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携带长链非编码RNA H19“过载”的小细胞外囊泡：作为肌腱修复治疗策略的Yes相关蛋白（YAP）调控

Small extracellular vesicles with LncRNA H19 "overload": YAP Regulation as a Tendon Repair Therapeutic Tactic.

作者信息

Tao Shi-Cong, Huang Ji-Yan, Li Zi-Xiang, Zhan Shi, Guo Shang-Chun

机构信息

Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai 200233, China.

Department of Stomatology, Shanghai Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 185 Pu'an Road, Shanghai 200021, China.

出版信息

iScience. 2021 Feb 17;24(3):102200. doi: 10.1016/j.isci.2021.102200. eCollection 2021 Mar 19.

DOI:10.1016/j.isci.2021.102200
PMID:33733065
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7937563/
Abstract

Functional healing of tendon injuries remains a great challenge. Small extracellular vesicles (sEVs) have received attention as pro-regenerative agents. H19 overexpression could bring tendon regenerative ability, but the mechanism is still not fully elucidated, and reliable method for delivery of long non-coding RNAs (LncRNAs) was demanded. We identified the downstream mechanism of H19, the activation of yes-associated protein (YAP) via the H19-PP1-YAP axis. We established tendon stem/progenitor cells (TSPCs) stably overexpressing H19 with CRISPR-dCas9-based hnRNP A2/B1 activation (H19-CP-TSPCs). H19-OL-sEVs (H19 "overloading" sEVs) could be produced effectively from H19-CP-TSPCs. Only H19-OL-sEVs were able to significantly load large amounts of H19 rather than other competitors, and the potential of H19-OL-sEVs to promote tendon healing was far better than that of other competitors. Our study established a relatively reliable method for enrichment of LncRNAs into sEVs, providing new hints for modularized sEV-based therapies, and modularized sEVs represented a potential strategy for tendon regeneration.

摘要

肌腱损伤的功能性愈合仍然是一个巨大的挑战。小细胞外囊泡（sEVs）作为促再生剂受到了关注。H19过表达可赋予肌腱再生能力，但其机制仍未完全阐明，因此需要一种可靠的长链非编码RNA（LncRNAs）递送方法。我们确定了H19的下游机制，即通过H19-PP1-YAP轴激活Yes相关蛋白（YAP）。我们利用基于CRISPR-dCas9的hnRNP A2/B1激活技术建立了稳定过表达H19的肌腱干/祖细胞（TSPCs）（H19-CP-TSPCs）。H19-OL-sEVs（H19“过载”sEVs）可从H19-CP-TSPCs中有效产生。只有H19-OL-sEVs能够显著负载大量H19而非其他竞争物，且H19-OL-sEVs促进肌腱愈合的潜力远优于其他竞争物。我们的研究建立了一种相对可靠的将LncRNAs富集到sEVs中的方法，为基于模块化sEVs的治疗提供了新线索，且模块化sEVs代表了一种肌腱再生的潜在策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f4c/7937563/21ac15358939/gr9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f4c/7937563/c502121564a9/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f4c/7937563/0eb61c4c2a29/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f4c/7937563/f1fdf0a31345/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f4c/7937563/4146cff069ff/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f4c/7937563/d06d3fc56410/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f4c/7937563/3f4fb4bba76f/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f4c/7937563/0de554737285/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f4c/7937563/031ce271db80/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f4c/7937563/816b866ba1b9/gr8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f4c/7937563/21ac15358939/gr9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f4c/7937563/c502121564a9/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f4c/7937563/0eb61c4c2a29/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f4c/7937563/f1fdf0a31345/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f4c/7937563/4146cff069ff/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f4c/7937563/d06d3fc56410/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f4c/7937563/3f4fb4bba76f/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f4c/7937563/0de554737285/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f4c/7937563/031ce271db80/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f4c/7937563/816b866ba1b9/gr8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f4c/7937563/21ac15358939/gr9.jpg

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