Scholarlink

Background <p>Acute lung injury (ALI) can initiate early epithelial remodeling that may precede pulmonary fibrosis, with EMT of alveolar epithelial cells implicated in this acute phase. While mesenchymal stromal cell (MSC)-derived exosomes exhibit repair potential, their conventional culture conditions fail to mimic the hypoxic microenvironment of ALI. Here, we explored the therapeutic effects and regulatory mechanisms of hypoxia-preconditioned bone marrow MSC-derived exosomes (HExos) in LPS-induced ALI with early epithelial remodeling.</p> Methods <p>BMSCs were characterized via osteogenic/adipogenic differentiation and flow cytometry. Exosomes derived under normoxia (NExos) and hypoxia (HExos) were isolated and validated using nanoparticle tracking analysis (NTA), transmission electron microscopy (TEM), and Western blot. An LPS-induced ALI mouse model was employed to evaluate exosome efficacy. Through integrated miRNA sequencing, luciferase reporter assays, and gain-/loss-of-function experiments, we examined a working model involving the miR-486a-5p/Skp2/GATA4 axis.</p> Results <p>HExos markedly alleviated LPS-induced acute lung injury and early-stage collagen deposition. Mechanistically, HExos were enriched with miR-486a-5p, which directly targeted Skp2, thereby reducing Skp2-mediated ubiquitin–proteasome degradation of GATA4 and attenuating EMT-like changes. Notably, miR-486a-5p mimics reversed EMT-like changes in alveolar epithelial cells, while its knockdown abolished the protective effect.</p> Conclusions <p>Hypoxia-preconditioned bone marrow-derived mesenchymal stromal cell (BMSC) exosomes demonstrate significant potential to alleviate LPS-induced acute injury and early epithelial remodeling by engaging a miR-486a-5p/Skp2/GATA4 working model, offering a proof-of-concept therapeutic strategy for ALI.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Hypoxia-preconditioned mesenchymal stromal cell–derived exosomes attenuate LPS-induced acute lung injury and early epithelial remodeling in mice: evidence for a miR-486a-5p–Skp2–GATA4 axis

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年2月10日

查看全文
  • Qun Lin,
  • Siling Zou,
  • Can Lin,
  • Jun Lin,
  • Yanlin Wu,
  • Rifeng Liu,
  • Lihua Lei

摘要

Background

Acute lung injury (ALI) can initiate early epithelial remodeling that may precede pulmonary fibrosis, with EMT of alveolar epithelial cells implicated in this acute phase. While mesenchymal stromal cell (MSC)-derived exosomes exhibit repair potential, their conventional culture conditions fail to mimic the hypoxic microenvironment of ALI. Here, we explored the therapeutic effects and regulatory mechanisms of hypoxia-preconditioned bone marrow MSC-derived exosomes (HExos) in LPS-induced ALI with early epithelial remodeling.

Methods

BMSCs were characterized via osteogenic/adipogenic differentiation and flow cytometry. Exosomes derived under normoxia (NExos) and hypoxia (HExos) were isolated and validated using nanoparticle tracking analysis (NTA), transmission electron microscopy (TEM), and Western blot. An LPS-induced ALI mouse model was employed to evaluate exosome efficacy. Through integrated miRNA sequencing, luciferase reporter assays, and gain-/loss-of-function experiments, we examined a working model involving the miR-486a-5p/Skp2/GATA4 axis.

Results

HExos markedly alleviated LPS-induced acute lung injury and early-stage collagen deposition. Mechanistically, HExos were enriched with miR-486a-5p, which directly targeted Skp2, thereby reducing Skp2-mediated ubiquitin–proteasome degradation of GATA4 and attenuating EMT-like changes. Notably, miR-486a-5p mimics reversed EMT-like changes in alveolar epithelial cells, while its knockdown abolished the protective effect.

Conclusions

Hypoxia-preconditioned bone marrow-derived mesenchymal stromal cell (BMSC) exosomes demonstrate significant potential to alleviate LPS-induced acute injury and early epithelial remodeling by engaging a miR-486a-5p/Skp2/GATA4 working model, offering a proof-of-concept therapeutic strategy for ALI.