An update on the use of stem cell therapy for erectile dysfunction

doi:10.1016/j.ajur.2023.07.005

Asian Journal of Urology, 2024, 11 (4): 530-544 doi: 10.1016/j.ajur.2023.07.005

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An update on the use of stem cell therapy for erectile dysfunction

Mohamad Abou Chakra^a,*(

),Hugo Bailly^b,Fabian Klampke^b,Johann Boaz^c,Mouatasem Jida^d,Ahmad Abou Yassine^e,Ian M. McElree^f,Mohamad Moussa^a

^aDepartment of Urology, Lebanese University, Beirut, Lebanon
^bDepartment of Urology, Vivantes Klinikum, Berlin, Germany
^cDepartment of Urology, Royal Liverpool University Hospital, Liverpool, UK
^dLorenz Clinic, Kaiserslautern, Germany
^eDepartment of Internal Medicine, Staten Island University Hospital, Staten Island, NY, USA
^fCarver College of Medicine, University of Iowa, Iowa City, IA, USA

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Abstract

Objective: This systematic review aimed to analyze animal and human trial data to better understand the efficacy of stem cell therapy (SCT) for erectile dysfunction (ED) and the obstacles that may hinder its application in this field.

Methods: We searched electronic databases, including PubMed and Scopus, for published studies with the Medical Subject Heading terms of “erectile dysfunction” (AND) “stem cell therapy” (OR) “erectile dysfunction” (AND) “clinical trial of stem cell therapy” (OR) “stem cell therapy” (AND) “sexual dysfunction”. The search was limited to English-language journals and full papers only. The initial search resulted in 450 articles, of which 90 relevant to our aims were included in the analysis.

Results: ED is a multifactorial disease. Current treatment options rely on pharmacotherapy as well as surgical options. Patients may have side effects or unsatisfactory results following the use of these treatment options. SCT may restore pathophysiological changes leading to ED rather than treating the symptoms. It has been evaluated in animal models and shown promising results in humans. Results confirm that SCT does improve erectile function in animals with different types of SC use. In humans, evidence showed promising results, but the trials were heterogeneous and limited mainly by a lack of randomization and the small sample size. Many challenges could limit future research in this field, including ethical dilemmas, regulation, patient recruitment, the cost of therapy, and the lack of a standardized SCT regimen. Repairing and possibly replacing diseased cells, tissue, or organs and eventually retrieving normal function should always be the goals of any therapy, and this can only be guaranteed by SCT.

Conclusion: SCT is a potential and successful treatment for ED, particularly in patients who are resistant to the classic therapy. SCT may promote nerve regeneration and vascular cell regeneration, not only symptomatic treatment.

Key words： Erectile dysfunction Stem cell therapy Regenerative medicine Andrology

Received: 13 May 2023 Available online: 20 October 2024

Corresponding Authors: *E-mail address: mohamedabouchakra@hotmail.com (M.A. Chakra).

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	Mohamad Abou Chakra
	Hugo Bailly
	Fabian Klampke
	Johann Boaz
	Mouatasem Jida
	Ahmad Abou Yassine
	Ian M. McElree
	Mohamad Moussa

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Cite this article:

Mohamad Abou Chakra,Hugo Bailly,Fabian Klampke, et al. An update on the use of stem cell therapy for erectile dysfunction[J]. Asian Journal of Urology, 2024, 11(4): 530-544.

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http://www.ajurology.com/EN/10.1016/j.ajur.2023.07.005 OR http://www.ajurology.com/EN/Y2024/V11/I4/530

Mechanisms suggested for stem cell therapy in erectile function restoration. IGF-1, insulin-like growth factor 1; VEGF, vascular endothelial growth factor; FGF-2, fibroblast growth factor 2.

Study	Type of stem cells used	Source of stem cell	Mode of delivery	ED induction mechanism	Results summary
Kendirci et al., 2010 [32]	•Multipotent stromal cell	Rat	IC	•CNI	•Rats injected with typical multipotent stromal cells had partial EF rescue
Xu et al., 2014 [33]	•ADSC and ADSC-based MT	Rat	IC	•CNI	•EF, the contents of smooth muscle and endothelial cells, and the number of nNOS-positive nerves were significantly ameliorated in the MT group than those in the traditional ADSC group
Albersen et al., 2010 [34]	•ADSC and ADSC-derived lysate	Rat	IC	•CNI	•Both ADSC and lysate treatments resulted in significant recovery of EF •nNOS content was preserved in both the ADSC and lysate groups
Jeon et al., 2016 [35]	•h-ADSC	Human	CN	•CNI	•h-ADSCs showed effect on the recovery of injured CN
Chen et al., 2019 [36]	•ADSC and iMSC	Human	IC	• CNI	•iMSCs and adMSCs had similar beneficial effect on recovery of EF
Ouyang et al., 2018 [37]	•MSC and MSC-Exos	Rat	IC	•CNI	•MSC-Exos could ameliorate CNI-induced ED in rats with similar potency to that observed in the MSC-treated group
Liu et al., 2019 [38]	•MSC and MSC-Exos	Cell bank	IC	•Arteriogenic	•MSC-Exos could ameliorate rat EF with similar potency compared with the MSC group
Chen et al., 2017 [39]	•ADSC and ADSC-derived Exos	N/A	IC	•DiabeticED model	•IC injection of ADSC-derived Exos could ameliorate diabetic-induced ED rat
Zhou et al., 2017 [40]	•ADSC and ADSC-based MT	Rat	IC	•DiabeticED model	•MT injection had a higher retention than ADSC injection and improved EF
Lu et al., 2016 [41]	•ADSC and PEDF-transfected ADSC	Rat	IC	•DiabeticED model	•ADSCs restored EF •PEDF overexpression resulted in higher survival rates and decreased apoptosis of ADSCs
Liu et al., 2013 [42]	•ADSC and ADSC-modified with the VEGF gene	Human or rat	IC	•DiabeticED model	•IC injection of ADSCs expressing VEGF has more efficiently promoted the recovery of EF
Feng et al., 2022 [43]	•HUCMSC	Human	IC or VI	•DiabeticED model	•HUCMSCs can effectively and safely alleviate ED and attenuate diabetes-induced ferroptosis in CC
Wang et al., 2015 [44]	•AMSC and HP-AMSC	Rat	IC	•DiabeticED model	•Hypoxic preconditioning of MSCs is an effective approach to enhance their therapeutic effect on ED
Sun et al., 2012 [45]	•BM-MSC and BM-MSC-conditioned medium	N/A	IC	•DiabeticED model	•IC BM-MSC injection is effective in improving nerve regeneration in diabetic rats
Ouyang et al., 2014 [47]	•UDSC and UDSC-FGF2	Human	IC	•DiabeticED model	•Paracrine effect of UDSCs or UDSC-FGF2 induced improvement of EF in diabetic rats
Ouyang et al., 2019 [48]	•UDSC-EV	Human	IC	•DiabeticED model	•UDSC-EV transplantation can ameliorate EF in diabetic rats •Its mechanism involves the delivery of proangiogenic miRNA
Zhuang et al., 2022 [49]	•UDSC-EV and UDSC-EV-HA	Human	Local	•DiabeticED model	•Topical application of UDSC-EVs-HA in the treatment of ED in diabetic rats has been proven effective
Galhom et al., 2022 [51]	•UDSC and UDSC-L	Rat	IC	•DiabeticED model	•Both UDSCs and UDSC-L can repair the structure and ultrastructure of CCs and improve the copulatory functions in the diabetic rat model
Zheng et al., 2018 [52]	•I-PSC	Rat	IC	•CNI	•ADSCs treated with Icariside II markedly preserved the EF of the CNI model rats
Yang et al., 2020 [53]	•ADSC-V and ADSC G&V	Rat	MPG	•CNI	•ADSCs co-overexpressed VEGF and GDNF-induced synergistic effects and could be a potential tool for recovering EF
Kim et al., 2013 [54]	•h-ADSC	Human	CN	•CNI	•Transplantation of hADSCs and NGF-hydrogel into damaged CN improved EF
You et al., 2013 [55]	•h-BMSC	Human	IC with/without PI	•CNI	•PI of h-BMSCs potentiates recovery of EF by IC of h-BMSCs via regeneration of nNOS-containing nerve fibers
Fang et al., 2016 [56]	•d-MSC and r-BM-MSC	Rat	IC and PI	•CNI	•PI of d-MSCs effectively restored EF in rats with CNI
Kim et al., 2012 [57]	•MSC, MSC plus matrixen	Rat	MPG	•CNI	•The functional and histological restoration was observed in the rats with CNI •The effect of MSCs on recovery of EF might be improved by using a cell carrier such as Matrixen
Kim et al., 2012 [58]	•MSC-rAd/hBDNF and MSC	Rat	MPG	•CNI	•Combination treatment with MSCs and BDNF resulted in better functional and histological preservation in ED than MSCs alone
You et al., 2013 [59]	•h-ADSC	Human	PI and/or IC	•CNI	•PI and IC injections of ADSCs were equally effective in recovering penile erection
Bochinski et al., 2004 [60]	• ENSC	N/A	MPG or IC	•CNI	•IC injection ENSCs can improve EF in a rat model of neurogenic impotence
Matsuda et al., 2018 [61]	•MSC	Rat	REJV	•CNI	•Intravenous infusion of MSCs after CNI decreases postoperative ED
Chen et al., 2023 [62]	•PRDX2-ADSC	Rat	Culture-based	•CNI	•Overexpression of PRDX2 in ADSCs enhanced the therapeutic effect of ADSCs by inhibiting ferroptosis
Huo et al., 2020 [63]	•MSC-Exos containing miR-21-5p	Rat	IC	•DiabeticED model	•MSC-Exos can transport miR-21-5p to cavernous muscle and inhibit its apoptosis
Sun et al., 2023 [64]	•RXFP1-ADSC	Rat	IC	•DiabeticED model	•RXFP1-ADSCs had more potent efficacy than regular ADSCs
Chen et al., 2023 [65]	•MT-EV and NC-EV	Rat	IC	•CNI	•Transplantation of MT-EVs could significantly alleviate ED
Liang et al., 2021 [66]	•miR-301-3p-overexpressing ADSC	Rat	N/A	•Hypoxia-induced ED	•miR-301a-3p-overexpressing Exos treatment had significant therapeutic effects in the ED model
Song et al., 2020 [67]	•MSC-Exos vs. CCSMC-Exos	Rat	IC	•DiabeticED model	•CCSMC-Exos or MSC-Exos could preserve EF
Li et al., 2018 [68]	•ADSC-Exos and BMSC-Exos	N/A	IC	•CNI	•ADSC-Exos and BMSC-Exos therapy could significantly alleviate pathological changes associated with ED and improve EF
Yang et al., 2020 [69]	•UDSC-Exos	Human	IC	•Peyronie's disease rat model	•UDSC-Exos could significantly ameliorate tunica fibrosis and EF

Summary of results of preclinical studies on stem cell therapy for ED reported.

Study	Study design	Type of the SC used	Regimen used (cells)	Mode of delivery	ED etiology	Patient, n	F/U, month	Outcome^a
Study	Study design	Type of the SC used	Regimen used (cells)	Mode of delivery	ED etiology	Patient, n	F/U, month	Baseline	After SCT
Bahk et al., 2010 [15]	•Single-blinded	•Human umbilical cord blood SC	•1.5×10⁷	IC	•DM	•Tx group: 7 •Ctrl group: 3	11	•Number of erections: 1	•Number of erections:2.3
Yiou et al., 2016 [17]	•Nonrandomized trial	•BM-mononuclear cell	•4 doses: 2×10⁷, 2×10⁸, 1×10⁹, and 2×10⁹	IC	•RP	•12	6	•IIEF-IS:3.9±2.5 •IIEF-EF:7.3±4.5	•IIEF-IS:6.8±3.6 •IIEF-EF:17.4±8.9
Haahr et al., 2016 [18]	•Open-label and single-arm	•Adipose-derived regenerative cell	•2.2×10⁷	IC	•RP	•17	6	•IIEF o- Ctrl group: 7 o- Tx group: 5	•IIEF o- Ctrl group: 17 o- Tx group: 5
Levy et al., 2016 [16]	•Open-label and single-arm	•Placental matrix-derived MSC	•N/A	IC	•Organic	•8	6	•PSV:23.1-49.3 •IIEF: 21-54	•PSV:50.7-73.9 •IIEF: 23-63
Yiou et al., 2017 [14]	•Open-label and single-arm	•BM-mononuclear cell	•1×10⁹	IC	•RP	•6	6	•IIEF-IS:2.2±3.4 •IIEF-EF:3.7±4.1	•IIEF-IS:7.8±3.1 •IIEF-EF:18±8.3
Al Demour et al., 2018 [13]	•Open-label and single-arm	•BM-derived MSC	•30×10⁶ cells/4 mL injected at baseline and at 30 days	IC	•DM	•4	12	•EHS: 1 •IIEF-15: 10	•EHS:2.75 •IIEF-15:42.5
You et al., 2021 [12]	•Open-label and single-arm	•Human BM-derived MSC	•30×10⁷	IC	•DM (5 patients) and RP (5 patients)	•10	12	•IIEF:18.1±10.7	•IIEF:23.3±15.8
Al Demour et al., 2021 [11]	•Open-label and single-arm	•Allogeneic Wharton's jelly-derived MSC	•20×10⁶ cells/4 mL	IC	•DM	•22	12	•IIEF-5:11.5±2.7 • EHS: 1.7±0.7	•IIEF-5:13.6±4.2 • EHS: 2.4±0.7
Mirzaei et al., 2021 [9]	•Randomized single-blinded	•Autologous MSC	•50-60×10⁶	IC	•DM	•Tx group: 10 •Ctrl group: 10	6	•IIEF o- Tx group: 7.2±2.1 o- Ctrl group: not change	•IIEF o- Tx group: 10.6±4.7 o- Ctrl group: not change
Moussa et al., 2021 [10]	•Single-blinded	•Autologous ADSC	•N/A	IC	•RC	•Tx group: 5 •Ctrl group: 5	6	•IIEF-5 o- Tx group: 5 o- Ctrl group: not change	•IIEF-5 o- Tx group: 18.6 o- Ctrl group: not change
Fode et al., 2023 [19]	•Case series	•Autologous ADSC	•N/A	IC	•Organic	•10	3	•3/10 men achieved an improvement equal to or greater than the minimal clinically important difference according to their baseline IIEF-EF score

Summary of results of clinical studies on SCT for ED reported.

Barriers that may encounter stem cell research in ED treatment. ED, erectile dysfunction.

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