Adipose-derived mesenchymal stem cells employed exosomes to attenuate AKI-CKD transition through tubular epithelial cell dependent Sox9 activation

// Fengming Zhu 1 , Octavia L. S. Chong Lee Shin 1 , Guangchang Pei 1 , Zhizhi Hu 1 , Juan Yang 1 , Han Zhu 1 , Meng Wang 1 , Jingyi Mou 1 , Jie Sun 1 , Yuxi Wang 1 , Qian Yang 1 , Zhi Zhao 1 , Huzi Xu 1 , Hui Gao 2 , Weiqi Yao 3 , Xiao Luo 4 , Wenhui Liao 5 , Gang Xu 1 , Rui Zeng 1 and Ying Yao 1 1 Division of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China 2 Department of Clinical Nutrition, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China 3 Wuhan Institute of Biotechnology, Guanggu Biolake, Wuhan 430000, Hubei, China 4 Department of Plastic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China 5 Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China Correspondence to: Ying Yao, email: yaoyingkk@126.com Rui Zeng, email: zengrui@tjh.tjmu.edu.cn Keywords: adipose-derived mesenchymal stem cells, exosomes, Sox9, AKI-CKD, tubular epithelial cells Received: February 08, 2017     Accepted: July 18, 2017     Published: August 07, 2017 ABSTRACT Acute kidney injury (AKI) predisposes patients to an increased risk into progressive chronic kidney disease (CKD), however effective treatments are still elusive. This study aimed to investigate the therapeutic efficacy of human adipose-derived MSCs (hAD-MSCs) in the prevention of AKI-CKD transition, and illuminate the role of Sox9, a vital transcription factor in the development of kidney, in this process. C57BL/6 mice were subjected to unilateral renal ischemia/reperfusion (I/R) with or without hAD-MSC treatment. We found that hAD-MSC treatment upregulated the expression of tubular Sox9, promoted tubular regeneration, attenuated AKI, and mitigated subsequent renal fibrosis. However, these beneficial effects were abolished by a drug inhibiting the release of exosomes from hAD-MSCs. Similarly, Sox9 inhibitors reversed these protective effects. Further, we verified that hAD-MSCs activated tubular Sox9 and prevented TGF-β1-induced transformation of TECs into pro-fibrotic phenotype through exosome shuttling in vitro , but the cells did not inhibit TGF-β1-induced transition of fibroblasts into myofibroblasts. Inhibiting the release of exosomes from hAD-MSCs or the expression of Sox9 in TECs reversed these antifibrotic effects. In conclusion, hAD-MSCs employed exosomes to mitigate AKI-CKD transition through tubular epithelial cell dependent activation of Sox9.