Exosomes from human adipose-derived mesenchymal stem cells attenuate localized scleroderma fibrosis by the let-7a-5p/TGF-βR1/Smad axis

Background: Inflammation and fibrosis of the skin are characteristics of localized scleroderma (LS). Emerging evidence has demonstrated that exosomes from human adipose tissue-derived mesenchymal stem cells (ADSC-Exo) could alleviate skin fibrosis.

Objective: The impact and potential mechanism of ADSC-Exo on LS fibrosis was examined.

Methods: ADSC-Exo was isolated and identified. The effects of ADSC-Exo on the abilities of proliferation and migration of LS-derived fibroblasts (LSFs) were assessed by CCK-8 and scratch assays, respectively. qRT-PCR, western blot, and immunofluorescence were conducted to detect LSFs stimulated with ADSC-Exo, ADSC-Exo^{Anti-let-7a-5p}, let-7a-5p mimic/TGF-βR1 shRNA virus, and negative controls. The impact of ADSC-Exo on C57BL/6j LS mice was evaluated by photographic morphology, hematoxylin-eosin (H&E), Masson's trichrome, and immunohistochemical staining.

Results: The verified ADSC-Exo limited the proliferation and migration of LSFs and reduced the expression of COL1, COL3, α-SMA, TGF-βR1, and p-Smad2/ 3 in vitro and in vivo. TGF-βR1 knockdown and let-7a-5p mimic in LSFs reduced the expression of COL1, COL3, α-SMA, and p-Smad2/3. However, compared with the ADSC-Exo^NC group, the dermal thickness was increased, collagen arrangement was disordered, and α-SMA and TGF-βR1 levels were increased after exposure to ADSC-Exo^{Anti-let-7a-5p}.

Conclusions: In this study, it might show that ADSC-Exo may successfully prevent LSF bioactivity, collagen deposition, and myofibroblast trans-differentiation. Additionally, we confirmed that let-7a-5p in ADSC-Exo could directly target TGF-R1 to control the Smad pathway and reduce fibrosis in LSFs. Our work offered a brand-new therapeutic approach and clarified the unique mechanism for the clinical management of LS.