Mesenchymal stem cell secretome: A promising therapeutic strategy for erectile dysfunction?

doi:10.1016/j.ajur.2024.02.003

Asian Journal of Urology, 2024, 11 (3): 391-405 doi: 10.1016/j.ajur.2024.02.003

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Mesenchymal stem cell secretome: A promising therapeutic strategy for erectile dysfunction?

Ria Margiana^{a,b,c,d,e,f,*}(

),Younes Pilehvar^g,Fatkhurrohmah L. Amalia^c,d,h,Silvia W. Lestari^b,e,f,i,Supardi Supardi^c,d,Reny I’tishom^c,j,*(

)

^aDepartment of Anatomy, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
^bMaster’s Programme Biomedical Sciences, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
^cAndrology Program, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
^dDr. Soetomo General Academic Hospital, Surabaya, Indonesia
^eIndonesia General Academic Hospital, Depok, Indonesia
^fCiptomangunkusumo General Academic Hospital, Jakarta, Indonesia
^gCellular and Molecular Research Center, Cellular and Molecular Medicine Research Institute, Urmia University of Medical Science, Urmia, Iran
^hDr. Kariadi Hospital, Semarang, Indonesia
ⁱDepartment of Medical Biology, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
^jDepartment of Biomedical Science, Faculty of Medicine, Universitas Airlangga Surabaya, Indonesia

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Abstract

Objective: The secretome, comprising bioactive chemicals released by mesenchymal stem cells (MSCs), holds therapeutic promise in regenerative medicine. This review aimed to explore the therapeutic potential of the MSC secretome in regenerative urology, particularly for treating erectile dysfunction (ED), and to provide an overview of preclinical and clinical research on MSCs in ED treatment and subsequently to highlight the rationales, mechanisms, preclinical investigations, and therapeutic potential of the MSC secretome in this context.

Methods: The review incorporated an analysis of preclinical and clinical research involving MSCs in the treatment of ED. Subsequently, it delved into the existing knowledge regarding the MSC secretome, exploring its therapeutic potential. The methods included a comprehensive examination of relevant literature to discern the processes underlying the therapeutic efficacy of the MSC secretome.

Results: Preclinical research indicated the effectiveness of the MSC secretome in treating various models of ED. However, the precise mechanisms of its therapeutic efficacy remain unknown. The review provided insights into the anti-inflammatory, pro-angiogenic, and trophic properties of the MSC secretome. It also discussed potential advantages, such as avoiding issues related to cellular therapy, including immunogenicity, neoplastic transformation, and cost.

Conclusion: This review underscores the significant therapeutic potential of the MSC secretome in regenerative urology, particularly for ED treatment. While preclinical studies demonstrate promising outcomes, further research is essential to elucidate the specific mechanisms underlying the therapeutic efficacy before clinical application. The review concludes by discussing future perspectives and highlighting the challenges associated with the clinical translation of the MSC secretome in regenerative urology.

Key words： Erectile dysfunction Mesenchymal stem cell Mesenchymal stem cell secretome Mesenchymal stem cell-derived exosome

Received: 31 May 2023 Available online: 20 July 2024

Corresponding Authors: *Department of Anatomy, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia (R. Margiana). E-mail address: ria.margiana@ui.ac.id (R. Margiana).Andrology Program, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia (R. I’tishom). E-mail address: ritishom@fk.unair.ac.id (R. I’tishom).

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Cite this article:

Ria Margiana,Younes Pilehvar,Fatkhurrohmah L. Amalia, et al. Mesenchymal stem cell secretome: A promising therapeutic strategy for erectile dysfunction?[J]. Asian Journal of Urology, 2024, 11(3): 391-405.

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http://www.ajurology.com/EN/10.1016/j.ajur.2024.02.003 OR http://www.ajurology.com/EN/Y2024/V11/I3/391

Study	Study design	Cell type	Comorbidity	Administration; dose route	Patient, n; FU, month
Fode et al., 2023 [55]	Prospective case series	AT-MSCs	Chronic organic ED	Single ICI; unquantified	10; 6
Koga and Horiguchi, 2022 [59]	Open label and pilot	SHED-CM	Chronic organic ED	3-8 ICI; unquantified	38; 8
Mirzaei et al., 2021 [58]	Randomized single-blinded	Oral mucosa-MSCs	T2DM	Single ICI; (50-60)×10⁶ cells	20; 6
You et al., 2021 [100]	Phase I open label	BM-MSCs	Post-prostatectomy ED and T2DM	Single ICI; 30×10⁶ cells	10; 12
Al Demour et al., 2021 [51]	Phase I open label	WJ-MSCs	T2DM	Two ICIs; 20×10⁶ cells	22; 12
Bieri et al., 2020 [49]	Phase I dose escalation	ABMC	Chronic organic ED	Two ICIs; 3 mL or 6 mL dose group (10⁸ cells)	40; 12
Zasieda, 2020 [57]	Prospective cohort	MSC-DEs	Metabolic syndrome	6 ICIs; 5 mL	38; 3
Protogerou et al., 2020 [48]	Phase I open label pilot	AT-MSCs and PL	T2DM, hypertension, hypercholesterolemia, and Peyronie disease	Single ICI; 47×10⁶ cells	5; 6
Ory et al., 2020 [56]	Retrospective cohort	Transendocardial hMSCs	Cardiomyopathy-ED	Single ICI; 2×10⁸ cells	36; 12
Protogerou et al., 2019 [54]	Open label pilot	AT-MSCs and PL	T2DM, hypertension, hypercholesterolemia, and peyronie disease	Single ICI; 47×10⁶ cells	8; 3
Al Demour et al., 2018 [46]	Phase I open label	BM-MSCs	T2DM	Two ICIs; 30×10⁶ cells	4; 12-24
Haahr et al., 2016 [47]	Phase I open label	AT-MSCs	Post-radical prostatectomy	Single ICI; (8.4-37.2)×10⁶ cells	17; 6
Haahr et al., 2018 [50]	Phase I open label	AT-MSCs	Post-radical prostatectomy	Single ICI; (8.4-37.2)×10⁶ cells	21; 12
Yiou et al., 2016 [45]	Phase I	BM-MNCs	Post-radical prostatectomy	Single ICI; 2×10⁷-2×10⁹ cells	12; 12
Yiou et al., 2017 [44]	Phases II	BM-MNCs	Post-radical prostatectomy	Single ICI; 10×10⁸ cells	18; 62.1
Levy et al., 2016 [43]	Phase I-II open label	PM-MSCs	Chronic organic ED	Single ICI; unquantified	8; 6
Garber and Carlos, 2015 [53]	Pilot study	AT-MSCs	T2DM	Single ICI; 1.5×10⁷ cells	6; 12
Ichim et al., 2013 [101]	Case report	BM-MSCs	Chronic organic ED	Single ICI; unquantified	1; 18
Bahk et al., 2010 [42]	Phase I pilot study, single blinded	UC-MSCs	T2DM	Single ICI; 1.5×10⁷ cells	7; 9

MSC therapy of ED in the clinical trials.

Study	Producer cell	Isolation method	Exosome dose, μg	Cargo	ED model^a	Establishment method	Injection method	Investigated parameter
Chen et al., 2017 [102]	AT-MSCs	Multistep centrifugation	100	miR-301a-3p	T2DM	High-fat diet, intraperitoneal injection of 30 mg/kg STZ	ICI	Bcl-2, caspase 3, ICP/MAP, and CD31
Liang et al., 2021 [103]	AT-MSCs	ExoQuick-TC (Systems Biosciences, Palo Alto, CA, USA)	400	NM	Hypoxia	Chronic intermittent hypoxia exposure	ICI	α-SMA, eNOS, and ICP/RT-AP
Song et al., 2020 [90]	AT-MSCs and BM-MSCs	Multistep centrifugation	100	NM	T1DM	Intraperitoneal injection of 60 mg/kg STZ	ICI	cGMP, ICP/MAP, and NO
Li et al., 2018 [104]	BM-MSCs and AT-MSCs	Ultracentrifugation and ultrafiltration	100	Corin	CNI	Bilateral cavernous nerve crush injury	ICI	α-SMA, ratio of smooth muscle to collagen content, nNOS, and vWF
Wang et al., 2020 [93]	AT-MSCs	Ultracentrifugation and ultrafiltration	200	NM	T1DM	Intraperitoneal injection of 60 mg/kg STZ	Intravenous	ICP/MAP, ANP, BNP, and nNOS
Liu et al., 2019 [105]	BM-MSCs	Multistep centrifugation	50 or 100	NM	AI	Internal iliac artery ligation	ICI	eNOS, α-SMA, ratio of smooth muscle to collagen content, ICP/MAP, CD31, VEGF, and nNOS
Ouyang et al., 2018 [83]	BM-MSCs	Multistep centrifugation	100	NM	CNI	Bilateral cavernous nerves crush injury	ICI	ICP/MAP, nNOS, ratio of smooth muscle to collagen content, and caspase 3
Liang et al., 2022 [106]	AT-MSCs	Differential centrifugation	150	NM	CNI	Bilateral cavernous nerves crush injury	ICI	α-SMA, eNOS, nNOS, and mICP/MAP
Zhu et al., 2018 [92]	AT-MSCs	Exosome precipitation solution and ExoQuick (System Bioscience, Mountain View, CA, USA)	10 or 100	miRNAs	T1DM	Intraperitoneal injection of 60 mg/kg STZ	Corpus cavernosum injection	Ratio of smooth muscle to collagen content, endothelial content, and ICP/MAP
Yang et al., 2020 [107]	HUSCs	Ultracentrifugation and ultrafiltration	100	NM	PD	Intratunical injection of TGF-β1	Intratunical	Collagen III, ratio of smooth muscle to collagen content, Smad2/3 protein, ICP/MAP, elastin, and TGF-β1
Ouyang et al., 2019 [108]	HUSCs	Ultracentrifugation	100	miRNAs	T1DM	Intraperitoneal injection of 60 mg/kg STZ	ICI	nNOS, ratio of smooth muscle to collagen content, CD31, eNOS, and phospho-eNOS

Utilization of stem cells-derived exosomes to treat erectile dysfunction in animal models.

[1]	Defeudis G, Mazzilli R, Tenuta M, Rossini G, Zamponi V, Olana S, et al. Erectile dysfunction and diabetes: a melting pot of circumstances and treatments. Diabetes Metab Res Rev 2022; 38:e3494. https://doi.org/10.1002/dmrr.3494 doi: https://doi.org/10.1002/dmrr.3494
[2]	Cayetano-Alcaraz AA, Tharakan T, Chen R, Sofikitis N, Minhas S. The management of erectile dysfunction in men with diabetes mellitus unresponsive to phosphodiesterase type 5 inhibitors. Andrology 2023; 11:257-69.
[3]	Kim SG, You D, Kim K, Aum J, Kim YS, Jang MJ, et al. Therapeutic effect of human mesenchymal stem cell-conditioned medium on erectile dysfunction. World J Mens Health 2022; 40:653-62.
[4]	Yao C, Zhang X, Yu Z, Jing J, Sun C, Chen M. Effects of stem cell therapy on diabetic mellitus erectile dysfunction: a systematic review and meta-analysis. J Sex Med 2022; 19:21-36.
[5]	Matz EL, Thakker PU, Gu X, Terlecki RP, Dou L, Walker SJ, et al. Administration of secretome from human placental stem cell-conditioned media improves recovery of erectile function in the pelvic neurovascular injury model. J Tissue Eng Regen Med 2020; 14:1394-402.
[6]	Matz E, Dou L, Zhang Y, Terlecki R, Atala A, Jackson J. 322 Stem cell conditioned media profiles and potential uses in erectile dysfunction. J Sex Med 2018; 15:S254-5. https://doi.org/10.1016/j.jsxm.2018.04.285 doi: https://doi.org/10.1016/j.jsxm.2018.04.285
[7]	Moore CR, Wang R. Pathophysiology and treatment of diabetic erectile dysfunction. Asian J Androl 2006; 8:675-84.
[8]	MacDonald SM, Burnett AL. Physiology of erection and pathophysiology of erectile dysfunction. Urol Clin 2021; 48:513-25.
[9]	Sangiorgi G, Cereda A, Benedetto D, Bonanni M, Chiricolo G, Cota L, et al. Anatomy, pathophysiology, molecular mechanisms, and clinical management of erectile dysfunction in patients affected by coronary artery disease: a review. Biomedicines 2021; 9:432. https://doi.org/10.3390/biomedicines9040432 doi: https://doi.org/10.3390/biomedicines9040432
[10]	Allen MS, Walter EE. Erectile dysfunction: an umbrella review of meta-analyses of risk-factors, treatment, and prevalence outcomes. J Sex Med 2019; 16:531-41.
[11]	Wright LN, Moghalu OI, Das R, Horns J, Campbell A, Hotaling J, et al. Erectile dysfunction and treatment: an analysis of associated chronic health conditions. Urology 2021; 157:148-54.
[12]	Patel DP, Pastuszak AW, Hotaling JM. Emerging treatments for erectile dysfunction: a review of novel, non-surgical options. Curr Urol Rep 2019; 20:44. https://doi.org/10.1007/s11934-019-0908-2 doi: https://doi.org/10.1007/s11934-019-0908-2 pmid: 31214818
[13]	McMahon CG. Current diagnosis and management of erectile dysfunction. Med J Aust 2019; 210:469-76.
[14]	Burnett AL, Nehra A, Breau RH, Culkin DJ, Faraday MM, Hakim LS, et al. Erectile dysfunction: AUA guideline. J Urol 2018; 200:633-41.
[15]	He M, von Schwarz ER. Stem-cell therapy for erectile dysfunction: a review of clinical outcomes. Int J Impot Res 2021; 33:271-7.
[16]	Matz EL, Terlecki R, Zhang Y, Jackson J, Atala A. Stem cell therapy for erectile dysfunction. Sex Med Rev 2019; 7:321-8.
[17]	Gur S, Abdel-Mageed AB, Sikka SC, Hellstrom WJ. Advances in stem cell therapy for erectile dysfunction. Expert Opin Biol Ther 2018; 18:1137-50.
[18]	Saei Arezoumand K, Alizadeh E, Pilehvar-Soltanahmadi Y, Esmaeillou M, Zarghami N. An overview on different strategies for the stemness maintenance of MSCs. Artif Cells Nanomed Biotechnol 2017; 45:1255-71.
[19]	Nejati-Koshki K, Mortazavi Y, Pilehvar-Soltanahmadi Y, Sheoran S, Zarghami N. An update on application of nanotechnology and stem cells in spinal cord injury regeneration. Biomed Pharmacother 2017; 90:85-92.
[20]	Huang CY, Liu CL, Ting CY, Chiu YT, Cheng YC, Nicholson MW, et al. Human iPSC banking: barriers and opportunities. J Biol Sci 2019; 26:87. https://doi.org/10.1186/s12929-019-0578-x doi: https://doi.org/10.1186/s12929-019-0578-x
[21]	Chen J, Wang H, Zhou J, Feng S. Advances in the understanding of poor graft function following allogeneic hematopoietic stem-cell transplantation. Ther Adv Hematol 2020; 11:2040620720948743. https://doi.org/10.1177/2040620720948743 doi: https://doi.org/10.1177/2040620720948743
[22]	Friedenstein A, Chailakhjan R, Lalykina K. The development of fibroblast colonies in monolayer cultures of guinea-pig bone marrow and spleen cells. Cell Prolif 1970; 3:393-403.
[23]	Dadashpour M, Pilehvar-Soltanahmadi Y, Mohammadi SA, Zarghami N, Pourhassan-Moghaddam M, Alizadeh E, et al. Watercress-based electrospun nanofibrous scaffolds enhance proliferation and stemness preservation of human adiposederived stem cells. Artif Cells Nanomed Biotechnol 2018; 46:819-30.
[24]	Serati-Nouri H, Mahmoudnezhad A, Bayrami M, Sanajou D, Tozihi M, Roshangar L, et al. Sustained delivery efficiency of curcumin through ZSM-5 nanozeolites/electrospun nanofibers for counteracting senescence of human adiposederived stem cells. J Drug Deliv Sci Technol 2021; 66:102902. https://doi.org/10.1016/j.jddst.2021.102902 doi: https://doi.org/10.1016/j.jddst.2021.102902
[25]	Ahmadi S, Pilehvar Y, Zarghami N, Abri A. Efficient osteoblastic differentiation of human adipose-derived stem cells on TiO2 nanoparticles and metformin co-embedded electrospun composite nanofibers. J Drug Deliv Sci Technol 2021; 66:102798. https://doi.org/10.1016/j.jddst.2021.102798 doi: https://doi.org/10.1016/j.jddst.2021.102798
[26]	Viswanathan S, Shi Y, Galipeau J, Krampera M, Leblanc K, Martin I, et al. Mesenchymal stem versus stromal cells: International Society for Cell & Gene Therapy (ISCT?) Mesenchymal Stromal Cell committee position statement on nomenclature. Cytotherapy 2019; 21:1019-24.
[27]	Bianco P, Cao X, Frenette PS, Mao JJ, Robey PG, Simmons PJ, et al. The meaning, the sense and the significance: translating the science of mesenchymal stem cells into medicine. Nat Med 2013; 19:35-42.
[28]	Nejati-Koshki K, Pilehvar-Soltanahmadi Y, Alizadeh E, Ebrahimi- Kalan A, Mortazavi Y, Zarghami N. Development of Emu oil-loaded PCL/collagen bioactive nanofibers for proliferation and stemness preservation of human adipose-derived stem cells: possible application in regenerative medicine. Drug Dev Ind Pharm 2017; 43:1978-88.
[29]	Pourpirali R, Mahmoudnezhad A, Oroojalian F, Zarghami N, Pilehvar Y. Prolonged proliferation and delayed senescence of the adipose-derived stem cells grown on the electrospun composite nanofiber co-encapsulated with TiO2 nanoparticles and metformin-loaded mesoporous silica nanoparticles. Int J Pharm 2021; 604:120733. https://doi.org/10.1016/j.ijpharm.2021.120733 doi: https://doi.org/10.1016/j.ijpharm.2021.120733
[30]	Dadashpour M, Pilehvar-Soltanahmadi Y, Zarghami N, Firouzi- Amandi A, Pourhassan-Moghaddam M, Nouri M. Emerging importance of phytochemicals in regulation of stem cells fate via signaling pathways. Phytother Res 2017; 31:1651-68.
[31]	Pilehvar-Soltanahmadi Y, Nouri M, Martino MM, Fattahi A, Alizadeh E, Darabi M, et al. Cytoprotection, proliferation and epidermal differentiation of adipose tissue-derived stem cells on emu oil based electrospun nanofibrous mat. Exp Cell Res 2017; 357:192-201.
[32]	Deldar Y, Zarghami F, Pilehvar-Soltanahmadi Y, Dadashpour M, Zarghami N. Antioxidant effects of chrysinloaded electrospun nanofibrous mats on proliferation and stemness preservation of human adipose-derived stem cells. Cell Tissue Bank 2017; 18:475-87.
[33]	Moll G, Ankrum JA, Kamhieh-Milz J, Bieback K, Ringdén O, Volk HD, et al. Intravascular mesenchymal stromal/stem cell therapy product diversification: time for new clinical guidelines. Trends Mol Med 2019; 25:149-63.
[34]	Moll G, Ankrum JA, Olson SD, Nolta JA. Improved MSC minimal criteria to maximize patient safety: a call to embrace tissue factor and hemocompatibility assessment of MSC products. Stem Cells Transl Med 2022; 11:2-13.
[35]	Caplan H, Olson SD, Kumar A, George M, Prabhakara KS, Wenzel P, et al. Mesenchymal stromal cell therapeutic delivery: translational challenges to clinical application. Front Immunol 2019; 10:1645. https://doi.org/10.3389/fimmu.2019.01645 doi: https://doi.org/10.3389/fimmu.2019.01645 pmid: 31417542
[36]	Bochinski D, Lin GT, Nunes L, Carrion R, Rahman N, Lin CS, et al. The effect of neural embryonic stemcell therapy in a ratmodel of cavernosal nerve injury. BJU Int 2004; 94:904-9.
[37]	Shan H, Chen F, Zhang T, He S, Xu L, Wei A. Stem cell therapy for erectile dysfunction of cavernous nerve injury rats: a systematic review and meta-analysis. PLoS One 2015; 10:e0121428. https://doi.org/10.1371/journal.pone.0121428 doi: https://doi.org/10.1371/journal.pone.0121428
[38]	Pérez-Aizpurua X, Garranzo-Ibarrola M, Simón-Rodríguez C, García-Cardoso JV, Chávez-Roa C, López-Martín L, et al. Stem cell therapy for erectile dysfunction: a step towards a future treatment. Life 2023; 13:502. https://doi.org/10.3390/life13020502 doi: https://doi.org/10.3390/life13020502
[39]	Hou QL, Ge MY, Zhang CD, Tian DD, Wang LK, Tian HZ, et al. Adipose tissue-derived stem cell therapy for erectile dysfunction in rats: a systematic review and meta-analysis. Int Urol Nephrol 2017; 49:1127-37.
[40]	He L, Yu T, Xiao Y, Huang Y, Guan Y, Zhao F, et al. Co-overexpression of VEGF and Smad 7 improved the therapeutic effects of adipose-derived stem cells on neurogenic erectile dysfunction in the rat model. Andrologia 2022; 54:e14538. https://doi.org/10.1111/and.14538 doi: https://doi.org/10.1111/and.14538
[41]	Zhuang J, Gao P, Chen H, Fang Z, Zheng J, Zhu D, et al. Extracellular vesicles from human urine-derived stem cells merged in hyaluronic acid ameliorate erectile dysfunction in type 2 diabetic rats by glans administration. Andrology 2022; 10:1673-86.
[42]	Bahk JY, Jung JH, Han H, Min SK, Lee YS. Treatment of diabetic impotence with umbilical cord blood stem cell intracavernosal transplant:preliminary report of 7 cases. Exp Clin Transplant 2010; 8:150-60.
[43]	Levy JA, Marchand M, Iorio L, Cassini W, Zahalsky MP. Determining the feasibility of managing erectile dysfunction in humans with placental-derived stem cells. Int J Osteopath Med 2016; 116:e1-5. https://doi.org/10.7556/jaoa.2016.007 doi: https://doi.org/10.7556/jaoa.2016.007
[44]	Yiou R, Hamidou L, Birebent B, Bitari D, Le Corvoisier P, Contremoulins I, et al. Intracavernous injections of bone marrow mononucleated cells for postradical prostatectomy erectile dysfunction: final results of the INSTIN clinical trial. Eur Urol Focus 2017; 3:643-5.
[45]	Yiou R, Hamidou L, Birebent B, Bitari D, Lecorvoisier P, Contremoulins I, et al. Safety of intracavernous bone marrow-mononuclear cells for postradical prostatectomy erectile dysfunction: an open dose-escalation pilot study. Eur Urol 2016; 69:988-91.
[46]	Al Demour S, Jafar H, Adwan S, AlSharif A, Alhawari H, Alrabadi A, et al. Safety and potential therapeutic effect of two intracavernous autologous bone marrow derived mesenchymal stem cells injections in diabetic patients with erectile dysfunction: an open label phase I clinical trial. Urol Int 2018; 101:358-65.
[47]	Haahr MK, Jensen CH, Toyserkani NM, Andersen DC, Damkier P, S?rensen JA, et al. Safety and potential effect of a single intracavernous injection of autologous adiposederived regenerative cells in patients with erectile dysfunction following radical prostatectomy: an open-label phase I clinical trial. EBioMedicine 2016; 5:204-10.
[48]	Protogerou V, Beshari SE, Michalopoulos E, Mallis P, Chrysikos D, Samolis AA, et al. The combined use of stem cells and platelet lysate plasma for the treatment of erectile dysfunction: a pilot studye 6 months results. Medicines 2020; 7:14. https://doi.org/10.3390/medicines7030014 doi: https://doi.org/10.3390/medicines7030014
[49]	Bieri M, Said E, Antonini G, Dickerson D, Tuma J, Bartlett CE, et al. Phase I and registry study of autologous bone marrow concentrate evaluated in PDE 5 inhibitor refractory erectile dysfunction. J Transl Med 2020; 18:24. https://doi.org/10.1186/s12967-019-02195-w doi: https://doi.org/10.1186/s12967-019-02195-w pmid: 31937310
[50]	Haahr MK, Jensen CH, Toyserkani NM, Andersen DC, Damkier P, S?rensen JA, et al. A 12-month follow-up after a single intracavernous injection of autologous adiposederived regenerative cells in patients with erectile dysfunction following radical prostatectomy: an open-label phase I clinical trial. Urology 2018; 121:203.e6-13. https://doi.org/10.1016/j.urology.2018.06.018 doi: https://doi.org/10.1016/j.urology.2018.06.018
[51]	Al Demour S, Adwan S, Jafar H, Rahmeh R, Alhawari H, Awidi A. Safety and efficacy of 2 intracavernous injections of allogeneic Wharton’s jelly-derived mesenchymal stem cells in diabetic patients with erectile dysfunction: phase 1/2 clinical trial. Urol Int 2021; 105:935-43.
[52]	Lin G, Banie L, Ning H, Bella AJ, Lin CS, Lue TF. Potential of adipose-derived stem cells for treatment of erectile dysfunction. J Sex Med 2009; 6:320-7.
[53]	Garber M, Carlos N. Intracavernous administration of adipose stem cells:a new technique of treating erectile dysfunction in diabetic patient, preliminary report of 6 cases. MOJ Cell Sci Rep 2015; 2:00018. https://doi.org/10.15406/mojcsr.2015.02.00018 doi: https://doi.org/10.15406/mojcsr.2015.02.00018
[54]	Protogerou V, Michalopoulos E, Mallis P, Gontika I, Dimou Z, Liakouras C, et al. Administration of adipose derived mesenchymal stem cells and platelet lysate in erectile dysfunction: a single center pilot study. Bioengineering 2019; 6:21. https://doi.org/10.3390/bioengineering6010021 doi: https://doi.org/10.3390/bioengineering6010021
[55]	Fode M, Nadler N, Lund L, Azawi N. Feasibility of minimally invasive, same-day injection of autologous adipose-derived stem cells in the treatment of erectile dysfunction. Scand J Urol 2023; 57:110-4.
[56]	Ory J, Saltzman RG, Blachman-Braun R, Dadoun S, DiFede DL, Premer C, et al. The effect of transendocardial stem cell injection on erectile function in men with cardiomyopathy: results from the TRIDENT, POSEIDON, and TAC-HFT trials. J Sex Med 2020; 17:695-701.
[57]	Zasieda Y. Erectile dysfunction treatment with combination of mesenchymal stem cell derived exosomes and focused low-intensive shock wave therapy. J Mens Health Gend 2020. https://doi.org/10.37321/UJMH.2020.1-2-08 doi: https://doi.org/10.37321/UJMH.2020.1-2-08
[58]	Mirzaei M, Bagherinasabsarab M, Pakmanesh H, Mohammadi R, Teimourian M, Jahani Y, et al. The effect of intracavernosal injection of stem cell in the treatment of erectile dysfunction in diabetic patients: a randomized single-blinded clinical trial. Urol J 2021; 18:675-81.
[59]	Koga S, Horiguchi Y. Efficacy of a cultured conditioned medium of exfoliated deciduous dental pulp stem cells in erectile dysfunction patients. J Cell Mol Med 2022; 26:195-201.
[60]	Daneshmandi L, Shah S, Jafari T, Bhattacharjee M, Momah D, Saveh-Shemshaki N, et al. Emergence of the stem cell secretome in regenerative engineering. Trends Biotechnol 2020; 38:1373-84.
[61]	He X, Zhang C, Amirsaadat S, Jalil AT, Kadhim MM, Abasi M, et al. Curcumin-loaded mesenchymal stem cellederived exosomes efficiently attenuate proliferation and inflammatory response in rheumatoid arthritis fibroblast-like synoviocytes. Appl Biochem Biotechnol 2023; 195:51-67.
[62]	Hu C, Zhao L, Zhang L, Bao Q, Li L. Mesenchymal stem cellbased cell-free strategies: safe and effective treatments for liver injury. Stem Cell Res Ther 2020; 11:377. https://doi.org/10.1186/s13287-020-01895-1 doi: https://doi.org/10.1186/s13287-020-01895-1
[63]	Sun DZ, Abelson B, Babbar P, Damaser MS. Harnessing the mesenchymal stem cell secretome for regenerative urology. Nat Rev Urol 2019; 16:363-75.
[64]	Nasser M, Wu Y, Danaoui Y, Ghosh G. Engineering microenvironments towards harnessing pro-angiogenic potential of mesenchymal stem cells. Mater Sci Eng C Mater Biol Appl 2019; 102:75-84.
[65]	Tran C, Damaser MS. Stem cells as drug delivery methods: application of stem cell secretome for regeneration. Adv Drug Deliv Rev 2015; 82:1-11.
[66]	Song N, Scholtemeijer M, Shah K. Mesenchymal stem cell immunomodulation: mechanisms and therapeutic potential. Trends Pharmacol Sci 2020; 41:653-64.
[67]	Malik S, Malik T. Mesenchymal stem cells lysate as a cell-free therapy: a review. Curr Biotechnol 2021; 10:78-87.
[68]	Zhang Z, Nie P, Yang W, Ma X, Chen Z, Wei H. Lipopolysaccharide- preconditioned allogeneic adipose-derived stem cells improve erectile function in a rat model of bilateral cavernous nerve injury. Basic Clin Androl 2022; 32:5. https://doi.org/10.1186/s12610-022-00156-w doi: https://doi.org/10.1186/s12610-022-00156-w
[69]	Seo H, Choi HJ, Kim OH, Park JH, Hong HE, Kim SJ. The secretome obtained under hypoxic preconditioning from human adipose-derived stem cells exerts promoted antiapoptotic potentials through upregulated autophagic process. Mol Biol Rep 2022; 49:8859-70.
[70]	Takahashi M, Li TS, Suzuki R, Kobayashi T, Ito H, Ikeda Y, et al. Cytokines produced by bone marrow cells can contribute to functional improvement of the infarcted heart by protecting cardiomyocytes from ischemic injury. Am J Physiol Heart Circ Physiol 2006; 291:H886-93. https://doi.org/10.1152/ajpheart.00142.2006 doi: https://doi.org/10.1152/ajpheart.00142.2006
[71]	Li B, Zhang H, Zeng M, He W, Li M, Huang X, et al. Bone marrow mesenchymal stem cells protect alveolar macrophages from lipopolysaccharide-induced apoptosis partially by inhibiting the Wnt/b-catenin pathway. Cell Biol Int 2015; 39:192-200.
[72]	Fall PA, Izikki M, Tu L, Swieb S, Giuliano F, Bernabe J, et al. Apoptosis and effects of intracavernous bone marrow cell injection in a rat model of postprostatectomy erectile dysfunction. Eur Urol 2009; 56:716-26.
[73]	Trost LW, McCaslin R, Linder B, Hellstrom WJ. Long-term outcomes of penile prostheses for the treatment of erectile dysfunction. Expert Rev Med Devices 2013; 10:353-66.
[74]	Albersen M, Fandel TM, Lin G, Wang G, Banie L, Lin CS, et al. Injections of adipose tissue-derived stem cells and stem cell lysate improve recovery of erectile function in a rat model of cavernous nerve injury. J Sex Med 2010; 7:3331-40.
[75]	Sun C, Lin H, Yu W, Li X, Chen Y, Qiu X, et al. Neurotrophic effect of bone marrow mesenchymal stem cells for erectile dysfunction in diabetic rats. Int J Androl 2012; 35:601-7.
[76]	Drago D, Cossetti C, Iraci N, Gaude E, Musco G, Bachi A, et al. The stem cell secretome and its role in brain repair. Biochimie 2013; 95:2271-85.
[77]	Deng K, Lin DL, Hanzlicek B, Balog B, Penn MS, Kiedrowski MJ, et al. Mesenchymal stem cells and their secretome partially restore nerve and urethral function in a dual muscle and nerve injury stress urinary incontinence model. Am J Physiol Renal Physiol 2015; 308:F92-100. https://doi.org/10.1152/ajprenal.00510.2014 doi: https://doi.org/10.1152/ajprenal.00510.2014
[78]	Han Y, Li X, Zhang Y, Han Y, Chang F, Ding J. Mesenchymal stem cells for regenerative medicine. Cells 2019; 8:886. https://doi.org/10.3390/cells8080886 doi: https://doi.org/10.3390/cells8080886
[79]	Zhu Y, Jiang T, Yao C, Zhang J, Sun C, Chen S, et al. Effects of stem cell-derived exosome therapy on erectile dysfunction: a systematic review and meta-analysis of preclinical studies. Sex Med 2023; 11:qfac019. https://doi.org/10.1093/sexmed/qfac019 doi: https://doi.org/10.1093/sexmed/qfac019
[80]	Al-Awsi GRL, Alsaikhan F, Margiana R, Ahmad I, Patra I, Najm MA, et al. Shining the light on mesenchymal stem cell-derived exosomes in breast cancer. Stem Cell Res Ther 2023; 14:21. https://doi.org/10.1186/s13287-023-03245-3 doi: https://doi.org/10.1186/s13287-023-03245-3 pmid: 36750912
[81]	Lai RC, Arslan F, Lee MM, Sze NSK, Choo A, Chen TS, et al. Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury. Stem Cell Res 2010; 4:214-22.
[82]	Zhang Y, Chopp M, Meng Y, Katakowski M, Xin H, Mahmood A, et al. Effect of exosomes derived from multipluripotent mesenchymal stromal cells on functional recovery and neurovascular plasticity in rats after traumatic brain injury. J Neurosurg 2015; 122:856-67.
[83]	Ouyang X, Han X, Chen Z, Fang J, Huang X, Wei H. MSCderived exosomes ameliorate erectile dysfunction by alleviation of corpus cavernosum smooth muscle apoptosis in a rat model of cavernous nerve injury. Stem Cell Res Ther 2018; 9:246. https://doi.org/10.1186/s13287-018-1003-1 doi: https://doi.org/10.1186/s13287-018-1003-1 pmid: 30257719
[84]	Gonzalez-Cadavid NF. Mechanisms of penile fibrosis. J Sex Med 2009; 6(Suppl 3):353-62. https://doi.org/10.1111/j.1743-6109.2008.01195.x doi: https://doi.org/10.1111/j.1743-6109.2008.01195.x
[85]	Mukti AI, Ilyas S, Warli SM, Putra A, Rasyid N, Munir D, et al. Umbilical cord-derived mesenchymal stem cells improve TGF-b, a-SMA and collagen on erectile dysfunction in streptozotocin-induced diabetic rats. Arch Med 2022; 76:4-11.
[86]	Li T, Yan Y, Wang B, Qian H, Zhang X, Shen L, et al. Exosomes derived from human umbilical cord mesenchymal stem cells alleviate liver fibrosis. Stem Cells Dev 2013; 22:845-54.
[87]	Azadzoi KM, Golabek T, Radisavljevic ZM, Yalla SV, Siroky MB. Oxidative stress and neurodegeneration in penile ischaemia. BJU Int 2010; 105:404-10.
[88]	Angulo J, González-Corrochano R, Cuevas P, Fernández A, Fuente JML, Rolo F, et al. Diabetes exacerbates the functional deficiency of NO/cGMP pathway associated with erectile dysfunction in human corpus cavernosum and penile arteries. J Sex Med 2010; 7:758-68.
[89]	Yafi FA, Jenkins L, Albersen M, Corona G, Isidori AM, Goldfarb S, et al. Erectile dysfunction. Nat Rev Dis Primers 2016; 2:16003. https://doi.org/10.1038/nrdp.2016.3 doi: https://doi.org/10.1038/nrdp.2016.3 pmid: 27188339
[90]	Song J, Sun T, Tang Z, Ruan Y, Liu K, Rao K, et al. Exosomes derived from smooth muscle cells ameliorate diabetesinduced erectile dysfunction by inhibiting fibrosis and modulating the NO/cGMP pathway. J Cell Mol Med 2020; 24:13289-302.
[91]	Baglio SR, Rooijers K, Koppers-Lalic D, Verweij FJ, Perez Lanzon M, Zini N, et al. Human bone marrow-and adiposemesenchymal stem cells secrete exosomes enriched in distinctive miRNA and tRNA species. Stem Cell Res Ther 2015; 6:127. https://doi.org/10.1186/s13287-015-0116-z doi: https://doi.org/10.1186/s13287-015-0116-z
[92]	Zhu L, Huang X, Yu W, Chen H, Chen Y, Dai Y. Transplantation of adipose tissue-derived stem cell-derived exosomes ameliorates erectile function in diabetic rats. Andrologia 2018; 50:e12871. https://doi.org/10.1111/and.12871 doi: https://doi.org/10.1111/and.12871
[93]	Wang J, Mi Y, Wu S, You X, Huang Y, Zhu J, et al. Exosomes from adipose-derived stem cells protect against high glucose-induced erectile dysfunction by delivery of corin in a streptozotocin-induced diabetic rat model. Regen Med 2020; 14:227-33.
[94]	Mirotsou M, Jayawardena TM, Schmeckpeper J, Gnecchi M, Dzau VJ. Paracrine mechanisms of stem cell reparative and regenerative actions in the heart. J Mol Cell Cardiol 2011; 50:280-9.
[95]	Liang X, Ding Y, Zhang Y, Tse HF, Lian Q. Paracrine mechanisms of mesenchymal stem cell-based therapy: current status and perspectives. Cell Transplant 2014; 23:1045-59.
[96]	Skalnikova H, Motlik J, Gadher SJ, Kovarova H. Mapping of the secretome of primary isolates of mammalian cells, stem cells and derived cell lines. Proteomics 2011; 11:691-708.
[97]	Kang HJ, Kim HS, Zhang SY, Park KW, Cho HJ, Koo BK, et al. Effects of intracoronary infusion of peripheral blood stemcells mobilised with granulocyte-colony stimulating factor on left ventricular systolic function and restenosis after coronary stenting in myocardial infarction: the MAGIC cell randomised clinical trial. Lancet 2004; 363:751-6.
[98]	Beohar N, Rapp J, Pandya S, Losordo DW. Rebuilding the damaged heart: the potential of cytokines and growth factors in the treatment of ischemic heart disease. J Am Coll Cardiol 2010; 56:1287-97.
[99]	Martínez-Castellanos MA, Schwartz S, Hernández-Rojas ML, Kon-Jara VA, García-Aguirre G, Guerrero-Naranjo JL, et al. Long-term effect of antiangiogenic therapy for retinopathy of prematurity up to 5 years of follow-up. Retina 2013; 33:329-38.
[100]	You D, Jang MJ, Song G, Shin HC, Suh N, Kim YM, et al. Safety of autologous bone marrow-derived mesenchymal stem cells in erectile dysfunction: an open-label phase 1 clinical trial. Cytotherapy 2021; 23:931-8.
[101]	Ichim TE, Warbington T, Cristea O, Chin JL, Patel AN. Intracavernous administration of bone marrow mononuclear cells: a new method of treating erectile dysfunction? J Transl Med 2013; 11:139. https://doi.org/10.1186/1479-5876-11-139 doi: https://doi.org/10.1186/1479-5876-11-139 pmid: 23758954
[102]	Chen F, Zhang H, Wang Z, Ding W, Zeng Q, Liu W, et al. Adipose-derived stem cell-derived exosomes ameliorate erectile dysfunction in a rat model of type 2 diabetes. J Sex Med 2017; 14:1084-94.
[103]	Liang L, Zheng D, Lu C, Xi Q, Bao H, Li W, et al. Exosomes derived from miR-301a-3p-overexpressing adipose-derived mesenchymal stem cells reverse hypoxia-induced erectile dysfunction in rat models. Stem Cell Res Ther 2021; 12:87. https://doi.org/10.1186/s13287-021-02161-8 doi: https://doi.org/10.1186/s13287-021-02161-8
[104]	Li M, Lei H, Xu Y, Li H, Yang B, Yu C, et al. Exosomes derived from mesenchymal stem cells exert therapeutic effect in a rat model of cavernous nerves injury. Andrology 2018; 6:927-35.
[105]	Liu Y, Zhao S, Luo L, Wang J, Zhu Z, Xiang Q, et al. Mesenchymal stem cell-derived exosomes ameliorate erection by reducing oxidative stress damage of corpus cavernosum in a rat model of artery injury. J Cell Mol Med 2019; 23:7462-73.
[106]	Liang L, Shen Y, Dong Z, Gu X. Photoacoustic image-guided corpus cavernosum intratunical injection of adipose stem cell-derived exosomes loaded polydopamine thermosensitive hydrogel for erectile dysfunction treatment. Bioact Mater 2022; 9:147-56.
[107]	Yang Q, Chen W, Han D, Zhang C, Xie Y, Sun X, et al. Intratunical injection of human urine-derived stem cells derived exosomes prevents fibrosis and improves erectile function in a rat model of Peyronie’s disease. Andrologia 2020; 52:e13831. https://doi.org/10.1111/and.13831 doi: https://doi.org/10.1111/and.13831
[108]	Ouyang B, Xie Y, Zhang C, Deng C, Lv L, Yao J, et al. Extracellular vesicles from human urine-derived stem cells ameliorate erectile dysfunction in a diabetic rat model by delivering proangiogenic microRNA. Sex Med 2019; 7:241-50.