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Research Paper|Volume 12, Issue 5|pp 4093—4110

Exosomal miR-19a from adipose-derived stem cells suppresses differentiation of corneal keratocytes into myofibroblasts

Ting Shen1, Qingqing Zheng1, Hongbo Luo1, Xin Li2, Zhuo Chen3, Zeyu Song2, Guanfang Zhou3, Chaoyang Hong2,4
  • 1Department of Ophthalmology, Zhejiang Provincial People’s Hospital and People’s Hospital of Hangzhou Medical College, Hangzhou 310014, Zhejiang, P. R. China
  • 2Wenzhou School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou 325035, Zhejiang, P. R. China
  • 3Bengbu Medical College, Bengbu 233030, Anhui, P. R. China
  • 4Department of Ophthalmology, Zhejiang Hospital, Hangzhou 310007, Zhejiang, P. R. China
Received: July 3, 2019Accepted: January 19, 2020Published: February 29, 2020
https://doi.org/10.18632/aging.102802

Copyright © 2020 Shen et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

In this study, we investigated the effects of exosomal microRNAs (miRNAs) from adipose-derived stem cells (ADSCs) on the differentiation of rabbit corneal keratocytes. Keratocytes grown in 10% FBS differentiated into myofibroblasts by increasing HIPK2 kinase levels and activity. HIPK2 enhanced p53 and Smad3 pathways in FBS-induced keratocytes. Keratocytes grown in 10% FBS also showed increased levels of pro-fibrotic proteins, including collagen III, MMP9, fibronectin, and α-SMA. These effects were reversed by knocking down HIPK2. Moreover, ADSCs and exosomes derived from ADSCs (ADSCs-Exo) suppressed FBS-induced differentiation of keratocytes into myofibroblasts by inhibiting HIPK2. Quantitative RT-PCR analysis showed that ADSCs-Exos were significantly enriched in miRNA-19a as compared to ADSCs. Targetscan and dual luciferase reporter assays confirmed that the HIPK2 3’UTR is a direct binding target of miR-19a. Keratocytes treated with 10% FBS and ADSCs-Exo-miR-19a-agomir or ADSCs-Exo-NC-antagomir showed significantly lower levels of HIPK2, phospho-Smad3, phospho-p53, collagen III, MMP9, fibronectin and α-SMA than those treated with 10% FBS plus ADSCs-Exo-NC-agomir or ADSCs-Exo-miR-19a-antagomir. Thus, exosomal miR-19a derived from the ADSCs suppresses FBS-induced differentiation of rabbit corneal keratocytes into myofibroblasts by inhibiting HIPK2 expression. This suggests their potential use in the treatment of corneal fibrosis.