Stem Cell Research & Therapy (Nov 2020)

Exosomes from adipose tissue-derived mesenchymal stem cells ameliorate histone-induced acute lung injury by activating the PI3K/Akt pathway in endothelial cells

  • Yukie Mizuta,
  • Tomohiko Akahoshi,
  • Jie Guo,
  • Shuo Zhang,
  • Sayoko Narahara,
  • Takahito Kawano,
  • Masaharu Murata,
  • Kentaro Tokuda,
  • Masatoshi Eto,
  • Makoto Hashizume,
  • Ken Yamaura

DOI
https://doi.org/10.1186/s13287-020-02015-9
Journal volume & issue
Vol. 11, no. 1
pp. 1 – 12

Abstract

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Abstract Background Mesenchymal stem cells (MSCs), including adipose-derived mesenchymal stem cells (ADSCs), have been shown to attenuate organ damage in acute respiratory distress syndrome (ARDS) and sepsis; however, the underlying mechanisms are not fully understood. In this study, we aimed to explore the potential roles and molecular mechanisms of action of ADSCs in histone-induced endothelial damage. Methods Male C57BL/6 N mice were intravenously injected with ADSCs, followed by histones or a vehicle. The mice in each group were assessed for survival, pulmonary vascular permeability, and histological changes. A co-culture model with primary human umbilical vein endothelial cells (HUVECs) exposed to histones was used to clarify the paracrine effect of ADSCs. Overexpression and inhibition of miR-126 ADSCs were also examined as causative factors for endothelial protection. Results The administration of ADSCs markedly improved survival, inhibited histone-mediated lung hemorrhage and edema, and attenuated vascular hyper-permeability in mice. ADSCs were engrafted in the injured lung and attenuated histone-induced endothelial cell apoptosis. ADSCs showed endothelial protection (via a paracrine effect) and Akt phosphorylation in the histone-exposed HUVECs. Notably, increased Akt phosphorylation by ADSCs was mostly mediated by exosomes in histone-induced cytotoxicity and lung damage. Moreover, the expression of miR-126 was increased in exosomes from histone-exposed ADSCs. Remarkably, the inhibition of miR-126 in ADSCs failed to increase Akt phosphorylation in histone-exposed HUVECs. Conclusion ADSC-derived exosomes may exert protective effects on endothelial cells via activation of the PI3K/Akt pathway.

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