Stem cell therapy and diabetic erectile dysfunction: A critical review

Table 1 List of articles on stem cell therapy in animal models of diabetic erectile dysfunction

Ref.	Animal model (species, age, n number)	ED model	Evidence of previous DE	Type of stem cell	Source of stem cell	Characterization of stem cell	Number of cells injected and site of injection	Modification	Duration of follow-up	Parameter of therapy	Conclusion
Garcia et al[68]	10-wk-old Zucker (fa/fa) rats; n = 10 in each group (ADSCs and control)	Obese and type 2 diabetic rats with ED	Yes, CN electrostimulation	ADSCs; Autologous	Perigonadal adipose tissue	Not clear	1 × 106/IC	None	3 wk	ICP-MAP, nNOS, corporal body collagen, and corporal body endothelial cell	ADSCs improve ED
Liu et al[57]	10-wk-old male Sprague-Dawley rats; n = 12 in each group (lentivirus-VEGF, GFP ADSCs, VEGF/GFP ADSCs, control)	Type 1 diabetes induced by streptozotocin with ED	Yes, APO procedure	ADSCs; Allogenic	Bilateral groin	Yes, by flow cytometry	1 × 106/IC	VEGF, GFP	3 wk	ICP-MAP, VEGF, and e-NOS in vivo Endothelial, smooth muscle, and pericyte marker	Injection of ADSCs expressing VEGF displayed more efficiently and significantly raised ICP-MAP and increased endothelial markers
Ouyang et al[55]	Male Sprague-Dawley rats unspecific age; n = 10 in control group, n = 15 in each treatment group (USCs, lentivirus FGF2, USCs-FGF2)	High-fat diet following streptozotocin-induced diabetes	Yes, APO procedure	HUDSCs	Human urine	Yes, flow cytometry (CD24, CD29, CD31, CD34, CD44, CD45, CD73, CD90, CD105, CD146)	1 × 106/IC	FGF-2	4 wk	ICP-MAP, expression of endothelial markers (CD31, VEGF, and eNOS), smooth muscle markers (desmin and smoothelin), histological changes	USCs or USCs-FGF2 improved erectile function in type 2 diabetic rats
Li et al[69]	8-wk-old BALB/c mice; n = 8 in each group (control and treatment)	Streptozotocin-induced diabetes with ED	Not clear	BMSCs; Allogenic	Unspecified bone marrow	Yes, by flow cytometry. Identification with Sca-1 micromagnetic, identification of CD29, CD44, CD13, and CD34	Not mentioned	None	3 wk	ICP-MAP, penile histology	Flk-1 Sca-1 MSCs differentiate into skeletal and endothelial cells in vivo and in vitro
Liu et al[45]	Male Sprague-Dawley rats with no mentioned age; n = 10 in each group (negative control, ADSCs, ADSCs + hepatocyte growth factor)	Streptozotocin-induced diabetes with ED	Not clear	ADSCs	Not mentioned	Yes	2 × 106/IC	Hepatocyte growth factor	4 wk	ICP-MAP, smooth muscle, and endothelium (PECAM-1, SMA), apoptotic index	Significantly enhance the erectile function
Wang et al[70]	10-wk-old Male Sprague-Dawley rats; n = 15-16 in each group (control, normoxia AMCS, and hypoxia AMCS)	Streptozotocin-induced diabetic mouse	Yes, APO procedure	ADSCs; Allogenic	Inguinal adipose	Yes, fluorescent-activated cell sorting (CD90, CD29, CD34, CD45)	1 × 106/IC	Normoxia-hypoxia	4 wk	ICP-MAP, n-NOS, endothelial and smooth muscle histology	Hypoxia AMSCs improved ICP-MAP, nNOS. Hypoxia AMSCs condition effective to enhance theuraphetic effect of ED
Kovanecz et al[71]	7-mo-old Zucker (fa/fa) rats; n = 8 in each group (untreated, early diabetic treated with SC, early diabetic with high glucose treated with SC, late diabetic treated with SC, non-diabetic untreated)	Not mentioned specifically	Not clear	MSDCs; Allogenic	Hindlimb muscles	Not clear	1 × 106/IC	Early and late diabetes	8 wk	ICP-MAP, nNOS-eNOS, collagen ratio, calponin, inflammation marker	Stem cell decreased collagen and fat infiltration, upregulated nNOS-eNOS, and improved erectile function
Ryu et al[46]	12-wk-old C57BL/6J mice; n = 6 in each group (control, diabetic, diabetic with PBS, and diabetic with BMSCs)	Streptozotocin-induced diabetic mouse	Not clear	BMSCs; Allogenic	Tibiae and Femur	Yes, flow cytometry (CD3, CD44, CD45, CD103, CD105, CD117, MHC-1, and Sca-1)	3 × 105/IC	None	2 wk	e-NOS-nNOS, endothelial and smooth muscle content histology	BMSCs improved significant recovery of erectile tissue
Zhou et al[48]	8-wk-old male Sprague-Dawley; n = 5 in each group (negative control, ASCs + ad-luc-myocardin, ASCs + ad-luc, ED without treatment)	Streptozotocin-induced diabetic mouse	Not clear	ADSCs; Autologous	Paratesticular fat tissue	Not clear	1 × 106 ADSC/IC	Insulin and neutral protamine hagedorn	4 wk	ICP-MAP, AGEs, and RAGE; growth factors and cytokine in penis	ADSCs combined with insulin improved erectile function and pathological changes
Wang et al[52]	10-wk-old male Sprague-Dawley rats; n = 14-15 in each group (negative control, icariin, ADMSCs, ADMSCs + icariin)	Streptozotocin-induced diabetic mouse	Yes, APO procedure	ADSCs; Allogenic	Inguinal adipose	Yes, fluorescent-activated cell sorting (CD90, CD29, CD34, CD45)	1 × 106/IC	Icariin	4 wk	ICP-MAP, histology and immunohistology of penis tissue, intracellular ROS levels	Icariin-enhanced ADSCs in erectile function Icariin could protect ADSCs against oxidative stress
Zhou et al[50]	8-wk-old male Sprague-Dawley rats; (n = 8 in control, n = 20 in treated groups)	Streptozotocin-induced diabetic mouse	Yes, APO procedure	ADSCs; Allogenic	Paratesticular fat tissue	Not clear	1 × 106 ADSC and 1 × 104 ADSCs per MT/IC	Microtissues (MTs)	4 wk	ICP-MAP, nNOS, smooth and endothelial content histology	MTs improved histopathology and erectile function rather than traditional ADSC
Zhu et al[49]	10-wk-old male Sprague-Dawley rats; n = 8-10 in each group (non-diabetic controls, diabetic with PBS, ADSCs, ADSCs + Magnetic application	Streptozotocin-induced diabetic mouse	Not clear	ADSCs; Autologous	Paratesticular fat tissue	Yes, by flow cytometry (CD34, CD45, CD44)	1 × 106 ADSC	Magnetic iron oxide nanoparticle	4 wk	ICP-MAP, contents, smooth muscle (α-SMA), endothelium (von Willebrand factor), VEGF	ADSCs improved erectile function External magnetic field improved efficiency of labeled ADSC in the corpus cavernosum
Jeon et al[56]	8-wk-old male Sprague-Dawley rats; n = 12 in each group (control, DM ED, BM-MSC, SDF-1 (stromal cell-derived factor-1)	Streptozotocin-induced diabetic with ED	Not clear	BMSCs	Not mentioned	Not mentioned	1 × 106/IC	SDF-1	4 wk	ICP-MAP, nNOS-eNOS, FGF-VEGF in vivo	SDF-1 improved ED recovery and smooth muscle content, increased nNOS-eNOS, FGF-VEGF
Chen et al[42]	Male Sprague-Dawley rats with unspecific age; n = 10 in each group (ADSC, BMSC, and control)	ED in type 2 rats with diabetes induced by high-fat and high-sugar diet and streptozotocin	Yes, by APO procedure	ADSCs and BMSCs; Allogenic	Medullary cavity of femur, tibia, and fibula	Yes, by flow cytometry Identification with CD34,CD45,CD73,CD90, and CD105	1 × 106/IC	None	2 wk	ICP-MAP, number of blood vessels, collagen	Stem cell improved ICP-MAP, increased the number of blood vessels, and reduced collagen content
Ouyang et al[72]	Male Sprague-Dawley rats with unspecific age; n = 8 in each group (control and treatment)	Streptozotocin-induced diabetes	Yes, APO procedure	HUDSCs	Human urine	Yes, flow cytometry and Western blot (CD63 and protein calnexin)	Not mentioned	None	4 wk	ICP-MAP, eNOA, phospho-eNOS, nNOS, and endothelial markers (CD31)	Human-derived stem cells improved ICP, eNOS, nNOS, and endothelial markers
Zhang et al[51]	Male Sprague-Dawley rats; n = 10 in each group (negative control, ASCs + ad-luc-myocardin, ASCs + ad-luc, ED without treatment)	Streptozotocin-induced diabetic mouse	Yes, APO procedure	ADSCs; Allogenic	Inguinal fat tissue	Yes, flow cytometry (CD29, CD90, CD34, and CD45)	1 × 106/IC	Ad-luc-myocardin modified	3 wk	ICP-MAP, collagen and smooth muscle histology: myocardin, collagen 1, cleaved caspase 3, α-SMA, and calponin	Myocardin enhanced therapeutic for ASCs for ED in diabetic mouse
Zhang et al[58]	CCECs culture, not specific rats; n = 15 each group (case and control)	CCECs treated with advanced glycation end products and streptozotocin-induced diabetic mouse	In vivo CCECs mimicking diabetic and APO procedure	HUDSCs	Human urine	Yes, by flow cytometry (CD24, CD31, CD34, CD44, CD45, CD73, CD90, CD105)	Not mentioned	None	4 wk	ICP-MAP, eNOS, p-NOS, VEGFRA, VEGFR2, authophagic flux	Urine stem cell improved cavernosal endothelium through upregulated authophagic activity
Zhang et al[47]	8-wk-old male Sprague-Dawley rats; n = 9 in each group (control group, DM with ED, ADSCs, ADSCs-EFGP, ADSCs + iNOS)	Streptozotocin-induced diabetic mouse	Yes, APO procedure	ADSCs; Allogenic	Inguinal fat tissues	Yes, by flow cytometry (CD2, CD31, CD49, CD90, CD106, CD34, CD45, CD73)	5 × 105/IC	EFGP and iNOS	2 wk	ICP-MAP, endothelial and smooth muscle content marker (NO, collagen-I, collagen IV, TGF-β, β- actin)	ADSCS-iNOS significantly reduced penile fibrosis
Song et al[54]	Male Sprague-Dawley rats; n = 7-8 in each group (BMSC-EXO, ADSC-EXO, CCSMC-EXO, control)	Streptozotocin-induced diabetic mouse	Yes, APO procedure	ADSCs and BMSCs; Allogenic	Inguinal adipose and rat femoral	Yes, flow cytometry (CD29, CD34, CD45, and CD90	100 μg of exosome/IC	Exosome CCSMC	4 wk	ICP-MAP, α-SMA collagen, TGF-β1, β-actin, e-NOS, and n-NOS, NO, and cGMP	CCSMC-EXOs improve erectile function, reducing collagen deposition and expression of eNOS-nNOS, NO, and cGMP
Wang et al[53]	Male Sprague-Dawley rats with unspecified age; no data on n number, four experimental groups in total (negative control, DM, DM + ADSC-EXO, DM + siCorin-ADSC-EXO)	Streptozotocin-induced diabetic mouse	Yes, but not mention what method	ADSCs; Allogenic	Not Mention	Yes, CD29, CD90, CD44, CD105, and von Willebrand factor	100 μL of exosome from ADSCs/IV	siCorin ADSC-EXO	2 wk	ICP-MAP, neurovascular function (ANP, BNP, nNOS, cGMP, β-actin) , inflammatory factor (IL6, IL1β), expression, delivery of corin	ADSC-EXO enhanced endothelial recovery and decreased inflammatory process

APO: Apomorphine; ADSCs: Adipose-derived stem cells; BMSCs: Bone marrow stem cells; CCECs: Cavernosal vascular endothelial cells; CCSMC: Corpus cavernosal smooth muscle cell; DM: Diabetes mellitus; ED: Erectile dysfunction; HUDSCs: Human urine-derived stem cells; IC: Intracavernosal; ICP-MAP: Intracavernosal pressure-mean arterial pressure; MSCs: Muscle-derived stem cells; PMSCs: Placental matrix stem cells.