Table 1.

The therapeutic outcomes of MSC secretome (MSC-S) in wound healing.

Stem Cell Type	Type of Wound and Model	Secretome Component	In Vitro Outcome	In Vivo Outcome	Ref.
Human (BMSC) from SCD patients	Murine excisional wound/endothelial cells in a mouse model	VEGF, IL8, MCP-1, and ANG	Using HUVECs in a 3-dimensional in vitro model demonstrates proliferation and migration in the presence of hypoxic CM that supports angiogenesis.	BMSC condition media exerts high trophic factors that promote angiogenesis and skin regeneration with accelerated wound healing.	[56]
ADMSC	Full-thickness skin excision on SD rats	VEGF	Rat dermal fibroblast cell line was treated with secretome revealed viability, proliferation ability, and higher migration capability, which represent better-wound healing. Macrophages were treated with secretome exert reduction of pro-inflammatory cytokines, including IL-6, TNF-α, and MCP-1.	Rapid wound closure enhanced fibroblast proliferation and migration. Moreover, the higher expression of VEGF promotes angiogenesis, which accelerates wound healing potential.	[8]
hUCESCs	Corneal epithelial cells/corneal ulcer on SD rats	TIMP-1, TIMP-2, FGF, and HGF	Enhanced epithelial wound healing, rapid regeneration, and the constitution of the corneal surface.	Bactericidal effect on corneal contact lenses (CLs) infected with Escherichia coli and Staphylococcus epidermidis.	[48]
hASC transfected with miR-146a	In vitro model using HUVECs	miR-146a UPA, (DPP IV), HGF, FGF-1, and FGF 2	the secretome146a promotes proliferation, migration, and tube formation of endothelial cells, reflected in enhanced proangiogenic properties. Additionally, the secretome miR-146a has immunomodulation effect that can potentially promote wound healing.	In vivo outcome was not studied.	[57]
ADSCs	6-mm diameter biopsy punch piercing in mice dorsal skin of male balb/c-nude mice	TGF-b1 and VEGF	Increased transdermal delivery of secretome proteins was expressed in an ex vivo porcine skin using iontophoresis as a permeation enhancer.	Acceleration of wound closure with reduced scars, represented by rapid re-epithelization, proliferation, increased tissue remodeling rate, and high vascularization.	[40]
HAFS	The full-thickness cutaneous excisional wound created on the dorsal skin of BALB/c mice	VEGF	In vitro effect was not tested in this study.	Speeding up of wound closure due to a decrease in myofibroblasts’ positive expression of α-SMA-rather than contraction enhanced re-epithelialization after 14 days of treatment, and overall fetal-like wound healing without scarring as a result of high expression of type III collagen accomplished by transformation of dermal fibroblasts into fetal-like fibroblasts rather than myelo fibroblasts.	[58]
HGFs	Dorsal excisional wounds of female BALB/c mice	IL-6, arginase, MCP-1, and IL-8 are examples of cytokines. Growth factors and ECM proteins such as HGF, FGF-2, VEGF, Ang-1, Ang-2, MMP-2, MMP-9, and TIMP-1 are also present.	Human keratinocytes and foreskin fibroblasts cells were used in vitro to evaluate a higher proliferation and migration rate. There was also an increase in capillary density, indicating enhanced angiogenesis. Additionally, increased collagen deposition is reflected in higher wound contraction without reducing fibrosis.	Wound closure acceleration with reduced inflammation, promotion of angiogenesis, and higher collagen deposition. Higher re epithelization.	[43]
Human bone marrow MSC	Full-skin thickness incision wound on the dorsal part of diabetic Wistar male rats (chronic diabetic wound)	bFGF and EGF expression	Human dermal fibroblasts cultured in a high glucose concentration medium resulted in an in vitro advanced wound closure due to rapid fibroblast migration, higher proliferation, and increased bFGF gene expression.	Acceleration of wound healing in terms of reduction of inflammation, increased vascularization, granulation tissue formation and enhanced, collagen deposition, and some trophic factor genes expression.	[59]
(WJ-MSCs)	Radiation-induced skin injury on Female Sprague–Dawley (SD) rats	------------	(HUVECs) growth rate and proliferation rate are increased. Enhanced number of blood vessels due to increased a-SMA expression.	Acceleration of wound closure enhances the quality of wound healing by promoting cell proliferation, sebaceous gland cell-like regeneration, and angiogenesis.	[60]
Gamma irradiation to induce apoptosis PBMCs	Burn wounds of 40 cm2 were created on the dorsum of the female Dan Bred pigs	IL-8 and VEGF	Histology studies carried out by using wound biopsies.	Improved epidermal regeneration and differentiation, a better wound quality without scarring, and increased numbers of CD31+ and ASMA+ cells as markers for angiogenesis.	[61]
MSC from fetal umbilical cord	Burn wound on the dorsal area of the Wister rat (Rattus Norvegicus)	bFGF	Histological analysis of skin tissues using M and H stains	Acceleration of wound closure, a more significant number of fibroblasts, high density of collagen fiber, and significant number of blood vessels.	[62]
Warton Jelly MSC	Burns on a 47-year-old woman’s left hand due to hot water exposure.	________	________	Three weeks of treatment with 10% secretome gel acceleration wound healing without scarring t	[63]
UMSC-Exos	Full-thickness skin wound on ICR mice and nude mice.	Exosome enriched microRNA represented as (miR-21, -23a, -125b and -145)	fibroblasts cells treated with recombinant TGF-b protein upon exposure to CM, leading to α-SMA suppression.	Wound healing promotion due to suppression of myofibroblast and scar formation through inhibition of transforming growth factor-b2/SMAD2 pathway.	[64]