Down-Regulation of miR-301a-3p Reduces Burn-Induced Vascular Endothelial Apoptosis by potentiating hMSC-Secreted IGF-1 and PI3K/Akt/FOXO3a Pathway

Lingying Liu; Huinan Yin; Xingxia Hao; Huifeng Song; Jiake Chai; Hongjie Duan; Yang Chang; Longlong Yang; Yushou Wu; Shaofang Han; Xiaoteng Wang; Xiaotong Yue; Yunfei Chi; Wei Liu; Qiong Wang; Hongyu Wang; Hailiang Bai; Xiuxiu Shi; Shaozeng Li

doi:10.1016/j.isci.2020.101383

Down-Regulation of miR-301a-3p Reduces Burn-Induced Vascular Endothelial Apoptosis by potentiating hMSC-Secreted IGF-1 and PI3K/Akt/FOXO3a Pathway

iScience. 2020 Aug 21;23(8):101383. doi: 10.1016/j.isci.2020.101383. Epub 2020 Jul 18.

Authors

Lingying Liu¹, Huinan Yin², Xingxia Hao³, Huifeng Song², Jiake Chai⁴, Hongjie Duan², Yang Chang², Longlong Yang², Yushou Wu², Shaofang Han², Xiaoteng Wang², Xiaotong Yue², Yunfei Chi², Wei Liu², Qiong Wang⁵, Hongyu Wang⁵, Hailiang Bai⁶, Xiuxiu Shi⁷, Shaozeng Li⁸

Affiliations

¹ Nutrition Department, the Fourth Medical Center Affiliated to PLA General Hospital, Beijing 100037, China; Burns Institute of PLA, Department of Burn & Plastic Surgery, the Fourth Medical Center Affiliated to PLA General Hospital, Beijing 100037, China; College of Basic Medicine, the Inner Mongolia Medical University, Hohhot, 010110, Inner Mongolia, China.
² Burns Institute of PLA, Department of Burn & Plastic Surgery, the Fourth Medical Center Affiliated to PLA General Hospital, Beijing 100037, China.
³ College of Basic Medicine, the Inner Mongolia Medical University, Hohhot, 010110, Inner Mongolia, China.
⁴ Burns Institute of PLA, Department of Burn & Plastic Surgery, the Fourth Medical Center Affiliated to PLA General Hospital, Beijing 100037, China. Electronic address: cjk304@126.com.
⁵ Department of Burn Surgery, the Third Affiliated Hospital of Inner Mongolia Medical University (Inner Mongolia BaoGang Hospital), Baotou 014010, Inner Mongolia, China.
⁶ Department of Plastic Surgery, The Second Hospital, Shanxi Medical University, Taiyuan 030001, Shanxi Province, China.
⁷ Department of Orthopedic Rehabilitation, the Fourth Medical Center Affiliated to PLA General Hospital, Beijing, 100037, China.
⁸ Department of Clinical Laboratory, the Fourth Medical Center Affiliated to PLA General Hospital, Beijing 100037, China.

Abstract

Vascular endothelium dysfunction plays a pivotal role in the initiation and progression of multiple organ dysfunction. The mesenchymal stem cell (MSC) maintains vascular endothelial barrier survival via secreting bioactive factors. However, the mechanism of human umbilical cord MSC (hMSC) in protecting endothelial survival remains unclear. Here, we found IGF-1 secreted by hMSC suppressed severe burn-induced apoptosis of human umbilical vein endothelial cells (HUVECs) and alleviated the dysfunction of vascular endothelial barrier and multiple organs in severely burned rats. Severe burn repressed miR-301a-3p expression, which directly regulated IGF-1 synthesis and secretion in hMSC. Down-regulation of miR-301a-3p decreased HUVECs apoptosis, stabilized endothelial barrier permeability, and subsequently protected against multiple organ dysfunction in vivo. Additionally, miR-301a-3p negatively regulated PI3K/Akt/FOXO3 signaling through IGF-1. Taken together, our study highlights the protective function of IGF-1 against the dysfunction of multiple organs negatively regulated by miR-301a-3p, which may provide the theoretical foundation for further clinical application of hMSC.

Keywords: Cellular Therapy; Clinical Genetics; Stem Cells Research.