Exosomes secreted by human adipose mesenchymal stem cells promote scarless cutaneous repair by regulating extracellular matrix remodelling

Abstract

Scar formation is an intractable medical problem that appears after skin wounds have healed. Recent research has shown that exosomes secreted by human adipose mesenchymal stem cells (ASC-Exos) can benefit wound healing. To further explore the therapeutic potential of ASC-Exos, we investigated their effects on mitigating scar formation, and the underlying mechanisms of these effects. We found that intravenous injection of ASC-Exos decreased the size of scars and increased the ratio of collagen III to collagen I in murine incisional wounds. Exosome treatment also prevented the differentiation of fibroblasts into myofibroblasts and increased the ratio of transforming growth factor-β3 (TGF-β3) to TGF-β1 in vivo. Additionally, we found that ASC-Exos increased the matrix metalloproteinases-3 (MMP3) expression of skin dermal fibroblasts by activating the ERK/MAPK pathway, leading to a high ratio of MMP3 to tissue inhibitor of matrix metalloproteinases-1 (TIMP1), which is also beneficial for the remodelling of extracellular matrix (ECM). In conclusion, our results demonstrated that ASC-Exos promote ECM reconstruction in cutaneous wound repair by regulating the ratios of collagen type III: type I, TGF-β3:TGF-β1 and MMP3:TIMP1, and by regulating fibroblast differentiation to mitigate scar formation. Therefore, the application of ASC-Exos may be a novel therapeutic approach for scarless wound repair.

Molecular mechanism of myofibroblast formation and strategies for clinical drugs treatments in hypertrophic scars

“…Moreover, exosomes originated from human adipose mesenchymal stem cells (ASC‐Exos) could transfer fibroblasts to endogenous state and inhibit their differentiation. Meanwhile, the expression of MMP3 was increased in fibroblasts by activation of the ERK/MAPK pathway which is contributes to ECM remodeling (Wang et al, ). Also, it was also reported the use of human amniotic epithelial cells exosomes (hAECS‐Exo), and iRGD‐Exo‐doxorutin inhibited the formation of HTS (Zhao et al, ).…”

Biological approaches for hypertrophic scars

“…The exosomes secreted by human adipose mesenchymal stem cells could benefit wound healing and promote scarless cutaneous repair by regulating ECM remodelling. 200 At the same time, MSC inhibited the bioactivities of fibroblasts in the HSs, 201 inhibited the proliferation and the differentiation of fibroblasts to myofibroblasts, and further suppressed the scar formation. Finally, as the multipotent cells, MSC could migrate to local trauma to prevent excessive matrix deposition by fibroblasts, forming new microenvironment to promote healing and alleviate scar.…”

“…Moreover, not only stem cells themselves, the conditioned medium of MSCs and exosomes can be used as the treatment of anti‐scarring. The exosomes secreted by human adipose mesenchymal stem cells could benefit wound healing and promote scarless cutaneous repair by regulating ECM remodelling . At the same time, MSC inhibited the bioactivities of fibroblasts in the HSs, inhibited the proliferation and the differentiation of fibroblasts to myofibroblasts, and further suppressed the scar formation.…”

Current concepts on how to optimise skin needling 2020: A personal experience

“…Ferguson has shown that the higher the level of TGFB3 and the longer it is kept active, the better are the results 19 . Whereas 20 years ago, the concept that TGFB3 and IL10 should be a major determinant of regeneration instead of scar formation was a revolutionary idea, today we are seeing more and more research concentrating on promoting TGFB3 and IL10 through various procedures 26,27 . The chances are that new research will also highlight the use of new molecules in conjunction with skin needling to get better results.…”