Mesenchymal stem cell-derived exosomes: An emerging therapeutic strategy for normal and chronic wound healing

Table 1 Effects of mesenchymal stem cell-exosomes on cutaneous wound healing

Phase	Exosome source	Nomenclature	Related exosomal cargo	Secreted factors or expressed genes affected	Outcome	Ref.
Hemostasis Phase	Human mesenchymal stem cells (MSCs) from the umbilical cord	EVs	-	Phosphatidylserine(+)	Umbilical MSCs and extracellular vesicles derived from them have a reasonably high procoagulant potential	[42]
Inflammatory Phase	Human jaw bone marrow-derived MSCs and bone marrow MSCs	Exosomes	miR-223	TNF-α ↓ IL-10 ↑	Accelerated wound healing in mice	[46]
					Induced M2 macrophage polarization (CD206+ macrophage ↑)
	Human umbilical cord (UC)-MSCs	Exosomes	let-7b	TLR4, p-p65, iNOS ↓ p-STAT3, p-AKT, ARG1 ↑	Alleviated inflammation and enhanced diabetic cutaneous wound healing in rats	[47]
					Induced M2 macrophage polarization Inhibited TLR4 signaling pathway
	Human UC-MSCs	Exosomes	miR-181c	TNF-α, IL-1β, TLR4, p65, p-p65↓ IL-10 ↑	Reduced burn-induced inflammation in rats	[48]
					Reduced neutrophil and macrophage infiltration (MPO+ cell,CD68+ cell↓) Inhibited TLR4 signaling pathway
	Human menstrual blood derived MSCs (MenSCs)	Exosomes	-	iNOS ↓ ARG1, VEGF ↑	Resolved inflammation and ameliorate cutaneous non healing wounds in diabetic mice	[49]
					Induced M2 macrophage polarization
Proliferative Phase	Human bone marrow MSC-derived exosomes	Exosomes	TGF-β/Smad	TGF-β1, Smad2, Smad3, Smad4 ↓TGF-β3, Smad7↑	Effectively promoted the cutaneous wound healing by inhibiting the TGF-β/Smad signal pathway	[59]
	Human adipose MSCs (ASCs)	Exosomes	-	N-cadherin, cyclin 1, PCNA, collagen I/III, elastin ↑	Facilitated cutaneous wound healing via optimizing the characteristics of fibroblasts	[62]
	Human ASCs	Exosomes	-	Collagen I/II, TGF-β1/3, MMP1/3 α-SMA ↓	Promoted 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	[63]
	Human fetal dermal MSCs	Exosomes	Jagged 1	Collagen I/III, elastin, fibronectin mRNA ↑	Promoted wound healing by activating the ADF cell motility and secretion ability via the Notch signaling pathway	[64]
	Human UC-MSCs	Exosomes	Wnt4	CK19, PCNA, collagen I ↑	Stimulated the AKT pathway to protect immortalized keratinocytes from heat-induced apoptosis	[65]
					Stimulated the AKT pathway to protect immortalized keratinocytes from heat-induced apoptosis
	Human UC-MSCs	Exosomes	Akt, ERK, STAT3	HGF, IGF1, NGF, SDF1↑	Promoted the proliferation and migration of fibroblasts in normal and chronic wounds. This effect was positively correlated with the dose of exosomes	[66]
	Induced pluripotent stem cell-derived MSCs	Exosomes	-	Collagen ↑	Increased the secretion of collagen by HaCaT cells to accelerate skin cell proliferation	[67]
	Adipose mesenchymal stem cells (ADSCs)	Exosomes	AKT/HIF-1α	-	Promoted the proliferation and migration of HaCaT cells by regulating the activation of the AKT/HIF-1α signaling pathway, thus promoting wound healing	[68]
	Human UC-MSCs	Exosomes	-	PARP-1, PAR↑	Suppressed HaCaT cell apoptosis induced by H2O2 by restraining the nuclear translocation of apoptosis-inducing factor (AIF) and promoting poly (ADP-ribose) (PAR) and poly ADP ribose polymerase 1 (PARP-1) expression	[69]
	Human adipose-derived MSCs (adMSC-Exo)	Exosomes	miR-125a	Angiogenic inhibitor delta-like 4 (DLL4)↓	Transferred miR-125a to endothelial cells and promoted angiogenesis by repressing DLL4	[70]
	Mouse BM- MSCs	Exosomes	miR-17 miR-23a miR-125b	TNF-α, IL-1β, iNOS, TLR4, IRAK1, p65↓ ARG1, IL-10, TGF-β↑	Decreased the threshold for thermal and mechanical stimuli in mice	[71]
					Increased nerve conduction velocity, the number of intraepidermal nerve fibers, myelin thickness, and axonal diameters
	Rat BM-MSCs	Exosomes	-	MDA, HIF1α, NOX2, Caspase 3, BAX, PARP1, MPO, ICAM1, IL-1β, NF-κB↓SOD, CAT, GPX, HO-1, BCL2, IL-10, bFGF, HGF, SOX9, VEGF↑	Decreased histopathological score of kidney injury in rats	[72]
					Reduced the levels of blood urea nitrogen (BUN) and creatinineReduced the level of oxidative stress
					Increased anti-oxidant status
					Reduced apoptosis and inflammation
					Improved regeneration and enhanced angiogenesis
	Human endometrial MSCs	Exosomes	-	Tie2, VEGF, Ang1, Ang2↑	Increased the expression of angiogenesis markers, including Tie2, VEGF, Ang1, and Ang2, and increased the proliferation, migration, and angiogenesis of HUVECs	[73]
	Human umbilical cord mesenchymal stem cells (hUCMSCs)	Exosomes	-	Ang2↑	hucMSC-Ex-derived Ang-2 plays a significant role in tube formation of HUVECs and promotion of angiogenesis	[74]
	Human UC blood-MSCs	Exosomes	-	Ang, Ang1, HFG, VEGF↑	Human umbilical cord blood (UCB)-MSC-derived exosomes pretreated with thrombin could accelerate skin wound healing in rats with full-thickness wounds. Exosomes from human UCB-MSCs increased angiogenesis factors, such as VEGF, HGF, and Ang1, and decreased TNFα and IL-6	[75]
	Human UC-MSCs	Exosomes	Wnt4	β-catenin, N-cadherin, PCNA, Cyclin D3↑	Enhanced angiogenesis in rats through the Wnt4/β-catenin pathway. When the expression of Wnt4 was knocked out by shRNA, the proangiogenic effect of hUC-MSC-derived exosomes was eliminated	[76]
	Human UC-MSCs	Exosomes	-	α-SMA, collagen I↓	Increased the formation and maturation of new blood vessels at the wound site, although the mechanism is still unclear	[77]
	Human UC-MSCs	Exosomes	GSK3β-Wnt/β-catenin	-	Alleviated hepatic IRI by transporting miR-1246 via regulating GSK3β-mediated Wnt/β-catenin pathway	[78]
Remodeling Phase	Human gingival MSCs	Exosomes	-	Collagen↑	Reduced the formation of scars by inhibiting the accumulation of mouse myofibroblasts	[79]
	Adipose mesenchymal stem cells (ASCs)	Exosomes	-	N-cadherin, cyclin-1, PCNA collagen I, III↑	Facilitates cutaneous wound healing via optimizing the characteristics of fibroblasts	[62]
	ASCs	Exosomes	ERK/MAPK	Matrix metalloproteinases-3 (MMP3)↑	APromoted 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	[63]
	MenSCs	Exosomes	-	iNOS↓ ARG1, VEGF↑	Resolved inflammation and ameliorated cutaneous non-healing wounds in diabetic mice	[49]
					Induced M2 macrophage polarization

MSCs: Mesenchymal stem cells; EVs: Extracellular vesicles; ILVs: Intraluminal vesicles; IL: Interleukin; MVBs: Multivesicular bodies; PF-4: Platelet factor 4; EGF: Epidermal growth factor; PDGF: Platelet-derived growth factor; TGF-β: Transforming growth factor; VEGF: Vascular endothelial growth factor; NAP-2: Neutrophil activating peptide-2; SDF-1α: Stromal-cell-derived factor-1; BMSC: Bone marrow-derived stem cells; MMP: Matrix metalloproteinases; ROS: Reactive oxygen species; IGF-1: Insulin growth factor 1; FGFs: Fibroblast growth factors; KGFs: Keratinocyte growth factors; TIMP1: Tissue inhibitor of metalloproteinase 1; TNF-a: Tumor necrosis factor alpha; CTGF: Connective tissue growth factor; IFNs: Interferons; HGF: Hepatocyte growth factor; ECM: Extracellular matrix; hUC: Human umbilical cord; hBM: Human bone marrow; BMMSC: Bone marrow MSC; JMMSC: Jaw bone marrow MSC; HDFs: Human dermal fibroblasts; HaCaTs: Human keratinocytes; LPS: Lipopolysaccharide; ASC: Human adipose mesenchymal stem cell; FD: Human fetal dermis; iPSC: Induced pluripotent stem cell; AIF: Apoptosis-inducing factor; HUVECs: Human umbilical vein endothelial cells; DLL4: Delta-like 4; Ang: Angiopoietin; iNOS: Inducible nitricoxide synthase.