Exosome Derived from Mesenchymal Stem Cells Alleviates Pathological Scars by Inhibiting the Proliferation, Migration and Protein Expression of Fibroblasts via Delivering miR-138-5p to Target SIRT1

Abstract

Introduction The therapies of using exosomes derived from mesenchymal stem cells (MSC-Exo) for wound healing and scar attenuation and micro RNAs (miRNAs) for regulation of genes by translational inhibition and mRNA destabilization obtained great achievements. Silent information regulator 1 (SIRT1) is the silent information, which has an intricate role in many biological processes. However, the effects of SIRT1 and miR-138-5p loaded in MSC-Exo on pathological scars remain unclear. Methods MSC-Exo was isolated and identified by ultracentrifugation, transmission electron microscopy, nanoparticle size measuring instrument and Western blot assays. The relationship between SIRT1 and miR-138-5p was verified by a double-luciferase reporter assay. Cell Counting Kit-8, Τranswell, scratch, and Western blot assays were used to evaluate the proliferation and migration of human skin fibroblasts (HSFs), and the protein expression of SIRT1, NF-κB, α-SMA and TGF-β1 in HSFs, respectively. Flow cytometry was used to assess the apoptosis and cell cycle of HSFs affected by SIRT1. Results Our study demonstrated that miR-138-5p loaded in MSC-Exo could attenuate proliferation, migration and protein expression of HSFs-derived NF-κB, α-SMA, and TGF-β1 by targeting to SIRT1 gene, which confirmed the potential effects of MSC-Exo in alleviating pathological scars by performing as a miRNA’s delivery vehicle. Conclusion Exosomes derived from MSCs acting as a delivery vehicle to deliver miR-138-5p can downregulate SIRT1 to inhibit the growth and protein expression of HSFs and attenuate pathological scars.

Small extracellular vesicles from mesenchymal stem cells: A potential Weapon for chronic non-healing wound treatment

“…In line with the same idea, Fang et al examined miRNA profiles in hucMSC-sEVs by high-throughput sequencing and verified that a couple of miRNAs (miR-21, −125b, −23a and −145) decreased myofibroblast formation via suppression of transforming growth factor β (TGF-β) Smad2 pathway (Fang et al, 2016). Encouragingly, similar therapeutic effects were also obtained by another team when they applied MSC-sEVs loaded with tumor necrosis factor-α stimulated gene-6 (TSG-6) or miR-138-5p (Jiang et al, 2020b;Zhao et al, 2022). Additionally, the wounds treated with ADSC-Exos also demonstrated faster wound healing and less collagen deposition (Li et al, 2022).…”

Knowledge mapping of extracellular vesicles in wound healing: A bibliometric analysis (2002‐2022)

“…From the perspective of the author, Professor Zhang Wei published 11 papers, pointing out that EVs derived from human stem cells, amniotic epithelial cells and platelet‐rich plasma can interfere with the proliferation and migration of fibroblasts and vascular endothelial cells during wound healing by regulating miRNA and signalling pathways, and improve the collagen deposition of wound, to inhibit scar formation and promote wound healing 50‐56 . In addition, there is a review that the exocrine released by adipose‐derived stem cells can combine with various biomaterials to promote the healing of large‐scale wounds 57 .…”

“…From the perspective of the author, Professor Zhang Wei published 11 papers, pointing out that EVs derived from human stem cells, amniotic epithelial cells and platelet-rich plasma can interfere with the proliferation and migration of fibroblasts and vascular endothelial cells during wound healing by regulating miRNA and signalling pathways, and improve the collagen deposition of wound, to inhibit scar formation and promote wound healing. [50][51][52][53][54][55][56] In addition, there is a review that the exocrine released by adipose-derived stem cells can combine with various biomaterials to promote the healing of large-scale wounds. 57 Hu, Dahai published 11 papers, among which, except two copublished with Zhang Wei, the other eight papers pointed out that fatderived stem cell exosomes, such as miR-192-5p and miR-21, can accelerate the migration and proliferation of keratinocytes by regulating SIRT3/SOD2, L-17RA/ Smad, PI3K/AKT signalling pathways to promote wound healing.…”

Engineered Extracellular Vesicles in Wound Healing: Design, Paradigms, and Clinical Application

“…MSC-EVs help to shrink scar tissue, reduce pathological scarring, and lead to faster wound closure. [47] This may be achieved by regulating MMP levels and collagen deposition. [48,49]…”