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

Publisher: Impact Journals, LLC Country of Publication: United States NLM ID: 101508617 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1945-4589 (Electronic) Linking ISSN: 19454589 NLM ISO Abbreviation: Aging (Albany NY) Subsets: MEDLINE

Original Publication: Albany, NY : Impact Journals, LLC

Adipose Tissue/*metabolism ; Cell Differentiation/*physiology ; Corneal Keratocytes/*metabolism ; Exosomes/*metabolism ; Mesenchymal Stem Cells/*metabolism ; MicroRNAs/*metabolism ; Myofibroblasts/*metabolism; Adipose Tissue/cytology ; Animals ; Cells, Cultured ; Corneal Keratocytes/cytology ; Mesenchymal Stem Cells/cytology ; Myofibroblasts/cytology ; Protein Serine-Threonine Kinases/metabolism ; Rabbits ; Signal Transduction/physiology ; Smad3 Protein/metabolism ; Tumor Suppressor Protein p53/metabolism

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.

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Keywords: adipose-derived stem cells; corneal stroma; exosomes; keratocytes; miRNA

0 (MicroRNAs)
0 (Smad3 Protein)
0 (Tumor Suppressor Protein p53)
EC 2.7.11.1 (Protein Serine-Threonine Kinases)

Date Created: 20200301 Date Completed: 20210218 Latest Revision: 20211204

20231215

PMC7093196

10.18632/aging.102802

32112551