Exosomes from adipose tissue-derived mesenchymal stem cells ameliorate histone-induced acute lung injury by activating t
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(2020) 11:508
RESEARCH
Open Access
Exosomes from adipose tissue-derived mesenchymal stem cells ameliorate histone-induced acute lung injury by activating the PI3K/Akt pathway in endothelial cells Yukie Mizuta1,2, Tomohiko Akahoshi1,3* , Jie Guo1, Shuo Zhang1, Sayoko Narahara4, Takahito Kawano4, Masaharu Murata4, Kentaro Tokuda2,5, Masatoshi Eto4, Makoto Hashizume4 and Ken Yamaura2
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 coculture 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 miR126 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. (Continued on next page)
* Correspondence: [email protected] 1 Department of Disaster and Emergency Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan 3 Emergency and Critical Care Center, Kyushu University Hospital, Fukuoka, Japan Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or
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