extracellular vesicles (sEVs) for tendinopathy has been validated in recent years. However, whether large extracellular vesicles (lEVs), another...

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Autores principales: Ye, Teng, Chen, Zhengsheng, Zhang, Jieyuan, Luo, Lei, Gao, Renzhi, Gong, Liangzhi, Du, Yuhang, Xie, Zongping, Zhao, Bizeng, Li, Qing, Wang, Yang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: KeAi Publishing 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9440485/
https://www.ncbi.nlm.nih.gov/pubmed/36101856
http://dx.doi.org/10.1016/j.bioactmat.2022.08.007
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author Ye, Teng
Chen, Zhengsheng
Zhang, Jieyuan
Luo, Lei
Gao, Renzhi
Gong, Liangzhi
Du, Yuhang
Xie, Zongping
Zhao, Bizeng
Li, Qing
Wang, Yang
author_facet Ye, Teng
Chen, Zhengsheng
Zhang, Jieyuan
Luo, Lei
Gao, Renzhi
Gong, Liangzhi
Du, Yuhang
Xie, Zongping
Zhao, Bizeng
Li, Qing
Wang, Yang
author_sort Ye, Teng
collection PubMed
description Tendinopathy is a common musculoskeletal disorder which results in chronic pain and reduced performance. The therapeutic effect of stem cell derived-small extracellular vesicles (sEVs) for tendinopathy has been validated in recent years. However, whether large extracellular vesicles (lEVs), another subset of extracellular vesicles, possesses the ability for the improvement of tendinopathy remains unknown. Here, we showed that lEVs secreted from iPSC-derived MSCs (iMSC-lEVs) significantly mitigated pain derived from tendinopathy in rats. Immunohistochemical analysis showed that iMSC-lEVs regulated the heterogeneity of infiltrated macrophages and several inflammatory cytokines in rat tendon tissue. Meanwhile, in vitro experiments revealed that the M1 pro-inflammatory macrophages were repolarized towards M2 anti-inflammatory macrophages by iMSC-lEVs, and this effect was mediated by regulating p38 MAPK pathway. Moreover, liquid chromatography-tandem mass spectrometry analysis identified 2208 proteins encapsulated in iMSC-lEVs, including 134 new-found proteins beyond current Vesiclepedia database. By bioinformatics and Western blot analyses, we showed that DUSP2 and DUSP3, the negative regulator of p38 phosphorylation, were enriched in iMSC-lEVs and could be transported to macrophages. Further, the immunomodulatory effect of iMSC-lEVs on macrophages was validated in explant tendon tissue from tendinopathy patients. Taken together, our results demonstrate that iMSC-lEVs could reduce inflammation in tendinopathy by regulating macrophage heterogeneity, which is mediated via the p38 MAPK pathway by delivery of DUSP2 and DUSP3, and might be a promising candidate for tendinopathy therapy.
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spelling pubmed-94404852022-09-12 Large extracellular vesicles secreted by human iPSC-derived MSCs ameliorate tendinopathy via regulating macrophage heterogeneity Ye, Teng Chen, Zhengsheng Zhang, Jieyuan Luo, Lei Gao, Renzhi Gong, Liangzhi Du, Yuhang Xie, Zongping Zhao, Bizeng Li, Qing Wang, Yang Bioact Mater Article Tendinopathy is a common musculoskeletal disorder which results in chronic pain and reduced performance. The therapeutic effect of stem cell derived-small extracellular vesicles (sEVs) for tendinopathy has been validated in recent years. However, whether large extracellular vesicles (lEVs), another subset of extracellular vesicles, possesses the ability for the improvement of tendinopathy remains unknown. Here, we showed that lEVs secreted from iPSC-derived MSCs (iMSC-lEVs) significantly mitigated pain derived from tendinopathy in rats. Immunohistochemical analysis showed that iMSC-lEVs regulated the heterogeneity of infiltrated macrophages and several inflammatory cytokines in rat tendon tissue. Meanwhile, in vitro experiments revealed that the M1 pro-inflammatory macrophages were repolarized towards M2 anti-inflammatory macrophages by iMSC-lEVs, and this effect was mediated by regulating p38 MAPK pathway. Moreover, liquid chromatography-tandem mass spectrometry analysis identified 2208 proteins encapsulated in iMSC-lEVs, including 134 new-found proteins beyond current Vesiclepedia database. By bioinformatics and Western blot analyses, we showed that DUSP2 and DUSP3, the negative regulator of p38 phosphorylation, were enriched in iMSC-lEVs and could be transported to macrophages. Further, the immunomodulatory effect of iMSC-lEVs on macrophages was validated in explant tendon tissue from tendinopathy patients. Taken together, our results demonstrate that iMSC-lEVs could reduce inflammation in tendinopathy by regulating macrophage heterogeneity, which is mediated via the p38 MAPK pathway by delivery of DUSP2 and DUSP3, and might be a promising candidate for tendinopathy therapy. KeAi Publishing 2022-08-26 /pmc/articles/PMC9440485/ /pubmed/36101856 http://dx.doi.org/10.1016/j.bioactmat.2022.08.007 Text en © 2022 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Ye, Teng
Chen, Zhengsheng
Zhang, Jieyuan
Luo, Lei
Gao, Renzhi
Gong, Liangzhi
Du, Yuhang
Xie, Zongping
Zhao, Bizeng
Li, Qing
Wang, Yang
Large extracellular vesicles secreted by human iPSC-derived MSCs ameliorate tendinopathy via regulating macrophage heterogeneity
title Large extracellular vesicles secreted by human iPSC-derived MSCs ameliorate tendinopathy via regulating macrophage heterogeneity
title_full Large extracellular vesicles secreted by human iPSC-derived MSCs ameliorate tendinopathy via regulating macrophage heterogeneity
title_fullStr Large extracellular vesicles secreted by human iPSC-derived MSCs ameliorate tendinopathy via regulating macrophage heterogeneity
title_full_unstemmed Large extracellular vesicles secreted by human iPSC-derived MSCs ameliorate tendinopathy via regulating macrophage heterogeneity
title_short Large extracellular vesicles secreted by human iPSC-derived MSCs ameliorate tendinopathy via regulating macrophage heterogeneity
title_sort large extracellular vesicles secreted by human ipsc-derived mscs ameliorate tendinopathy via regulating macrophage heterogeneity
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9440485/
https://www.ncbi.nlm.nih.gov/pubmed/36101856
http://dx.doi.org/10.1016/j.bioactmat.2022.08.007
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