Considerations for the clinical use of stem cells in genitourinary regenerative medicine

Table 3 Preclinical studies of urogenital related pathologies/disease using adipose-derived stromal/stem cells in tissue engineering (2016-2020)

Year	Organ/tissue	Approach	Animal model	Substitute implantation (cell type and scaffold/host anatomic site)	Cell concentration per scaffold	Outcomes	Ref.
2020	Kidney	Diabetic nephropathy/unilateral nephrectomy	SDT fatty rats 5-week-old males, n = 21	SC rat ASCs three-layer sheets/renal capsule transplantation	1 × 106 cells in 35-mm culture dish/sheet	14-d survival of transplanted sheets/significantly lower urinary TNF-α levels/maintained renal tubular structure in treated rats	Takemura et al[155], 2020
2018		Kidney reconstruction	Wistar rats 6-8 week-old males	Inguinal rat ASCs seeded onto a rat decellularized kidney/no implantation	1 × 107 cells in 2 ml of culture medium per decellularized kidney	ASCs differentiated into endothelial and tubular cells after 5 d of culture/few cells attached to the scaffold after 10 d	Xue et al[154], 2018
2016	Ureter	Artificial ureter injury/surgical excision	New Zealand white rabbits3.5 kg females, n = 20	Smooth muscle like-cells from SC rabbit ASCs seeded onto ventral aorta/decellularized matrix/graft placed over ureter defect	N/S	Seeded ASCs showed urothelial and smooth muscle-like cells phenotype in the ureter substitute 8 wk after implantation	Zhao et al[165], 2016
2020	Bladder	Complete bladder removal/surgical excision	SD rats 300 g adult females, n = 9	SFP human ASCs seeded onto a decellularized rat bladder matrix/bladder transplantation	1 × 106 cells in 500 μL of cells suspension/bladder scaffold	Acquisition of a smooth muscle-like phenotype of seeded ASCs seeded/ASC paracrine effect increased vascularization and innervation	Moreno-Manzano et al[163], 2020
2020		Sub-totally resected urinary bladder/upper two-thirds bladder excision	Athymic rats 200 g adult females, n = 9	Smooth muscle-like cells from SC human ASCs seeded onto 3-layer PLGA sheet/bladder graft anastomosis	1 × 106 cells mixed with 500 μL of human plasma/scaffold	Complete bladder regeneration and functionality restoration/fusion of smooth muscle-like cells in the regenerated muscular layer	Salem et al[162], 2020
2019		Bladder injury/surgical incision(1 cm)	SD rats 6-week-old females, n = 48	Inguinal rat ASCs cells and PGA combined sheets/bladder patch anastomose	1 × 105 cells/cm2 per sheet reconstruction	Patches promote urothelium, smooth muscle, neural and blood vessel regeneration/restored bladder function	Wang et al[151], 2019
2018		Bladder augmentation/cystotomy incision (1 cm)	SD rats 8 week-old males, n = 34	Inguinal rat ASCs seeded onto PCL-Chitosan scaffold/bladder substitute anastomose	15 × 107 cells/mL per scaffold	Higher smooth-muscle regeneration from ASCs/larger bladder capacity/increased angiogenesis	Zhou et al[161], 2018
2017		Bladder augmentation/surgical incision(1 cm)	SD rats 8 week-old females, n = 46	SC rat ASCs seeded onto an AM-SF scaffold/bladder substitute anastomose	10 × 107 cells/mL in 40 μL of saline per scaffold	Bladder capacity augmentation (30%)/relatively normal micturition pattern/ASC viability after 12 wk of implantation	Wang et al[157], 2017
2017		Bladder augmentation/surgical incision (1 cm)	SD rats 8 week-old males, n = 30	Inguinal rat ASCs seeded onto a BAMG-SF scaffold/bladder substitute anastomosis	50 μL of cell suspension at 1 × 108 cells/mL per scaffold	Higher bladder capacity (2.3-fold)/Enhanced VEGF angiogenic potential by ERK ½ phosphorylation	Xiao et al[160], 2017
2017		Augmentation cystoplasty/surgical incision (1 cm)	SD rats 8 week-old males, n = 30	Rat ASCs encapsulated in an ADA/GEL seeded onto a porcine BAMG/bladder substitute anastomosis	100 μL of encapsulated cells at a 1 × 106/mL concentration per scaffold	Morphological bladder restoration by enhanced scaffold degradation/enhanced VEGF-mediated angiogenesis and smooth muscle regeneration in treated rats	Xiao et al[210], 2017
2016		Bladder augmentation/surgical incision (1 cm)	SD rats immunocompetent 36 week-old males, n = 30	Inguinal rat ASCs seeded onto a porcine BAMG/Bladder substitute anastomosis	15 × 107/mL cell suspension per scaffold	Greater bladder capacity in experimental group/equal urothelial regeneration in the treated and non-treated groups at 4- and 14-wk post-implantation	Zhe et al[156], 2016
2016		Partial cystectomy/half upper bladder transection	Beagle dogs 10-12 Kg males, n = 12	Human ASCs seeded onto a whole porcine BAMG/scaffold grafted onto bladders’ dome	1 × 105 cells per cm2 of each scaffold	Complete urothelial coverage of seeded and unseeded bladder after 6 mo/higher capillary density and smooth muscle organization in treated dogs’ bladder	Hou et al[159], 2016
2020	Urethra	Urethral injury/surgically induced	New Zealand white rabbits 9-week-old males, n = 24	SC rabbit ASCs seeded onto a human DAM scaffold/urethral graft	1 × 106 cells per scaffold	Higher number of urethras healed following seeding of ASCs onto DAM	Hariastawa et al[172], 2020
2020		Urethral injury/surgically induced (2 cm × 0.6 cm)	New Zealand white rabbits males, n = 15	Inguinal rabbit ASCs seeded in a nanofibrous scaffold/graft placed over urethral defect	1 × 107 cells per scaffold	Hypoxia preconditioning of ASCs increased urethral lumen diameter/preserved morphology/enhanced angiogenesis	Wan et al[173], 2020

ADA-GEL: Alginate dialdehyde-gelatin; AM-SF: Autologous myofibroblast-silk fibroin; ASCs: Adipose-derived stromal/stem cells; BAMG-SF: Bladder acellular matrix graft-silk fibroin; bFGF: Basic fibroblast growth factor; DAM: Dried amniotic membrane; g: gram; Kg: Kilogram; N/S: Not specified PCL: Polycaprolactone; PGA: Polyglycolic acid; PLGA: Poly(lactid-co-glycolic acid); SC: Subcutaneous; SD: Sprague-Dawley; SDT: Spontaneously diabetic Torii; SFP: Suprapatellar fat pad; TNF-α: Tumor necrosis factor-α; VEGF: Vascular endothelial growth factor.