Role of stem cell therapies in treating chronic wounds: A systematic review

Table 2 Stem cell therapies

Stem cell therapy	Cell markers	Indications	Mechanisms of action
Adipose-derived stem cells (ADSCs)	CD90+, CD105+, CD73+, CD44+, CD166+; CD34-, CD45-	Severe radiation injury, chronic ulcers, venous leg ulcers, chronic fistulae	Kim et al[61]: Promote angiogenesis, secrete growth factors and cytokines, and allow for human dermal fibroblast proliferation through direct cell contact and paracrine activation in the re-epithelialization phase; Trottier et al[62]: When combined with skin substitute with human extracellular matrix (ECM), ADSCs produce subcutaneous, dermal, and epidermal regenerated tissues
Bone marrow-derived stem cells (BMMSCs)	CD105+, CD73+, CD90+; CD13-, CD34-, CD45-	Severe radiation-associated wounds, chronic diabetic ulcers, advanced pressure ulcers in patients with spinal cord injury, and other intractable wounds	Han et al[64]: Synthesize high amounts of collagen, fibroblast growth factor (FGF), and vascular endothelial growth factor (VEGF); Ren et al[76]: Induce proliferation and potent differentiation of cells under low oxygen tension with morphologic and cell cycle changes towards bone and fat; Stoff et al[77]: Increase tensile strength of postoperative incisional wounds; Maxson et al[46]: Secrete antimicrobial factors and promote host immune response
Bone marrow-derived mononuclear cells (BMMNCs)	CD133+, CD117+, CD34+	Chronic ulcers	Amato et al[15]: Secrete angiogenic growth factors to decrease local inflammation and promote vascularization
Epidermally-derived mesenchymal stem cells (EMSCs)	CD90+, CD73+, CD105+/-; CD34-, CD271-	Chronic ulcers, burns, generalized junctional epidermolysis bullosa (JEMB)	Yang et al[89]: Promote re-epithelialization in wound healing and regenerate functional epidermal layer
Fibroblast stem cells (FSCs)	CD34+, CD11b+, CD13+, MHC II+, CD86+, CD45+, collagen-1+, procollagen-1+; CD44-	Chronic ulcers	Amato et al[15]: Increase cell proliferation, ECM deposition, wound contraction, and vascularization with additional secretion of growth factors and cytokines
Keratinocyte stem cells (KSCs)	K5, K14, K15, integrins; CD34-	Chronic ulcers	Lampert et al[94]: Enable the formation of the stratified keratinizing epidermis; Domaszewska-Szostek et al[26]: Proliferate, migrate, and differentiate during re-epithelialization with mechanical, antibacterial, and nutritious roles. Keratinocytes also interact with fibroblasts during the wound healing process and tissue regeneration. They perform autocrine secretion of IL-6 and nitric oxide, release growth factors, and help restore the barrier function of skin
Placental mesenchymal stem cells (PMSCs)	CD105+, CD73+, CD90+, CD44+; CD34-, CD45-	Chronic venous ulcers	Farivar et al[30]: Stimulate tissue regeneration and repair for improved wound healing
Umbilical cord mesenchymal stem cells (UMSCs)	CD105+, CD73+, CD90+; CD34-, CD45-	Chronic diabetic ulcers	Hashemi et al[37]: Secrete growth factors for wound healing and can differentiate into fibroblast, epithelial, and endothelial cells for wound healing
Embryonic stem cells (ESCs)	Oct-4, Stage specific embryonic antigens (SSEAs)	Intractable wounds	Guenou et al[102]: Capable of differentiating into all three germ cell layers and can form functional human basal keratinocytes