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

Table 2 Adipose-derived stromal/stem cells-based preclinical studies for treating urogenital related diseases/pathologies (2016-2021)

Year	Organ/tissue	Disease/method	Animal model	Type of therapy (cell type/host anatomic site)	Cell/molecule concentration	Outcomes	Ref.
2021	Kidney	Renal interstitial fibrosis/unilateral urethral obstruction	Nu/nu mice 6–8 week-old males, n = 40	Injection of genetically modified SC human GDNF-ASCs and non-modified ASCs/intravenous	5 × 105 cells in 150 μL of saline	Improvement of vascular rarefaction/Renal protection against microvascular injuries/Oxidative stress reduction	Li et al[144], 2021
2020		Kidney injury/ischemia-reperfusion	Wistar rats 100-200 g males, n = 28	Injection of SC rat ASCs/tail vein	2 × 106 cells in 1 mL of PBS	Reduction of total tissue damage and urine mineral concentration/ASC anti-inflammatory effects	Changizi-Ashtiyani et al[153], 2020
2020		Kidney injury/ischemia-reperfusion	SD rats 8–12 week-old males, n = N/S	Injection of epididymal rat ASCs/left kidney	2 × 106 cells in 100 μL of decellularized kidney ECMH	Epithelial differentiation of post transplanted ASCs/accelerated repair of renal tubular injury via ASC pro-angiogenic molecules	Zhou et al[152], 2020
2020		Sepsis-induced AKI/cecal ligation and puncture	C57/BL6 mice 6–8 week-old males, n = 140	Injection of SC human ASCs-derived exosomes/tail vein injection	100 μg of exosomes in 200 μL of vehicle solution	Exosome protective functions against AKI/apoptosis and inflammation reduction via Sirtuin-1 pathway regulation	Gao et al[149], 2020
2019		Renal interstitial fibrosis/unilateral ureteral obstruction	Nude mice, n = 12	Injection of SC human GDNF-ASCs/tail vein	5 × 105 cells in 150 μL of vehicle solution	Macrophage transition from inflammatory (M1) to reparative (M2) phenotype/reduction of renal fibrosis and inflammation	Wang et al[143], 2019
2019		Diabetic nephropathy/induced diabetes	C57BL/KsJ db/db mice 8 week-old males, n = 20	Injection of SC murine ASCs-derived exosomes/tail vein	N/S	Attenuation of spontaneous diabetes and nephropathy by reduced proteins levels in the urine of treated mice	Jin et al[148], 2019
2017		Renal interstitial fibrosis/unilateral ureteral obstruction	Wistar rats 6 week-old males, n = 45	Injection of epididymal rat ASCs/tail vein	5 × 106 cells in 1 mL of vehicle solution	Significantly reduced EMT and inflammatory response via TGF-β1 signaling pathway inhibition in treated rats	Song et al[140], 2017
2017		Chronic kidney injury/adenine intoxication	Wistar rats 250 g males, n = 12	Injection of SC human ASCs/tail vein	2 × 106 cells in vehicle solution	Reduction of kidney fibrosis/improved creatine and urea in serum/significantly lower expression of profibrogenic genes in treated rats	Rivera-Valdes et al[141], 2017
2017		Acute kidney injury/ischemia-reperfusion	SD rats 220-250 g males, n = 32	Injection of perinephric human ASCs or SVF/intra-parenchymal	2 × 106 cells in 100 μL of PBS	SVF and ASCs equally improved renal injury by promoting cell proliferation and decreasing tubular injury and cell apoptosis	Zhou et al[146], 2017
2016		Acute kidney injury/ischemia-reperfusion	SD rats 250-300 g males, n = 72	Injection of rat ASCs/tail vein	1 × 106 cells in vehicle solution	Significantly lower kidney injury scores at days 1 and 3 post-treatment/not significant improvement at day 7 post-treatment	Sheashaa et al[145], 2016
2016		Acute kidney injury/IRI	SD rats 320-350 g males, n = 40	Injection of epididymal rat ASCs and ASCs-derived exosomes/intravenous	1.2 × 106 cells + 100 μg of ASCs-derived exosomes	Combined ASCs and exosomes confer higher kidney protection towards IRI than either one alone	Lin et al[147], 2016
2016		Chronic kidney disease/already present	Cats (various sex, age and breeds), n = 8	Injection of allogenic cryopreserved feline ASCs/cephalic vein	2 × 106 cells per kg in vehicle solution	No significant improvement of renal functions between treated and control groups/not adverse side effects noticed using allogenic ASCs	Quimby et al[150], 2016
2018	Urethra	Stress Urinary Incontinence/pudendal nerve transection	SD rats adult females, n = 48	Injection of exosomes derived from SC human ASCs/peripheral urethral	50 μg of exosomes in 50 μL of saline	Increased bladder capacity and leak point pressure/higher muscle fiber and nerve fiber regeneration	Ni et al[171], 2018
2018		Stress Urinary Incontinence/pudendal nerve transaction	SD rats 6-7 week-old females, n = 144	Injection of inguinal rat ASCs/transurethral sphincter	1 × 106 cells in 400 μL of D-Hanks’s solution	ASCs in vivo viability 60 d post-implantation/higher content of striated muscle in the urethra/higher values of leak point pressure	Cui et al[170], 2018
2018		Urethral stricture/N/S	SD rats, N/S	Injection of miR-21 modified SC human ASCs/ urethral wall	1 × 106 cells in 100 μL of saline	miR-27 cells increased epithelium and smooth muscle layer formation compared to normal ASCs/improve the epithelial wound healing microenvironment	Feng et al[168], 2018
2016		Urethral fibrosis/TGF-β1 induced model	SD rats 300 g males, n = 18	Injection of inguinal rat ASCs/urethra	2 × 105 cells in 50 μL of saline	Significantly decreased fibrosis evaluated by reduced collagen type I and III expression	Sangkum et al[167], 2016
2016		Urethral stricture/induced by TGF-β1 and surgical incision	SD rats 300-350 g males, n = 36	Injection of SC human ASCs/urethral wall	1 × 106 cells in 100 μL of PBS	Increased bladder capacity (50%)/wider urethral lumen/decreased expression of fibrosis-related genes	Castiglione et al[166], 2016

AKI: Acute kidney injury; ASCs: Adipose-derived stromal/stem cells; db/db: Spontaneous diabetes; ECMH: Extracellular matrix hydrogel; EMT: Epithelial mesenchymal transition; g: grams; GDNF: Glial-derived neurotrophic factor; IRI: ischemia-reperfusion injury; N/S: Not specified; PBS: Phosphate-buffered saline; SC: Subcutaneous; SD: Sprague-Dawley; SVF: Stromal vascular fraction; TGF-β1: Transforming growth factor-β1.