Fetal Dermal Mesenchymal Stem Cell-Derived Exosomes Accelerate Cutaneous Wound Healing by Activating Notch Signaling

Abstract

Fetal dermal mesenchymal stem cells (FDMSCs), isolated from fetal skin, are serving as a novel MSC candidate with great potential in regenerative medicine. More recently, the paracrine actions, especially MSC-derived exosomes, are being focused on the vital role in MSC-based cellular therapy. This study was to evaluate the therapeutic potential of exosomes secreted by FDMSCs in normal wound healing. First, the in vivo study indicated that FDMSC exosomes could accelerate wound closure in a mouse full-thickness skin wound model. Then, we investigated the role of FDMSC-derived exosomes on adult dermal fibroblast (ADFs). The results demonstrated that FDMSC exosomes could induce the proliferation, migration, and secretion of ADFs. We discovered that after treatment of exosomes, the Notch signaling pathway was activated. Then, we found that in FDMSC exosomes, the ligands of the Notch pathway were undetectable expect for Jagged 1, and the results of Jagged 1 mimic by peptide and knockdown by siRNA suggested that Jagged 1 may lead the activation of the Notch signal in ADFs. Collectively, our findings indicated that the FDMSC exosomes may promote wound healing by activating the ADF cell motility and secretion ability via the Notch signaling pathway, providing new aspects for the therapeutic strategy of FDMSC-derived exosomes for the treatment of skin wounds.

Extracellular Vesicles Derived From Mesenchymal Stem Cells (MSC) in Regenerative Medicine: Applications in Skin Wound Healing

“…These authors have shown that the effects of such EV on fibroblasts were mediated by activation of the Notch pathway. That was a consequence of the EV carrying the Notch ligand, known as jagged 1 (JAG-1) (Wang et al, 2019b). That is in agreement with the important roles assigned to the Notch-signaling pathway in wound healing (Chigurupati et al, 2007;Shi et al, 2015).…”

“…Besides, they increased the proliferation and migration of dermal fibroblasts in vitro. In addition, they induced the expression of genes encoding ECM proteins, such as collagen type I and III, fibronectin 1, elastin, and alpha-smooth muscle actin (a-SMA) (Wang et al, 2019b). These authors have shown that the effects of such EV on fibroblasts were mediated by activation of the Notch pathway.…”

“…The MSC-derived EV increased the skin re-epithelialization in full-thickness cutaneous wounds in animal models (Robson et al, 2001;Zhang et al, 2015aZhang et al, , 2018Li et al, 2017;Tao et al, 2017;Ren et al, 2019;Wang et al, 2019b). However, there are few works analyzing the specific effects of such EV in keratinocytes.…”

The Anti-fibrotic Effect of Human Fetal Skin-derived Stem Cell Secretome on the Liver Fibrosis

“…Previous studies have indicated that the features of fetal tissue cells facilitate engraftment in vivo and may provide preferred effects against diseases di cult to treat [7]. Since 1928, hundreds of clinical trials using various types of fetal transplants have been performed worldwide [8][9][10].Moreover, recently studies have been demonstrated that human fetal stem cells have a great growth promoting potential, which bene ted to the tissue regeneration and cell therapy [11,12]. In comparison to other mesenchymal stem cell (MSCs), fetal stem cells (FSCs) are easier to culture and more readily proliferate, and less likely to be rejected by transplant recipients, as these cells are less antigenic [8].…”

Anti-fibrotic effect of human fetal skin-derived stem cell secretomeon the liver fibrosis

“…Since 1928, hundreds of clinical trials using various types of fetal transplants have been performed worldwide [8][9][10]. Moreover, recent studies have been demonstrated that human fetal stem cells have a signi cant growth promoting potential, which bene ted to tissue regeneration and cell therapy [11,12]. In comparison to other mesenchymal stem cells (MSCs), fetal stem cells (FSCs) are easier to culture and more readily proliferate, and less likely to be rejected by transplant recipients, as these cells are less antigenic [8].…”