Table 2.

Applications of USCs in skin, bone and articular cartilage repair

Applied tissue	Animal model	Defect	Dosage	Materials	Pretreatment	Outcome	Possible repair mechanisms	Ref.
Skin	New Zealand white rabbit	Full-thickness skin defects, 2 cm × 2 cm	2 × 104 USCs/24-well plate-sized membranes	Polycaprolactone/gelatin nanofibrous (PCL/GT) membranes	N/A	Faster wound closure, increased re-epithelialization, collagen formation, and angiogenesis	USCs secrete VEGF and TGF-β1 promoting angiogenesis	[47]
Skin	BALB/C nude mouse	Full-thickness skin defect, 10 mm in diameter	1 × 106 USCs/100 μL PBS (subcutaneous injection)	N/A	Treated by diluted bioglass ionic (BG) extracts	Better wound healing ability, improved angiogenesis, more collagen deposition, and the collagen structure is closer to that in the mouse	BG ionic extracts activate the paracrine effects (VEGF-KDR) between USCs and recipient cells (endothelial cells and fibroblasts) in wound healing	[80]
Skin	Streptozotocin-induced diabetic C57BL/6 mouse	Full-thickness skin defect, 6 mm in diameter	200 μg USCs-Exos/100 μL PBS (intraperitoneal injection)	N/A	N/A	Accelerated wound healing, higher rates of re-epithelialization, more collagen deposition, improved cell (keratinocytes, fibroblasts and vascular endothelial) proliferation, less scar formation and improved angiogenesis	Exosomes (Exos) from USCs could effectively enhance the proliferation, migration and tube formation of vascular endothelial, promoting angiogenesis via transferring DMBT1 protein	[61]
Skin	Sprague–Dawley rats	Full-thickness skin defect, 2 cm in diameter	5 × 103 USCs/96-well plate-sized membranes	Surface-structured bacterial cellulose nanofiber (S-BC) membranes	N/A	Accelerated wound healing, faster re-epithelialization, more collagen production and neovascularization	The substance secreted from USCs and the effect of S-BC on the adhesion and proliferation of vascular endothelial cells promote angiogenesis	[81]
Skin	BALB/C nude mouse	Full-thickness skin defect, 8 mm in diameter	1 × 106 USCs/SIS membrane (10 mm in diameter)	Porcine small intestine submucosa (SIS)	The composites were pretreated with hypoxia (1% O2) for 24 h	Accelerated neovascularization, facilitated re-epithelialization, promoted skin appendage regeneration, improved the quality of collagen deposition and enhanced the wound healing	Hypoxic preconditioning enhanced composites secreting a large amount of growth factors (VEGF, EGF and bFGF) for enhancing wound angiogenesis at the early stage of wound healing	[82]
Bone	N/A	N/A	USCs	N/A	Fresh medium containing 4 μg/mL silver nanoparticles (AgNPs) treated for 24 h	Promoted osteogenic differentiation of USCs	The AgNPs themselves, rather than the released silver ions, lead USCs into osteogenic differentiation via activating RhoA, inducing actin polymerization and increasing cytoskeletal tension	[98]
Bone	Nude mouse	Ectopic bone formation (muscle pockets in hindlimbs)	5 × 105 USCs/scaffold (5 × 5 × 3 mm)	Poly (lactic-co-glycolic acid)/calcium silicate composite (PLGA/CS) porous scaffold	One week culture in vitro	Induced osteogenic differentiation, ingrowth of blood vessels into scaffolds	CS induces the osteogenic differentiation of USCs through the Wnt/β-catenin signaling pathway	[44]
Bone	Sprague–Dawley rats	6 mm critically sized femoral defect	5 × 105 USCs/scaffold (5 × 5 × 6 mm)	β-TCP porous scaffold	Composites cultured in osteogenic differentiation media for 7 days	Increased new osseous formation, 5 out of 11 transplants completely bridged the critical-size bone defect	USCs can adhere, proliferate and differentiate into osteoblasts on a β-TCP scaffold	[45]
Bone	Nude mouse	Ectopic bone formation (muscle pockets in hindlimbs)	USCs (concentration not mentioned)	Porous ceramic scaffold made of β-tricalcium phosphate (β -TCP)	Lentiviral vectors-bone morphogenetic protein 2 (BMP2) gene transduction	Increased osteogenic activity of USCs, these transfected cells can undergo osteogenic differentiation without osteogenic medium in vitro, observed ectopic bone formation, USCs differentiate into osteoblasts	BMP2 gene transduction	[99]
Bone	New Zealand white rabbit	Critical-sized segmental bone defects model (the ulna bone together with the periosteum)	6 × 105 USCs/scaffold (Φ 5 × 5 mm)	Surface mineralized biphasic calcium phosphate (BCPs) ceramics scaffold	The composites were cultured in osteogenic differentiation media for 7 days	Promoted the formation of new bone and accelerated the maturation of new bone in ulna defects	Scaffold provided a favorable microenvironment that enabled USCs to adhere and proliferate, early (ALP, BMP2, and RUNX2) and late (OCN) osteogenic gene marker were continuously and significantly upregulated	[101]
Bone	Sprague–Dawley rats	Skull defects	1 × 105 USCs/hydrogel (5 mm in diameter)	Methacrylated solubilized decellularized cartilage (MeSDCC) hydrogel	USCs were infected with 10−6 mol/L BMP2 for 21 days	Increased bone formation, larger bone area	FAK plays a key role in regulating BMP2 enhanced osteogenic differentiation of USCs, the underlying mechanism might be the activation of AMPK and Wnt signaling pathways	[100]
Bone	Sprague–Dawley rat	Glucocorticoid-induced osteonecrosis of the femoral head	500 μg USCs-EVs/200 μL PBS (tail intervenous injection)	N/A	N/A	Prevention of early stage osteonecrosis, rescued angiogenesis impairment, reduced apoptosis of cells, prevented trabecular bone destruction and improved bone microarchitecture	TIMP1 and DMBT1, respectively, partly mediate the anti-apoptotic and pro-angiogenic effects of extracellular vesicles from USCs (USCs-EVs)	[43]
Articular cartilage	N/A	N/A	BMSCs	N/A	Seeded on USCs-ECM for one passage	ECM deposited by USCs (USCs-ECM) could recharge senescent BMSCs toward chondrogenic differentiation	The Wnt11-mediated noncanonical signaling pathway might be responsible for USCs-ECM mediated BMSCs rejuvenation in terms of chondrogenic potential	[64]
Articular cartilage	New Zealand white rabbit	Knee-joint cartilage defect model, 5 mm in diameter	1 × 107 USCs/1 mL HA (injection into cartilage-defect knee joints)	1% Hyaluronic acid solution (HA)	N/A	More neocartilage formation that matures over time, showed the expression of collagen type II and synthesized proteoglycans	USCs are able to differentiate into chondrocytes with characteristic deposition of aggrecan and collagen II	[46]
Articular cartilage	N/A	N/A	1 × 103 SDSCs/cm2	UECM	N/A	Promoted proliferation and chondrogenic potential of SDSCs	Biophysical and biochemical cues (UECM is softer than others and contains different growth factors and collagen)	[65]

N/A not applicable, BMSC bone marrow stromal cell, SDSC synovium-derived stem cells, β-TCP β-tricalcium phosphate, UECM ECM deposited by USCs, USCs urine-derived stem cells

Φ The diameter and height of 5 mm