4.7 Article

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

期刊

ISCIENCE
卷 24, 期 3, 页码 -

出版社

CELL PRESS
DOI: 10.1016/j.isci.2021.102200

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资金

  1. National Natural Science Foundation of China [81301589, 81802226, 81871834, 82072530]
  2. Shanghai Pujiang Programme [2019PJD038]
  3. Shanghai Rising Stars of Medical Talent Youth Development Program (Youth Medical Talents - Specialist Program)
  4. Shanghai Jiao Tong University K.C. Wong Medical Fellowship Fund

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The study identified the downstream mechanism of H19 in promoting tendon regeneration through activation of the YAP pathway. Stable overexpression of H19 in TSPCs was achieved using CRISPR technology, leading to the production of H19-enriched sEVs. These findings offer a new method for tendon repair and highlight the potential of modularized sEV-based therapies in tendon regeneration.
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.

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