Extracellular Vesicles From Human Urine-Derived Stem Cells Ameliorate Erectile Dysfunction in a Diabetic Rat Model by Delivering Proangiogenic MicroRNA

Overview

Journal Sex Med

Publisher Oxford University Press

Date 2019 Mar 27

PMID 30910509

Citations 35

Authors

Bin Ouyang

Yun Xie

Chi Zhang

Cuncan Deng

LinYan Lv

Jiahui Yao

Yuanyuan Zhang

Guihua Liu

Junhong Deng

Chunhua Deng

Affiliations

Soon will be listed here.

Abstract

Introduction: Stem cell therapies represent a promising new frontier for the treatment of refractory diabetic erectile dysfunction (DED). The use of stem cell-derived extracellular vesicles (EVs) is a novel strategy for cell-free stem cell therapy. We have reported that urine-derived stem cells (USCs) can improve DED; however, the therapeutic effects of EVs secreted by USCs (USC-EVs) remain unknown.

Aim: To determine the therapeutic effects of USC-EVs on DED in a rat model.

Methods: USC-EVs were isolated from conditioned medium by ultracentrifugation. DED was induced in male Sprague-Dawley rats via an intraperitoneal injection of streptozotocin. Sixteen DED rats were divided into phosphate-buffered saline (PBS) and USC-EV groups. Eight normal rats served as the normal control group. PBS or USC-EVs were transplanted into the corpora cavernosa in the corresponding groups.

Main Outcome Measure: Intracavernosal pressure (ICP), mean arterial pressure (MAP), expression of endothelial markers (CD31), endothelial nitric oxide synthase (eNOS), phospho-eNOS, and neural nitric oxide synthase (nNOS) were assessed in each group. Masson's trichrome staining was used to determine the collagen deposition and ratio of smooth muscle cells to collagen. The microRNA (miRNA) cargo of USC-EVs was characterized by high-throughput RNA sequencing.

Results: Recovery of erectile function was observed in the USC-EV group, as represented by improved ICP and ICP/MAP ratio. CD31, eNOS, phospho-eNOS, and nNOS expression in the penis was significantly improved in the USC-EV group. In addition, the ratio of smooth muscle to collagen was significantly increased in the USC-EV group. RNA sequencing revealed that USC-EVs were enriched for distinct classes of miRNA (miR-21-5p, let-7 family, miR-10 family, miR-30 family, and miR-148a-3p) that promote angiogenesis.

Conclusion: USC-EV transplantation can ameliorate DED in rats. Its mechanism may involve the delivery of proangiogenic miRNA. Ouyang B, Xie Y, Zhang C, 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;7:241-250.

Citing Articles

Using Network Pharmacology and in vivo Experiments to Uncover the Mechanisms of Radix Paeoniae Rubra and Radix Angelicae Sinensis Granules in Treating Diabetes Mellitus-Induced Erectile Dysfunction.

Wang J, Guo Y, Huang J, Yan J, Ma J Drug Des Devel Ther. 2024; 18:6243-6262.

PMID: 39735336 PMC: 11682668. DOI: 10.2147/DDDT.S493198.

Stem cell assisted low-intensity shockwave for erectile dysfunction treatment: Current perspective.

Daneshwar D, Lee Y, Nordin A Regen Ther. 2024; 26:1150-1158.

PMID: 39640922 PMC: 11617694. DOI: 10.1016/j.reth.2024.11.006.

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

Chakra M, Bailly H, Klampke F, Boaz J, Jida M, Abou Yassine A Asian J Urol. 2024; 11(4):530-544.

PMID: 39534008 PMC: 11551375. DOI: 10.1016/j.ajur.2023.07.005.

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

Margiana R, Pilehvar Y, Amalia F, Lestari S, Supardi S, Itishom R Asian J Urol. 2024; 11(3):391-405.

PMID: 39139521 PMC: 11318444. DOI: 10.1016/j.ajur.2024.02.003.

Investigating the consistency of extracellular vesicle production from breast cancer subtypes using CELLine adherent bioreactors.

Hisey C, Artuyants A, Guo G, Chang V, Reshef G, Middleditch M J Extracell Biol. 2024; 1(9):e60.

PMID: 38938775 PMC: 11080891. DOI: 10.1002/jex2.60.

References

Vakalopoulos I, Memmos D, Mykoniatis I, Toutziaris C, Dimitriadis G . Stem cell therapy in erectile dysfunction: science fiction or realistic treatment option?. Hormones (Athens). 2018; 17(3):315-320. DOI: 10.1007/s42000-018-0050-4. View

Ge H, Shrestha A, Liu C, Wu P, Cheng B . MicroRNA 148a-3p promotes Thrombospondin-4 expression and enhances angiogenesis during tendinopathy development by inhibiting Krüppel-like factor 6. Biochem Biophys Res Commun. 2018; 502(2):276-282. DOI: 10.1016/j.bbrc.2018.05.167. View

Ouyang B, Sun X, Han D, Chen S, Yao B, Gao Y . Human urine-derived stem cells alone or genetically-modified with FGF2 Improve type 2 diabetic erectile dysfunction in a rat model. PLoS One. 2014; 9(3):e92825. PMC: 3963968. DOI: 10.1371/journal.pone.0092825. View

Jiang Z, Liu Y, Niu X, Yin J, Hu B, Guo S . Exosomes secreted by human urine-derived stem cells could prevent kidney complications from type I diabetes in rats. Stem Cell Res Ther. 2016; 7:24. PMC: 4744390. DOI: 10.1186/s13287-016-0287-2. View

Wang X, Ling C, Li L, Qin Y, Qi J, Liu X . MicroRNA-10a/10b represses a novel target gene mib1 to regulate angiogenesis. Cardiovasc Res. 2016; 110(1):140-50. DOI: 10.1093/cvr/cvw023. View

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. 2017; 50(2). DOI: 10.1111/and.12871. View

Giugliano F, Maiorino M, Bellastella G, Gicchino M, Giugliano D, Esposito K . Determinants of erectile dysfunction in type 2 diabetes. Int J Impot Res. 2010; 22(3):204-9. DOI: 10.1038/ijir.2010.1. View

Kukreja R, Xi L . eNOS phosphorylation: a pivotal molecular switch in vasodilation and cardioprotection?. J Mol Cell Cardiol. 2006; 42(2):280-2. PMC: 3031790. DOI: 10.1016/j.yjmcc.2006.10.011. View

Sun X, Luo L, Feng L, Li D, Zhong K . B Cell Lymphoma-2-Modified Bone Marrow-Derived Mesenchymal Stem Cells Transplantation for the Treatment of Diabetes Mellitus-Induced Erectile Dysfunction in a Rat Model. Urol Int. 2016; 98(3):358-366. DOI: 10.1159/000452253. View

10.

Eulalio A, Huntzinger E, Izaurralde E . Getting to the root of miRNA-mediated gene silencing. Cell. 2008; 132(1):9-14. DOI: 10.1016/j.cell.2007.12.024. View

11.

Holman R, Paul S, Bethel M, Matthews D, Neil H . 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008; 359(15):1577-89. DOI: 10.1056/NEJMoa0806470. View

12.

Musicki B, Burnett A . Endothelial dysfunction in diabetic erectile dysfunction. Int J Impot Res. 2006; 19(2):129-38. DOI: 10.1038/sj.ijir.3901494. View

13.

Wu S, Yu W, Qu X, Wang R, Xu J, Zhang Q . Argonaute 2 promotes myeloma angiogenesis via microRNA dysregulation. J Hematol Oncol. 2014; 7:40. PMC: 4108130. DOI: 10.1186/1756-8722-7-40. View

14.

Yang Q, Chen X, Zheng T, Han D, Zhang H, Shi Y . Transplantation of Human Urine-Derived Stem Cells Transfected with Pigment Epithelium-Derived Factor to Protect Erectile Function in a Rat Model of Cavernous Nerve Injury. Cell Transplant. 2016; 25(11):1987-2001. DOI: 10.3727/096368916X691448. View

15.

Watson D, Bayik D, Srivatsan A, Bergamaschi C, Valentin A, Niu G . Efficient production and enhanced tumor delivery of engineered extracellular vesicles. Biomaterials. 2016; 105:195-205. PMC: 7156278. DOI: 10.1016/j.biomaterials.2016.07.003. View

16.

Chen X, Yang Q, Zheng T, Bian J, Sun X, Shi Y . Neurotrophic Effect of Adipose Tissue-Derived Stem Cells on Erectile Function Recovery by Pigment Epithelium-Derived Factor Secretion in a Rat Model of Cavernous Nerve Injury. Stem Cells Int. 2016; 2016:5161248. PMC: 4691496. DOI: 10.1155/2016/5161248. View

17.

Al Demour S, Jafar H, Adwan S, Alsharif A, Alhawari H, Alrabadi A . 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(3):358-365. DOI: 10.1159/000492120. View

18.

Zhang Y, McNeill E, Tian H, Soker S, Andersson K, Yoo J . Urine derived cells are a potential source for urological tissue reconstruction. J Urol. 2008; 180(5):2226-33. DOI: 10.1016/j.juro.2008.07.023. View

19.

Alwaal A, Zaid U, Lin C, Lue T . Stem cell treatment of erectile dysfunction. Adv Drug Deliv Rev. 2014; 82-83:137-44. DOI: 10.1016/j.addr.2014.11.012. View

20.

Liu G, Sun X, Bian J, Wu R, Guan X, Ouyang B . Correction of diabetic erectile dysfunction with adipose derived stem cells modified with the vascular endothelial growth factor gene in a rodent diabetic model. PLoS One. 2013; 8(8):e72790. PMC: 3758339. DOI: 10.1371/journal.pone.0072790. View