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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number508
JournalStem Cell Research and Therapy
Volume11
Issue number1
DOIs
Publication statusPublished - Dec 2020

All Science Journal Classification (ASJC) codes

  • Medicine (miscellaneous)
  • Molecular Medicine
  • Biochemistry, Genetics and Molecular Biology (miscellaneous)
  • Cell Biology

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