Exosomes from adipose-derived stem cells and application to skin wound healing

Abstract

Skin wound healing is an intractable problem that represents an urgent clinical need. To solve this problem, a large number of studies have focused on the use of exosomes (EXOs) derived from adipose-derived stem cells (ADSCs). This review describes the mechanisms whereby ADSCs-EXOs regulate wound healing and their clinical application. In the wound, ADSCs-EXOs modulate immune responses and inflammation. They also promote angiogenesis, accelerate proliferation and re-epithelization of skin cells, and regulate collagen remodelling which inhibits scar hyperplasia. Compared with ADSCs therapeutics, ADSCs-EXOs have highly stability and are easily stored. Additionally, they are not rejected by the immune system and have a homing effect and their dosage can be easily controlled. ADSCs-EXOs can improve fat grafting and promote wound healing in patients with diabetes mellitus. They can also act as a carrier and combined scaffold for treatment, leading to scarless cutaneous repair. Overall, ADSCs-EXOs have the potential to be used in the clinic to promote wound healing.

Keywords: adipose-derived stem cells; angiogenesis; exosomes; inflammation; skin wound healing.

FIGURE 1

EXOs bud from endosome and plasma membranes. Exosome biogenesis may use three mechanisms: (1) vesicle budding into discrete endosomes that mature into multivesicular bodies, releasing EXOs upon plasma membrane fusion; (2) direct budding from plasma membrane and (3) delayed release by budding at intracellular plasma membrane–connected compartments (IPMCs) followed by deconstriction of IPMC neck(s). We note that this is not a comprehensive list and it is just to illustrate some of the mechanisms. Abbreviations: ECM, extracellular matrix; ERM, ezrin‐radixin‐moesin; ESCRTs, endosomal sorting complexes required for transport; MHC, major histocompatibility complex; IGSF8, immunoglobulin superfamily member 8; ICAM‐1, intercellular adhesion molecule‐1; SDC1, syndecans 1; HSPs, heat shock proteins

FIGURE 2

Mechanisms by which ADSCs‐EXOs may promote wound healing. (A) adipose‐derived stem cells (ADSCs)‐EXOs contain immunoregulatory proteins and reduce the secretion of IFN‐α, subsequently inhibiting activation of T cells, resulting in reduced inflammation. Additionally, miR‐155 in ADSCs‐EXOs can induce monocyte differentiation into M1 macrophages, causing chronic inflammation; (B) ADSCs‐EXOs can transfer miRNA‐125a and miRNA‐31 to vascular endothelial cells, stimulating proliferation and migration to promote angiogenesis; (C) In the early stages, ADSCs‐EXOs may promote proliferation, migration and collagen synthesis in fibroblasts, stimulating N‐cadherin, cyclin‐1, PCNA and collagen I, III expression and increasing ECM production; (D) in late stages, ADSCs‐EXOs prevent the differentiation of fibroblasts into myofibroblasts, and reduce scarring by inhibition of the formation of collagen and activation the ERK/MAPK pathway to increase MMP3 expression. Abbreviations: ECM, extracellular matrix; MCSF, macrophage colony‐stimulating factor

FIGURE 3

Potential clinical applications of adipose‐derived stem cells (ADSCs)‐EXOs: improvement of fat grafting (A), wound healing therapy for diabetic patients (B), scarless repair (C) and carrier and combined scaffold for treatment (D)