Deletion of miR-126a Promotes Hepatic Aging and Inflammation in a Mouse Model of Cholestasis

Yi Yan; Dan Qin; Bian Hu; Chunjing Zhang; Shenghui Liu; Dongde Wu; Wendong Huang; Xingxu Huang; Liqiang Wang; Xiangmei Chen; Lisheng Zhang

doi:10.1016/j.omtn.2019.04.002

Deletion of miR-126a Promotes Hepatic Aging and Inflammation in a Mouse Model of Cholestasis

Mol Ther Nucleic Acids. 2019 Jun 7:16:494-504. doi: 10.1016/j.omtn.2019.04.002. Epub 2019 Apr 11.

Authors

Yi Yan¹, Dan Qin¹, Bian Hu², Chunjing Zhang¹, Shenghui Liu¹, Dongde Wu³, Wendong Huang⁴, Xingxu Huang², Liqiang Wang⁵, Xiangmei Chen⁵, Lisheng Zhang⁶

Affiliations

¹ College of Veterinary Medicine, Bio-medical Center, Huazhong Agricultural University, Wuhan, Hu Bei 430070, China.
² School of Life Science and Technology, Shanghai Tech University, 100 Haike Road, Pudong New Area, Shanghai 201210, China.
³ Department of Hepatobiliary and Pancreatic Surgery, Cancer Hospital of Wuhan University (Hubei Cancer Hospital), Wuhan, Hubei 430079, China.
⁴ Department of Diabetes Complications and Metabolism, Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA.
⁵ Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, 28th Fuxing Road, Beijing 100853, China.
⁶ College of Veterinary Medicine, Bio-medical Center, Huazhong Agricultural University, Wuhan, Hu Bei 430070, China. Electronic address: lishengzhang@mail.hzau.edu.cn.

Abstract

MicroRNAs (miRNAs) act as regulators of aging at the tissue or organism level or as regulators of cellular senescence. Targeted deletion of miR-126 in mice causes partial embryonic lethality, but its biological function in the liver is still largely unknown. Here, we deleted miR-126a, using the CRISPR/Cas9 system in vitro and in vivo. miR-126a was reduced in the aging livers, and disruption of miR-126a in bone mesenchymal stem cells (BMSCs) induced age-associated telomere shortening, DNA damage responses, and proinflammatory cytokines. Moreover, disruption of miR-126a in mice caused hepatocyte senescence, inflammation, and metabolism deficiency. In addition, disruption of miR-126a via BMSC transplantation aggravated the severity of liver defects induced by cholestasis compared with that in the functional miR-126a BMSC group. Mechanistically, we identified versican (VCAN) as a novel direct miR-126a-5p target that induces telomere shortening, BMSC senescence, and nuclear factor κB (NF-κB) pathway activation. This study identified aging-related reduced expression of miR-126a and promotion of its target VCAN as a key mechanism in the regulation of hepatic metabolic function during aging and hepatic damage by inducing NF-κB pathway activation, DNA repair function disorder, and telomere attrition. The findings indicate that miR-126a may be a drug target for the treatment of hepatic failure.

Keywords: BMSC; CRISPR-Cas9; VCAN; aging; inflammation; liver; miRNA-126a; transplantation.