METTL3-mediated m6A modification of ULK2 regulates autophagy to promote hypertrophic scar progression

Author:

Chen Wei-Wei1,Tian Fan1,Chen Meng-Nan1,Wu Jun-Jie2,Zhang Zhen-Yu1,Yuan Zheng-Dong2,Zhang Kai-Wen3,Jia Yuan3,Fu Yi-Fei1,Chen Yue-Chun1,Yuan Feng-Lai2

Affiliation:

1. Jiangnan University

2. The Hospital Affiliated to Jiangnan University

3. Nanjing University of Chinese Medicine

Abstract

Abstract Background: The role of autophagy in hypertrophic scar (HS) development and its mechanisms aren't completely understood yet. This study aimed to investigate the role and regulatory mechanisms of fibroblasts and their autophagy in the progression of HS. Results: Dermal tissues were collected from healthy individuals and those with HS. First, fibroblast autophagy was analyzed using quantitative real-time PCR, immunofluorescence, and western blotting. Autophagy increased markedly with the progression of HS in patients and rabbit models, resulting in the activation of fibroblast-associated α-SMA and COL-I. Impaired autophagy via 3-MA reduced fibroblast-to-myofibroblast differentiation. Second, the role of methyltransferase-like 3 (METTL3) in the regulation of autophagy was explored using N6-methyladenosine (m6A)-methylated RNA assays. Excessive m6A modification positively regulated autophagy in fibroblasts from hypertrophic scars (HSF); mechanistically, METTL3-mediated m6A modification increased the expression of unc-51-like kinase 2 (ULK2), which possibly plays redundant roles in autophagy initiation by promoting RNA stability. Third, western blotting, collagen gel contraction, and immunofluorescence assays were performed to determine the effects of autophagy and METTL3 on HS cells, and the regulatory effect of METTL3 on HS was investigated using a rabbit-ear hypertrophic scar model. METTL3 silencing impaired autophagic flux and inhibited fibroblast-to-myofibroblast differentiation. Subcutaneous injection of METTL3 siRNA suppressed cellular autophagy propagation in HSs and ameliorated HS formation in rabbit ears. Conclusions: Our study reveals an important role of autophagy in the progression of HS. Targeted METTL3 inhibition can alleviate autophagy in HSF and limit HS development in experimental animal models, thus providing a potential strategy for HS therapy.

Publisher

Research Square Platform LLC

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