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Autophagy is reported to be involved in the formation of skin hypertrophic scar (HTS). However, the role of autophagy in the process of fibrosis remains unclear, therefore an improved understanding of the molecular mechanisms associated with autophagy may accelerate the development of effective therapeutic strategies against HTS. The present study evaluated the roles of autophagy mediated by transcription factor EB (TFEB), a pivotal regulator of lysosome biogenesis and autophagy, in transforming growth factor‑β1 (TGF‑β1)‑induced fibroblast differentiation and collagen production. Fibroblasts were treated with TGF‑β1, TGF‑β1 + tauroursodeoxycholic acid (TUDCA) or TGF‑β1 + TFEB‑small interfering RNA (siRNA). TGF‑β1 induced phenotypic transformation of fibroblasts, as well as collagen synthesis and secretion in fibroblasts in a dose‑dependent manner. Western blotting and immunofluorescence analyses demonstrated that TGF‑β1 upregulated the expression of autophagy‑related proteins through the endoplasmic reticulum (ER) stress pathway, whereas TUDCA reversed TGF‑β1‑induced changes. Reverse transcription‑quantitative PCR (RT‑qPCR), western blotting and RFP‑GFP‑LC3 double fluorescence analyses demonstrated that knockdown of TFEB by TFEB‑siRNA decreased autophagic flux, upregulated the expression of proteins involved in the apoptotic pathway, such as phosphorylated‑α subunit of eukaryotic initiation factor 2, C/EBP homologous protein and cysteinyl aspartate specific proteinase 3, and also downregulated the expression of α‑smooth muscle actin and collagen I (COL I) in fibroblasts. Immunofluorescence confocal analyses and enzyme‑linked immunosorbent assay indicated that TGF‑β1 increased the colocalization of COL I with lysosomal‑associated membrane protein 1 and Ras‑related protein Rab‑8A, a marker of secretory vesicles, in fibroblasts, as well as the secretion of pro‑COL Iα1 in culture supernatants. Meanwhile, these effects were abolished by TFEB knockdown. The present results suggested that autophagy reduced ER stress, decreased cell apoptosis and maintained fibroblast activation not only through degradation of misfolded or unfolded proteins, but also through promotion of COL I release from the autolysosome to the extracellular environment.

international journal of molecular medicine

Transcription factor EB‑mediated autophagy promotes dermal fibroblast differentiation and collagen production by regulating endoplasmic reticulum stress and autophagy‑dependent secretion