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Mesenchymal stem cell-based gene therapy for erectile dysfunction

International Journal of Impotence Research volume 28, pages 81–87 (2016)Cite this article

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Abstract

Despite the overwhelming success of PDE5 inhibitor (PDE5I), the demand for novel pharmacotherapeutic and surgical options for ED continues to rise owing to the increased proportion of elderly individuals in the population, in addition to the growing percentage of ED patients who do not respond to PDE5I. Surgical treatment of ED is associated with many complications, thus warranting the need for nonsurgical therapies. Moreover, none of the above-mentioned treatments essentially corrects, cures or prevents ED. Although gene therapy is a promising option, many challenges and obstacles such as local inflammatory response and random transgene expression, in addition to other safety issues, limit its use at the clinical level. The use of stem cell therapy alone also has many shortcomings. To overcome these inadequacies, many scientists and clinicians are investigating new gene and stem cell therapies.

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References

  1. Giuliano F, Rampin O . Neural control of erection. Physiol Behav 2004; 83: 189–201.

    Article  CAS  PubMed  Google Scholar 

  2. Vicari E, La Vignera S, Condorelli R, Calogero AE . Endothelial antioxidant administration ameliorates the erectile response to PDE5 regardless of the extension of the atherosclerotic process. J Sex Med 2010; 7: 1247–1253.

    Article  CAS  PubMed  Google Scholar 

  3. Condorelli RA, Calogero AE, Vicari E, Favilla V, Morgia G, Cimino S et al. Vascular regenerative therapies for the treatment of erectile dysfunction: current approaches. Andrology 2013; 1: 533–540.

    Article  CAS  PubMed  Google Scholar 

  4. Alwaal A, Zaid UB, Lin CS, Lue TF . Stem cell treatment of erectile dysfunction. Adv Drug Deliv Rev 2015; 82-83: 137–144.

    Article  CAS  PubMed  Google Scholar 

  5. Gur S, Kadowitz PJ, Gokce A, Sikka SC, Lokman U, Hellstrom WJ . Update on drug interactions with phosphodiesterase-5 inhibitors prescribed as first-line therapy for patients with erectile dysfunction or pulmonary hypertension. Curr Drug Metab 2013; 14: 265–269.

    CAS  PubMed  Google Scholar 

  6. McCullough AR, Barada JH, Fawzy A, Guay AT, Hatzichristou D . Achieving treatment optimization with sildenafil citrate (Viagra) in patients with erectile dysfunction. Urology 2002; 60: 28–38.

    Article  PubMed  Google Scholar 

  7. Deng W, Bivalacqua TJ, Hellstrom WJ, Kadowitz PJ . Gene and stem cell therapy for erectile dysfunction. Int J Impot Res 2005; 17: S57–S63.

    Article  CAS  PubMed  Google Scholar 

  8. Bivalacqua TJ, Deng W, Champion HC, Hellstrom WJ, Kadowitz PJ . Gene therapy techniques for the delivery of endothelial nitric oxide synthase to the corpora cavernosa for erectile dysfunction. Methods Mol Biol 2004; 279: 173–185.

    CAS  PubMed  Google Scholar 

  9. Deng W, Bivalacqua TJ, Chattergoon NN, Hyman AL, Jeter JR Jr., Kadowitz PJ . Adenoviral gene transfer of eNOS: high-level expression in ex vivo expanded marrow stromal cells. Am J Physiol Cell Physiol 2003; 285: C1322–C1329.

    Article  CAS  PubMed  Google Scholar 

  10. Deng W, Bivalacqua TJ, Chattergoon NN, Jeter JR Jr., Kadowitz PJ . Engineering ex vivo-expanded marrow stromal cells to secrete calcitonin gene-related peptide using adenoviral vector. Stem Cells 2004; 22: 1279–1291.

    Article  CAS  PubMed  Google Scholar 

  11. Garcia MM, Fandel TM, Lin G, Shindel AW, Banie L, Lin CS et al. Treatment of erectile dysfunction in the obese type 2 diabetic ZDF rat with adipose tissue-derived stem cells. J Sex Med 2010; 7: 89–98.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Huang YC, Ning H, Shindel AW, Fandel TM, Lin G, Harraz AM et al. The effect of intracavernous injection of adipose tissue-derived stem cells on hyperlipidemia-associated erectile dysfunction in a rat model. J Sex Med 2010; 7: 1391–1400.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. 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: 3331–3340.

    Article  PubMed  Google Scholar 

  14. 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: 320–327.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 2006; 8: 315–317.

    Article  CAS  PubMed  Google Scholar 

  16. Ankrum J, Karp JM . Mesenchymal stem cell therapy: two steps forward, one step back. Trends Mol Med 2010; 16: 203–209.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Prockop DJ, Oh JY . Medical therapies with adult stem/progenitor cells (MSCs): a backward journey from dramatic results in vivo to the cellular and molecular explanations. J Cell Biochem 2012; 113: 1460–1469.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Le Blanc K, Tammik C, Rosendahl K, Zetterberg E, Ringden O . HLA expression and immunologic properties of differentiated and undifferentiated mesenchymal stem cells. Exp Hematol 2003; 31: 890–896.

    Article  CAS  PubMed  Google Scholar 

  19. Qiu X, Lin H, Wang Y, Yu W, Chen Y, Wang R et al. Intracavernous transplantation of bone marrow-derived mesenchymal stem cells restores erectile function of streptozocin-induced diabetic rats. J Sex Med 2011; 8: 427–436.

    Article  PubMed  Google Scholar 

  20. Iyer SS, Rojas M . Anti-inflammatory effects of mesenchymal stem cells: novel concept for future therapies. Expert Opin Biol Ther 2008; 8: 569–581.

    Article  CAS  PubMed  Google Scholar 

  21. Mias C, Lairez O, Trouche E, Roncalli J, Calise D, Seguelas MH et al. Mesenchymal stem cells promote matrix metalloproteinase secretion by cardiac fibroblasts and reduce cardiac ventricular fibrosis after myocardial infarction. Stem Cells 2009; 27: 2734–2743.

    Article  CAS  PubMed  Google Scholar 

  22. Magnasco A, Corselli M, Bertelli R, Ibatici A, Peresi M, Gaggero G et al. Mesenchymal stem cells protective effect in adriamycin model of nephropathy. Cell Transplant 2008; 17: 1157–1167.

    Article  PubMed  Google Scholar 

  23. Segers VF, Van Riet I, Andries LJ, Lemmens K, Demolder MJ, De Becker AJ et al. Mesenchymal stem cell adhesion to cardiac microvascular endothelium: activators and mechanisms. Am J Physiol Heart Circ Physiol 2006; 290: H1370–H1377.

    Article  CAS  PubMed  Google Scholar 

  24. Tang YL, Zhao Q, Zhang YC, Cheng L, Liu M, Shi J et al. Autologous mesenchymal stem cell transplantation induce VEGF and neovascularization in ischemic myocardium. Regul Pept 2004; 117: 3–10.

    Article  CAS  PubMed  Google Scholar 

  25. Lin CS, Xin Z, Dai J, Huang YC, Lue TF . Stem-cell therapy for erectile dysfunction. Expert Opin Biol Ther 2013; 13: 1585–1597.

    Article  CAS  PubMed  Google Scholar 

  26. Lin CS, Xin ZC, Dai J, Lue TF . Commonly used mesenchymal stem cell markers and tracking labels: Limitations and challenges. Histol Histopathol 2013; 28: 1109–1116.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Zhang H, Ning H, Banie L, Wang G, Lin G, Lue TF et al. Adipose tissue-derived stem cells secrete CXCL5 cytokine with chemoattractant and angiogenic properties. Biochem Biophys Res Commun 2010; 402: 560–564.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Zhang H, Yang R, Wang Z, Lin G, Lue TF, Lin CS . Adipose tissue-derived stem cells secrete CXCL5 cytokine with neurotrophic effects on cavernous nerve regeneration. J Sex Med 2011; 8: 437–446.

    Article  CAS  PubMed  Google Scholar 

  29. Hurt KJ, Musicki B, Palese MA, Crone JK, Becker RE, Moriarity JL et al. Akt-dependent phosphorylation of endothelial nitric-oxide synthase mediates penile erection. Proc Natl Acad Sci USA 2002; 99: 4061–4066.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Burnett AL, Lowenstein CJ, Bredt DS, Chang TS, Snyder SH . Nitric oxide: a physiologic mediator of penile erection. Science 1992; 257: 401–403.

    Article  CAS  PubMed  Google Scholar 

  31. Rajfer J, Aronson WJ, Bush PA, Dorey FJ, Ignarro LJ . Nitric oxide as a mediator of relaxation of the corpus cavernosum in response to nonadrenergic, noncholinergic neurotransmission. N Engl J Med 1992; 326: 90–94.

    Article  CAS  PubMed  Google Scholar 

  32. Bivalacqua TJ, Usta MF, Champion HC, Kadowitz PJ, Hellstrom WJ . Endothelial dysfunction in erectile dysfunction: role of the endothelium in erectile physiology and disease. J Androl 2003; 24: S17–S37.

    Article  CAS  PubMed  Google Scholar 

  33. Azadzoi KM, Schulman RN, Aviram M, Siroky MB . Oxidative stress in arteriogenic erectile dysfunction: prophylactic role of antioxidants. J Urol 2005; 174: 386–393.

    Article  CAS  PubMed  Google Scholar 

  34. Bivalacqua TJ, Armstrong JS, Biggerstaff J, Abdel-Mageed AB, Kadowitz PJ, Hellstrom WJ et al. Gene transfer of extracellular SOD to the penis reduces O2-* and improves erectile function in aged rats. Am J Physiol Heart Circ Physiol 2003; 284: H1408–H1421.

    Article  CAS  PubMed  Google Scholar 

  35. Bivalacqua TJ, Usta MF, Kendirci M, Pradhan L, Alvarez X, Champion HC et al. Superoxide anion production in the rat penis impairs erectile function in diabetes: influence of in vivo extracellular superoxide dismutase gene therapy. J Sex Med 2005; 2: 187–197.

    Article  CAS  PubMed  Google Scholar 

  36. Silva GV, Litovsky S, Assad JA, Sousa AL, Martin BJ, Vela D et al. Mesenchymal stem cells differentiate into an endothelial phenotype, enhance vascular density, and improve heart function in a canine chronic ischemia model. Circulation 2005; 111: 150–156.

    Article  CAS  PubMed  Google Scholar 

  37. Bivalacqua TJ, Deng W, Kendirci M, Usta MF, Robinson C, Taylor BK et al. Mesenchymal stem cells alone or ex vivo gene modified with endothelial nitric oxide synthase reverse age-associated erectile dysfunction. Am J Physiol Heart Circ Physiol 2007; 292: H1278–H1290.

    Article  CAS  PubMed  Google Scholar 

  38. El-Sakka AI, Lin CS, Chui RM, Dahiya R, Lue TF . Effects of diabetes on nitric oxide synthase and growth factor genes and protein expression in an animal model. Int J Impot Res 1999; 11: 123–132.

    Article  CAS  PubMed  Google Scholar 

  39. Lue TF, Lee KL . Pharmacotherapy for erectile dysfunction. Chin Med J (Engl) 2000; 113: 291–298.

    CAS  Google Scholar 

  40. Kinnaird T, Stabile E, Burnett MS, Shou M, Lee CW, Barr S et al. Local delivery of marrow-derived stromal cells augments collateral perfusion through paracrine mechanisms. Circulation 2004; 109: 1543–1549.

    Article  CAS  PubMed  Google Scholar 

  41. Strong TD, Gebska MA, Burnett AL, Champion HC, Bivalacqua TJ . Endothelium-specific gene and stem cell-based therapy for erectile dysfunction. Asian J Androl 2008; 10: 14–22.

    Article  CAS  PubMed  Google Scholar 

  42. Jesmin S, Sakuma I, Salah-Eldin A, Nonomura K, Hattori Y, Kitabatake A . Diminished penile expression of vascular endothelial growth factor and its receptors at the insulin-resistant stage of a type II diabetic rat model: a possible cause for erectile dysfunction in diabetes. J Mol Endocrinol 2003; 31: 401–418.

    Article  CAS  PubMed  Google Scholar 

  43. Liu G, Sun X, Dai Y, Zheng F, Wang D, Huang Y et al. Chronic administration of sildenafil modified the impaired VEGF system and improved the erectile function in rats with diabetic erectile dysfunction. J Sex Med 2010; 7: 3868–3878.

    Article  CAS  PubMed  Google Scholar 

  44. Burchardt M, Burchardt T, Chen MW, Shabsigh A, de la Taille A, Buttyan R et al. Expression of messenger ribonucleic acid splice variants for vascular endothelial growth factor in the penis of adult rats and humans. Biol Reprod 1999; 60: 398–404.

    Article  CAS  PubMed  Google Scholar 

  45. Ferrara N, Gerber HP, LeCouter J . The biology of VEGF and its receptors. Nat Med 2003; 9: 669–676.

    Article  CAS  PubMed  Google Scholar 

  46. Pons J, Huang Y, Arakawa-Hoyt J, Washko D, Takagawa J, Ye J et al. VEGF improves survival of mesenchymal stem cells in infarcted hearts. Biochem Biophys Res Commun 2008; 376: 419–422.

    Article  CAS  PubMed  Google Scholar 

  47. Rogers RS, Graziottin TM, Lin CS, Kan YW, Lue TF . Intracavernosal vascular endothelial growth factor (VEGF) injection and adeno-associated virus-mediated VEGF gene therapy prevent and reverse venogenic erectile dysfunction in rats. Int J Impot Res 2003; 15: 26–37.

    Article  CAS  PubMed  Google Scholar 

  48. Gholami SS, Rogers R, Chang J, Ho HC, Grazziottin T, Lin CS et al. The effect of vascular endothelial growth factor and adeno-associated virus mediated brain derived neurotrophic factor on neurogenic and vasculogenic erectile dysfunction induced by hyperlipidemia. J Urol 2003; 169: 1577–1581.

    Article  CAS  PubMed  Google Scholar 

  49. Yamanaka M, Shirai M, Shiina H, Tanaka Y, Enokida H, Tsujimura A et al. Vascular endothelial growth factor restores erectile function through inhibition of apoptosis in diabetic rat penile crura. J Urol 2005; 173: 318–323.

    Article  CAS  PubMed  Google Scholar 

  50. Lin CS, Ho HC, Chen KC, Lin G, Nunes L, Lue TF . Intracavernosal injection of vascular endothelial growth factor induces nitric oxide synthase isoforms. BJU Int 2002; 89: 955–960.

    Article  CAS  PubMed  Google Scholar 

  51. Ryu JK, Kim WJ, Koh YJ, Piao S, Jin HR, Lee SW et al. Designed angiopoietin-1 variant, COMP-angiopoietin-1, rescues erectile function through healthy cavernous angiogenesis in a hypercholesterolemic mouse. Sci Rep 2015; 5: 9222.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Kendirci M, Gur S, Sikka SC . Gene therapy for erectile dysfunction. Front Biosci 2005; 10: 2758–2769.

    Article  CAS  PubMed  Google Scholar 

  53. Ouyang B, Sun X, Han D, Chen S, Yao B, Gao Y et al. 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: e92825.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Green PJ, Walsh FS, Doherty P . Promiscuity of fibroblast growth factor receptors. Bioessays 1996; 18: 639–646.

    Article  CAS  PubMed  Google Scholar 

  55. Vlodavsky I, Korner G, Ishai-Michaeli R, Bashkin P, Bar-Shavit R, Fuks Z . Extracellular matrix-resident growth factors and enzymes: possible involvement in tumor metastasis and angiogenesis. Cancer Metastasis Rev 1990; 9: 203–226.

    Article  CAS  PubMed  Google Scholar 

  56. Bahramsoltani M, De Spiegelaere W, Janczyk P, Hiebl B, Cornillie P, Plendl J . Quantitation of angiogenesis in vitro induced by VEGF-A and FGF-2 in two different human endothelial cultures - an all-in-one assay. Clin Hemorheol Microcirc 2010; 46: 189–202.

    Article  PubMed  CAS  Google Scholar 

  57. Masaki I, Yonemitsu Y, Yamashita A, Sata S, Tanii M, Komori K et al. Angiogenic gene therapy for experimental critical limb ischemia: acceleration of limb loss by overexpression of vascular endothelial growth factor 165 but not of fibroblast growth factor-2. Circ Res 2002; 90: 966–973.

    Article  CAS  PubMed  Google Scholar 

  58. Cao R, Brakenhielm E, Pawliuk R, Wariaro D, Post MJ, Wahlberg E et al. Angiogenic synergism, vascular stability and improvement of hind-limb ischemia by a combination of PDGF-BB and FGF-2. Nat Med 2003; 9: 604–613.

    Article  CAS  PubMed  Google Scholar 

  59. Asplin IR, Wu SM, Mathew S, Bhattacharjee G, Pizzo SV . Differential regulation of the fibroblast growth factor (FGF) family by alpha(2)-macroglobulin: evidence for selective modulation of FGF-2-induced angiogenesis. Blood 2001; 97: 3450–3457.

    Article  CAS  PubMed  Google Scholar 

  60. Szebenyi G, Fallon JF . Fibroblast growth factors as multifunctional signaling factors. Int Rev Cytol 1999; 185: 45–106.

    Article  CAS  PubMed  Google Scholar 

  61. Ning H, Liu G, Lin G, Yang R, Lue TF, Lin CS . Fibroblast growth factor 2 promotes endothelial differentiation of adipose tissue-derived stem cells. J Sex Med 2009; 6: 967–979.

    Article  CAS  PubMed  Google Scholar 

  62. Bakircioglu ME, Lin CS, Fan P, Sievert KD, Kan YW, Lue TF . The effect of adeno-associated virus mediated brain derived neurotrophic factor in an animal model of neurogenic impotence. J Urol 2001; 165: 2103–2109.

    Article  CAS  PubMed  Google Scholar 

  63. Bella AJ, Lin G, Tantiwongse K, Garcia M, Lin CS, Brant W et al. Brain-derived neurotrophic factor (BDNF) acts primarily via the JAK/STAT pathway to promote neurite growth in the major pelvic ganglion of the rat: part I. J Sex Med 2006; 3: 815–820.

    Article  CAS  PubMed  Google Scholar 

  64. Lin G, Bella AJ, Lue TF, Lin CS . Brain-derived neurotrophic factor (BDNF) acts primarily via the JAK/STAT pathway to promote neurite growth in the major pelvic ganglion of the rat: part 2. J Sex Med 2006; 3: 821–827; discussion 8-9.

    Article  CAS  PubMed  Google Scholar 

  65. Bochinski D, Lin GT, Nunes L, Carrion R, Rahman N, Lin CS et al. The effect of neural embryonic stem cell therapy in a rat model of cavernosal nerve injury. BJU Int 2004; 94: 904–909.

    Article  PubMed  Google Scholar 

  66. Kim SJ, Choi SW, Hur KJ, Park SH, Sung YC, Ha YS et al. Synergistic effect of mesenchymal stem cells infected with recombinant adenovirus expressing human BDNF on erectile function in a rat model of cavernous nerve injury. Korean J Urol 2012; 53: 726–732.

    Article  PubMed  PubMed Central  Google Scholar 

  67. Cartledge JJ, Eardley I, Morrison JF . Nitric oxide-mediated corpus cavernosal smooth muscle relaxation is impaired in ageing and diabetes. BJU Int 2001; 87: 394–401.

    Article  CAS  PubMed  Google Scholar 

  68. Garban H, Vernet D, Freedman A, Rajfer J, Gonzalez-Cadavid N . Effect of aging on nitric oxide-mediated penile erection in rats. Am J Physiol 1995; 268: H467–H475.

    CAS  PubMed  Google Scholar 

  69. Bivalacqua TJ, Champion HC, Mehta YS, Abdel-Mageed AB, Sikka SC, Ignarro LJ et al. Adenoviral gene transfer of endothelial nitric oxide synthase (eNOS) to the penis improves age-related erectile dysfunction in the rat. Int J Impot Res 2000; 12: S8–S17.

    Article  PubMed  Google Scholar 

  70. Champion HC, Bivalacqua TJ, D'Souza FM, Ortiz LA, Jeter JR, Toyoda K et al. Gene transfer of endothelial nitric oxide synthase to the lung of the mouse in vivo. Effect on agonist-induced and flow-mediated vascular responses. Circ Res 1999; 84: 1422–1432.

    Article  CAS  PubMed  Google Scholar 

  71. Ryu JK, Cho CH, Shin HY, Song SU, Oh SM, Lee M et al. Combined angiopoietin-1 and vascular endothelial growth factor gene transfer restores cavernous angiogenesis and erectile function in a rat model of hypercholesterolemia. Mol Ther 2006; 13: 705–715.

    Article  CAS  PubMed  Google Scholar 

  72. Qiu X, Sun C, Yu W, Lin H, Sun Z, Chen Y et al. Combined strategy of mesenchymal stem cell injection with vascular endothelial growth factor gene therapy for the treatment of diabetes-associated erectile dysfunction. J Androl 2012; 33: 37–44.

    Article  CAS  PubMed  Google Scholar 

  73. Gou X, He WY, Xiao MZ, Qiu M, Wang M, Deng YZ et al. Transplantation of endothelial progenitor cells transfected with VEGF165 to restore erectile function in diabetic rats. Asian J Androl 2011; 13: 332–338.

    Article  CAS  PubMed  Google Scholar 

  74. Qiu X, Villalta J, Ferretti L, Fandel TM, Albersen M, Lin G et al. Effects of intravenous injection of adipose-derived stem cells in a rat model of radiation therapy-induced erectile dysfunction. J Sex Med 2012; 9: 1834–1841.

    Article  PubMed  PubMed Central  Google Scholar 

  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: 601–607.

    Article  CAS  PubMed  Google Scholar 

  76. Mangir N, Akbal C, Tarcan T, Simsek F, Turkeri L . Mesenchymal stem cell therapy in treatment of erectile dysfunction: Autologous or allogeneic cell sources? Int J Urol 2014; 21: 1280–1285.

    Article  PubMed  Google Scholar 

  77. Kendirci M, Trost L, Bakondi B, Whitney MJ, Hellstrom WJ, Spees JL . Transplantation of nonhematopoietic adult bone marrow stem/progenitor cells isolated by p75 nerve growth factor receptor into the penis rescues erectile function in a rat model of cavernous nerve injury. J Urol 2010; 184: 1560–1566.

    Article  PubMed  PubMed Central  Google Scholar 

  78. Qiu X, Fandel TM, Ferretti L, Albersen M, Orabi H, Zhang H et al. Both immediate and delayed intracavernous injection of autologous adipose-derived stromal vascular fraction enhances recovery of erectile function in a rat model of cavernous nerve injury. Eur Urol 2012; 62: 720–727.

    Article  PubMed  PubMed Central  Google Scholar 

  79. Fandel TM, Albersen M, Lin G, Qiu X, Ning H, Banie L et al. Recruitment of intracavernously injected adipose-derived stem cells to the major pelvic ganglion improves erectile function in a rat model of cavernous nerve injury. Eur Urol 2012; 61: 201–210.

    Article  PubMed  Google Scholar 

  80. Jeong HH, Piao S, Ha JN, Kim IG, Oh SH, Lee JH et al. Combined therapeutic effect of udenafil and adipose-derived stem cell (ADSC)/brain-derived neurotrophic factor (BDNF)-membrane system in a rat model of cavernous nerve injury. Urology 2013; 81: 1108.e7–1108.e14.

    Article  Google Scholar 

  81. You D, Jang MJ, Lee J, Jeong IG, Kim HS, Moon KH et al. Periprostatic implantation of human bone marrow-derived mesenchymal stem cells potentiates recovery of erectile function by intracavernosal injection in a rat model of cavernous nerve injury. Urology 2013; 81: 104–110.

    Article  PubMed  Google Scholar 

  82. Wei M, Macera CA, Davis DR, Hornung CA, Nankin HR, Blair SN . Total cholesterol and high density lipoprotein cholesterol as important predictors of erectile dysfunction. Am J Epidemiol 1994; 140: 930–937.

    Article  CAS  PubMed  Google Scholar 

  83. Butler A, Tsunoda S, McCobb DP, Wei A, Salkoff L . mSlo a complex mouse gene encoding ‘maxi’ calcium-activated potassium channels. Science 1993; 261: 221–224.

    Article  CAS  PubMed  Google Scholar 

  84. Salkoff L, Butler A, Ferreira G, Santi C, Wei A . High-conductance potassium channels of the SLO family. Nat Rev Neurosci 2006; 7: 921–931.

    Article  CAS  PubMed  Google Scholar 

  85. He Y, He W, Qin G, Luo J, Xiao M . Transplantation KCNMA1 modified bone marrow-mesenchymal stem cell therapy for diabetes mellitus-induced erectile dysfunction. Andrologia 2014; 46: 479–486.

    Article  CAS  PubMed  Google Scholar 

  86. Gokce A, Abd Elmageed ZY, Lasker GF, Bouljihad M, Braun SE, Kim H et al. Intratunical injection of genetically modified adipose tissue-derived stem cells with human interferon alpha-2b for treatment of erectile dysfunction in a rat model of Tunica Albugineal fibrosis. J Sex Med 2015; 12: 1533–1544.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Cheng L, Hu W, Qiu B, Zhao J, Yu Y, Guan W et al. Generation of neural progenitor cells by chemical cocktails and hypoxia. Cell Res 2015; 25: 645–646.

    Article  PubMed  PubMed Central  Google Scholar 

  88. Han DW, Tapia N, Hermann A, Hemmer K, Hoing S, Arauzo-Bravo MJ et al. Direct reprogramming of fibroblasts into neural stem cells by defined factors. Cell Stem Cell 2012; 10: 465–472.

    Article  CAS  PubMed  Google Scholar 

  89. Kim SM, Flasskamp H, Hermann A, Arauzo-Bravo MJ, Lee SC, Lee SH et al. Direct conversion of mouse fibroblasts into induced neural stem cells. Nat Protoc 2014; 9: 871–881.

    Article  CAS  PubMed  Google Scholar 

  90. Song YS, Lee HJ, Park IH, Lim IS, Ku JH, Kim SU . Human neural crest stem cells transplanted in rat penile corpus cavernosum to repair erectile dysfunction. BJU Int 2008; 102: 220–224; discussion 4.

    Article  CAS  PubMed  Google Scholar 

  91. Bivalacqua TJ, Musicki B, Usta MF, Champion HC, Kadowitz PJ, Burnett AL et al. Endothelial nitric oxide synthase gene therapy for erectile dysfunction. Curr Pharm Des 2005; 11: 4059–4067.

    Article  CAS  PubMed  Google Scholar 

  92. Bivalacqua TJ, Usta MF, Champion HC, Leungwattanakij S, Dabisch PA, McNamara DB et al. Effect of combination endothelial nitric oxide synthase gene therapy and sildenafil on erectile function in diabetic rats. Int J Impot Res 2004; 16: 21–29.

    Article  CAS  PubMed  Google Scholar 

  93. Champion HC, Bivalacqua TJ, Hyman AL, Ignarro LJ, Hellstrom WJ, Kadowitz PJ . Gene transfer of endothelial nitric oxide synthase to the penis augments erectile responses in the aged rat. Proc Natl Acad Sci USA 1999; 96: 11648–11652.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Magee TR, Ferrini M, Garban HJ, Vernet D, Mitani K, Rajfer J et al. Gene therapy of erectile dysfunction in the rat with penile neuronal nitric oxide synthase. Biol Reprod 2002; 67: 1033–1041.

    Article  PubMed  Google Scholar 

  95. Musicki B, Palese MA, Crone JK, Burnett AL . Phosphorylated endothelial nitric oxide synthase mediates vascular endothelial growth factor-induced penile erection. Biol Reprod 2004; 70: 282–289.

    Article  CAS  PubMed  Google Scholar 

  96. Chitaley K . Type 1 and Type 2 diabetic-erectile dysfunction: same diagnosis (ICD-9), different disease? J Sex Med 2009; 6: 262–268.

    Article  PubMed  Google Scholar 

  97. Hidalgo-Tamola J, Chitaley K . Review type 2 diabetes mellitus and erectile dysfunction. J Sex Med 2009; 6: 916–926.

    Article  CAS  PubMed  Google Scholar 

  98. Carmeliet P . VEGF gene therapy: stimulating angiogenesis or angioma-genesis? Nat Med 2000; 6: 1102–1103.

    Article  CAS  PubMed  Google Scholar 

  99. Liu G, Sun X, Bian J, Wu R, Guan X, Ouyang B et al. 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: e72790.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This research was supported by Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2010-0011678) and by Soonchunhyang University Research Fund.

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  1. Department of Urology, Soonchunhyang University Hospital, College of Medicine, Soonchunhyang University, Seoul, Korea

    J H Kim & Y S Song

  2. Biomedical Research Institute, Chung-Ang School of Medicine, Seoul, Korea

    H J Lee

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Kim, J., Lee, H. & Song, Y. Mesenchymal stem cell-based gene therapy for erectile dysfunction. Int J Impot Res 28, 81–87 (2016). https://doi.org/10.1038/ijir.2016.3

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  • DOI: https://doi.org/10.1038/ijir.2016.3

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