Review Article | Published:

The mechanisms and potential of stem cell therapy for penile fibrosis

Nature Reviews Urology (2018) | Download Citation


Fibrosis is often caused by chronic tissue injury leading to a persisting inflammatory response with excessive accumulation of extracellular connective tissue proteins. Peyronie’s disease, urethral stricture and penile (corpora cavernosa) fibrosis are localized fibrotic disorders of the penile connective tissues that can substantially impair a patient’s quality of life. Research over the past few decades has revealed the ability of stem cells to secrete a wide range of paracrine factors, a characteristic that could be exploited therapeutically to prevent and treat several inflammatory and fibrotic diseases. In preclinical studies, mesenchymal stem cells (MSCs) have proven to be the most effective and readily available type of stem cells for therapeutic use. An important advantage of MSCs is their ability to circumvent the immune system and function as immunomodulatory ‘drug stores’ to influence multiple cell types simultaneously. Many studies using stem cells have been applied exclusively to corpora cavernosa fibrosis owing to its well-established disease models. A plethora of preclinical data suggest the benefit of stem cells for use in penile fibrosis. However, their exact mechanism of action and optimal timing and mode of administration must be determined before clinical translation.

Key points

  • Fibrosis is a state of excessive wound-healing leading to the replacement of the local parenchyma with stiff and afunctional extracellular matrix, resulting in loss of organ function in advanced stages.

  • Owing to the complex network of cell types and interactions involved in fibrosis, very few effective medical treatment options are currently available for patients with fibrotic diseases, including penile fibrosis.

  • Stem cells can interrupt several key processes in the fibrotic cascade simultaneously and, therefore, have great potential as novel antifibrotic therapies.

  • Penile fibrosis can occur in the corpora cavernosa, tunica albuginea or urethra.

  • A large number of preclinical studies have investigated the effect of stem cells for the treatment of penile fibrosis, and have reported encouraging results.

  • Certain limitations (such as isolation, timing, administration and dosage) need to be addressed before preclinical findings can be translated into the clinical setting.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Additional information

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


  1. 1.

    Wynn, T. Cellular and molecular mechanisms of fibrosis. J. Pathol. 214, 199–210 (2008).

  2. 2.

    Wynn, T. A. Mechanisms of fibrosis: therapeutic translation for fibrotic disease. Nat. Med. 18, 1028–1040 (2013).

  3. 3.

    Rockey, D. C., Bell, P. D. & Hill, J. A. Fibrosis — a common pathway to organ injury and failure. N. Engl. J. Med. 372, 1138–1149 (2015).

  4. 4.

    Cannito, S., Novo, E. & Parola, M. Therapeutic pro-fibrogenic signaling pathways in fibroblasts. Adv. Drug Deliv. Rev. 121, 57–84 (2017).

  5. 5.

    Hinz, B. The extracellular matrix and transforming growth factor-β1: tale of a strained relationship. Matrix Biol. 47, 54–65 (2015).

  6. 6.

    Gonzalez-Cadavid, N. F. & Rajfer, J. Treatment of Peyronie’s disease with PDE5 inhibitors: an antifibrotic strategy. Nat. Rev. Urol. 7, 215–221 (2010).

  7. 7.

    Gonzalez-Cadavid, N. F. & Rajfer, J. Experimental models of peyronie’s disease. Implications for new therapies. J. Sex. Med. 6, 303–313 (2009).

  8. 8.

    Gonzalez-Cadavid, N. F. Mechanisms of penile fibrosis. J. Sex. Med. 6, 353–362 (2009).

  9. 9.

    Mundy, A. R. & Andrich, D. E. Urethral strictures. BJU Int. 107, 6–26 (2011).

  10. 10.

    Kucukdurmaz, F. et al. Duration of priapism is associated with increased corporal oxidative stress and antioxidant enzymes in a rat model. Andrologia 48, 374–379 (2016).

  11. 11.

    Garaffa, G., Trost, L. W., Serefoglu, E. C., Ralph, D. & Hellstrom, W. J. G. Understanding the course of Peyronie’s disease. Int. J. Clin. Pract. 67, 781–788 (2013).

  12. 12.

    Caplan, A. I. & Correa, D. The MSC: an injury drugstore. Cell Stem Cell 9, 11–15 (2011).

  13. 13.

    Caplan, A. I. MSCs: the sentinel and safe-guards of injury. J. Cell. Physiol. 231, 1413–1416 (2016).

  14. 14.

    Singer, N. G. & Caplan, A. I. Mesenchymal stem cells: mechanisms of inflammation. Annu. Rev. Pathol. Mech. Dis. 6, 457–478 (2011).

  15. 15.

    da Silva Meirelles, L., Fontes, A. M., Covas, D. T. & Caplan, A. I. Mechanisms involved in the therapeutic properties of mesenchymal stem cells. Cytokine Growth Factor Rev. 20, 419–427 (2009).

  16. 16.

    Lim, R., Ricardo, S. D. & Sievert, W. Cell-based therapies for tissue fibrosis. Front. Pharmacol. 8, 633 (2017).

  17. 17.

    El Agha, E. et al. Mesenchymal stem cells in fibrotic disease. Cell Stem Cell 21, 166–177 (2017).

  18. 18.

    Ghieh, F. et al. The use of stem cells in burn wound healing: a review. Biomed. Res. Int. 2015, 1–9 (2015).

  19. 19.

    Eom, Y. W., Shim, K. Y. & Baik, S. K. Mesenchymal stem cell therapy for liver fibrosis. Kor. J. Intern. Med. 30, 580–589 (2015).

  20. 20.

    Usunier, B., Benderitter, M., Tamarat, R. & Chapel, A. Management of fibrosis: the mesenchymal stromal cells breakthrough. Stem Cells Int. 2014, 1–26 (2014).

  21. 21.

    Geiger, S., Hirsch, D. & Hermann, F. G. Cell therapy for lung disease. Eur. Respir. Rev. 26, 170044 (2017).

  22. 22.

    Hostettler, K. E. et al. Multipotent mesenchymal stem cells in lung fibrosis. PLOS ONE 12, e0181946 (2017).

  23. 23.

    Sitanggang, E. J., Antarianto, R. D., Jusman, S. W. A., Pawitan, J. A. & Jusuf, A. A. Bone marrow stem cells anti-liver fibrosis potency: inhibition of hepatic stellate cells activity and extracellular matrix deposition. Int. J. Stem Cells 10, 69–75 (2017).

  24. 24.

    Milosavljevic, N. et al. Mesenchymal stem cells attenuate liver fibrosis by suppressing Th17 cells — an experimental study. Transpl. Int. 31, 102–115 (2018).

  25. 25.

    Lou, G., Chen, Z., Zheng, M. & Liu, Y. Mesenchymal stem cell-derived exosomes as a new therapeutic strategy for liver diseases. Exp. Mol. Med. 49, e346 (2017).

  26. 26.

    Matsui, F. et al. Mesenchymal stem cells protect against obstruction-induced renal fibrosis by decreasing STAT3 activation and STAT3-dependent MMP-9 production. Am. J. Physiol. Renal Physiol. 312, F25–F32 (2017).

  27. 27.

    Kuppe, C. & Kramann, R. Role of mesenchymal stem cells in kidney injury and fibrosis. Curr. Opin. Nephrol. Hypertens. 25, 372–377 (2016).

  28. 28.

    Reinders, M. E. J., de Fijter, J. W. & Rabelink, T. J. Mesenchymal stromal cells to prevent fibrosis in kidney transplantation. Curr. Opin. Organ. Transplant. 19, 54–59 (2014).

  29. 29.

    Wu, S.-Z. et al. Paracrine effect of CXCR4-overexpressing mesenchymal stem cells on ischemic heart injury. Cell Biochem. Funct. 35, 113–123 (2017).

  30. 30.

    Michler, R. E. Stem cell therapy for heart failure. Methodist Debakey Cardiovasc. J. 9, 187–194 (2013).

  31. 31.

    Castiglione, F. et al. Adipose-derived stem cells counteract urethral stricture formation in rats. Eur. Urol. 70, 1032–1041 (2016).

  32. 32.

    Soebadi, M. A., Milenkovic, U., Weyne, E. & Castiglione, F. Stem cells in male sexual dysfunction: are we getting somewhere? Sex. Med. Rev. 5, 222–235 (2016).

  33. 33.

    Soebadi, M. A., Moris, L., Castiglione, F., Weyne, E. & Albersen, M. Advances in stem cell research for the treatment of male sexual dysfunctions. Curr. Opin. Urol. 26, 129–139 (2016).

  34. 34.

    Dellis, A. & Papatsoris, A. Stem cell therapy for the treatment of Peyronie’s disease. Expert Opin. Biol. Ther. 17, 407–413 (2017).

  35. 35.

    Bernardo, M. E. & Fibbe, W. E. Mesenchymal stromal cells: sensors and switchers of inflammation. Cell Stem Cell 13, 392–402 (2013).

  36. 36.

    Vannella, K. M. & Wynn, T. A. Mechanisms of organ injury and repair by macrophages. Annu. Rev. Physiol. 79, 593–617 (2017).

  37. 37.

    Wynn, T. A. Common and unique mechanisms regulate fibrosis in various fibroproliferative diseases. J. Clin. Invest. 117, 524–529 (2007).

  38. 38.

    Duffield, J. S., Lupher, M., Thannickal, V. J. & Wynn, T. A. Host responses in tissue repair and fibrosis. Annu. Rev. Pathol. Mech. Dis. 8, 241–276 (2013).

  39. 39.

    Schneider, R. K. et al. Gli1+ mesenchymal stromal cells are a key driver of bone marrow fibrosis and an important cellular therapeutic target. Cell Stem Cell 20, 785–800 (2017).

  40. 40.

    Marshall, R. P., Simpson, J. K. & Lukey, P. T. Strategies for biomarker discovery in fibrotic disease. Biochim. Biophys. Acta 1832, 1079–1087 (2013).

  41. 41.

    Tzouvelekis, A. et al. Longitudinal “real-world” outcomes of pirfenidone in idiopathic pulmonary fibrosis in Greece. Front. Med. 4, 213 (2017).

  42. 42.

    Tzouvelekis, A. et al. Safety and efficacy of nintedanib in idiopathic pulmonary fibrosis: a real-life observational study in Greece. Pulm. Pharmacol. Ther. 49, 61–66 (2018).

  43. 43.

    Voog, J. & Jones, D. L. Stem cells and the niche: a dynamic duo. Cell Stem Cell 6, 103–115 (2010).

  44. 44.

    Wu, J. & Izpisua Belmonte, J. C. Dynamic pluripotent stem cell states and their applications. Cell Stem Cell 17, 509–525 (2015).

  45. 45.

    Enver, T., Pera, M., Peterson, C. & Andrews, P. W. Stem cell states, fates, and the rules of attraction. Cell Stem Cell 4, 387–397 (2009).

  46. 46.

    Bonfield, T. L. & Caplan, A. I. Adult mesenchymal stem cells: an innovative therapeutic for lung diseases. Discov. Med. 9, 337–345 (2010).

  47. 47.

    DiMarino, A. M., Caplan, A. I. & Bonfield, T. L. Mesenchymal stem cells in tissue repair. Front. Immunol. 4, 201 (2013).

  48. 48.

    Bianco, P., Robey, P. G. & Simmons, P. J. Mesenchymal stem cells: revisiting history, concepts, and assays. Cell Stem Cell 2, 313–319 (2008).

  49. 49.

    Caplan, A. I. & Dennis, J. E. Mesenchymal stem cells as trophic mediators. J. Cell. Biochem. 98, 1076–1084 (2006).

  50. 50.

    Guimarães-Camboa, N. et al. Pericytes of multiple organs do not behave as mesenchymal stem cells in vivo. Cell Stem Cell 20, 345–359.e5 (2017).

  51. 51.

    Thomas, H., Cowin, A. J. & Mills, S. J. The importance of pericytes in healing: wounds and other pathologies. Int. J. Mol. Sci. 18, E1129 (2017).

  52. 52.

    Różycka, J., Brzóska, E. & Skirecki, T. Aspects of pericytes and their potential therapeutic use. Postepy Hig. Med. Dosw. 71, 186–197 (2017).

  53. 53.

    Ferland-McCollough, D., Slater, S., Richard, J., Reni, C. & Mangialardi, G. Pericytes, an overlooked player in vascular pathobiology. Pharmacol. Ther. 171, 30–42 (2017).

  54. 54.

    Ankrum, J. A., Ong, J. F. & Karp, J. M. Mesenchymal stem cells: immune evasive, not immune privileged. Nat. Biotechnol. 32, 252–260 (2014).

  55. 55.

    Shi, Y. et al. How mesenchymal stem cells interact with tissue immune responses. Trends Immunol. 33, 136–143 (2012).

  56. 56.

    Trounson, A. & McDonald, C. Stem cell therapies in clinical trials: progress and challenges. Cell Stem Cell 17, 11–22 (2015).

  57. 57.

    Dominici, M. et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 8, 315–317 (2006).

  58. 58.

    Inaba, M. & Yamashita, Y. M. Asymmetric stem cell division: precision for robustness. Cell Stem Cell 11, 461–469 (2012).

  59. 59.

    Khavari, D. A., Sen, G. L. & Rinn, J. L. DNA methylation and epigenetic control of cellular differentiation. Cell Cycle 9, 3880–3883 (2010).

  60. 60.

    Collas, P. Programming differentiation potential in mesenchymal stem cells. Epigenetics 5, 476–482 (2010).

  61. 61.

    Sorrell, J. M. & Caplan, A. I. Topical delivery of mesenchymal stem cells and their function in wounds. Stem Cell Res. Ther. 1, 30 (2010).

  62. 62.

    Maxson, S., Lopez, E. A., Yoo, D., Danilkovitch-Miagkova, A. & LeRoux, M. A. Concise Review: Role of mesenchymal stem cells in wound repair. Stem Cells Transl Med. 1, 142–149 (2012).

  63. 63.

    Hanson, S. E. Mesenchymal stem cells: a multimodality option for wound healing. Adv. Wound Care 1, 153–158 (2012).

  64. 64.

    Mattoli, S., Bellini, A. & Schmidt, M. The role of a human hematopoietic mesenchymal progenitor in wound healing and fibrotic diseases and implications for therapy. Curr. Stem Cell Res. Ther. 4, 266–280 (2009).

  65. 65.

    Larson, B. J., Longaker, M. T. & Lorenz, H. P. Scarless fetal wound healing: a basic science review. Plast. Reconstr. Surg. 126, 1172–1180 (2010).

  66. 66.

    Leavitt, T. et al. Scarless wound healing: finding the right cells and signals. Cell Tissue Res. 365, 483–493 (2016).

  67. 67.

    Cerqueira, M. T., Pirraco, R. P. & Marques, A. P. Stem cells in skin wound healing: are we there yet? Adv. Wound Care 5, 164–175 (2016).

  68. 68.

    Pinggera, G.-M., Rehder, P., Bartsch, G. & Gozzi, C. Harnröhrentraumen. Urologe 44, 883–897 (2005).

  69. 69.

    Mooney, D. J. & Vandenburgh, H. Cell delivery mechanisms for tissue repair. Cell Stem Cell 2, 205–213 (2008).

  70. 70.

    Wynn, T. A. & Vannella, K. M. Macrophages in tissue repair, regeneration, and fibrosis. Immunity 44, 450–462 (2016).

  71. 71.

    Wang, Y. et al. Adipose derived mesenchymal stem cells transplantation via portal vein improves microcirculation and ameliorates liver fibrosis induced by CCl4 in rats. J. Transl Med. 10, 133 (2012).

  72. 72.

    Wu, Y. et al. Bone marrow-derived mesenchymal stem cell attenuates skin fibrosis development in mice. Int. Wound J. 11, 701–710 (2014).

  73. 73.

    Wu, Y. et al. Mesenchymal stem cells suppress fibroblast proliferation and reduce skin fibrosis through a TGF-β3-dependent activation. Int. J. Low. Extrem. Wounds 14, 50–62 (2015).

  74. 74.

    Williams, A. R. et al. Durable scar size reduction due to allogeneic mesenchymal stem cell therapy regulates whole-chamber remodeling. J. Am. Heart Assoc. 2, e000140 (2013).

  75. 75.

    Hashimoto, N., Jin, H., Liu, T., Chensue, S. W. & Phan, S. H. Bone marrow-derived progenitor cells in pulmonary fibrosis. J. Clin. Invest. 113, 243–252 (2004).

  76. 76.

    Jurado, M. et al. Adipose tissue-derived mesenchymal stromal cells as part of therapy for chronic graft-versus-host disease: a phase I/II study. Cytotherapy 19, 927–936 (2017).

  77. 77.

    Owen Pickrell, W. & Robertson, N. P. Stem cell treatment for multiple sclerosis. J. Neurol. 263, 2145–2147 (2016).

  78. 78.

    Lamo-Espinosa, J. M. et al. Intra-articular injection of two different doses of autologous bone marrow mesenchymal stem cells versus hyaluronic acid in the treatment of knee osteoarthritis: multicenter randomized controlled clinical trial (phase I/II). J. Transl Med. 14, 246 (2016).

  79. 79.

    Lindsay, J. O. et al. Autologous stem-cell transplantation in treatment-refractory Crohn’s disease: an analysis of pooled data from the ASTIC trial. Lancet Gastroenterol. Hepatol. 2, 399–406 (2017).

  80. 80.

    Fandel, T. M. et al. Transplanted human stem cell-derived interneuron precursors mitigate mouse bladder dysfunction and central neuropathic pain after spinal cord injury. Cell Stem Cell 19, 544–557 (2016).

  81. 81.

    Ranganath, S. H., Levy, O., Inamdar, M. S. & Karp, J. M. Harnessing the mesenchymal stem cell secretome for the treatment of cardiovascular disease. Cell Stem Cell 10, 244–258 (2012).

  82. 82.

    Gupta, M. K. & Ajay, A. K. Fat on sale: role of adipose-derived stem cells as anti-fibrosis agent in regenerative medicine. Stem Cell Res. Ther. 6, 233 (2015).

  83. 83.

    Cheng, S.-L., Lin, C.-H. & Yao, C.-L. Mesenchymal stem cell administration in patients with chronic obstructive pulmonary disease: state of the science. Stem Cells Int. 2017, 1–14 (2017).

  84. 84.

    Jackson, W. M., Nesti, L. J. & Tuan, R. S. Mesenchymal stem cell therapy for attenuation of scar formation during wound healing. Stem Cell Res. Ther. 3, 20 (2012).

  85. 85.

    Aurora, A. B. & Olson, E. N. Immune modulation of stem cells and regeneration. Cell Stem Cell 15, 14–25 (2014).

  86. 86.

    Bogdan, C. Nitric oxide synthase in innate and adaptive immunity: an update. Trends Immunol. 36, 161–178 (2015).

  87. 87.

    Oshimori, N. & Fuchs, E. The harmonies played by TGF-β in stem cell biology. Cell Stem Cell 11, 751–764 (2012).

  88. 88.

    Sreeramkumar, V., Fresno, M. & Cuesta, N. Prostaglandin E 2 and T cells: friends or foes? Immunol. Cell Biol. 90, 579–586 (2012).

  89. 89.

    Nakanishi, M. & Rosenberg, D. W. Multifaceted roles of PGE2 in inflammation and cancer. Semin. Immunopathol. 35, 123–137 (2013).

  90. 90.

    Kalinski, P. Regulation of immune responses by prostaglandin E2. J. Immunol. 188, 21–28 (2012).

  91. 91.

    Braga, T. T., Agudelo, J. S. H. & Camara, N. O. S. Macrophages during the fibrotic process: M2 as friend and foe. Front. Immunol. 6, 602 (2015).

  92. 92.

    Galli, S. J., Borregaard, N. & Wynn, T. A. Phenotypic and functional plasticity of cells of innate immunity: macrophages, mast cells and neutrophils. Nat. Immunol. 12, 1035–1044 (2011).

  93. 93.

    Sziksz, E. et al. Fibrosis related inflammatory mediators: role of the IL-10 cytokine family. Mediators Inflamm. 2015, 764641 (2015).

  94. 94.

    Dean, R. C. & Lue, T. F. Physiology of penile erection and pathophysiology of erectile dysfunction. Urol. Clin. North Am. 32, 379–395 (2005).

  95. 95.

    Lue, T. F., Brant, W. O., Shindel, A. & Bella, A. J. Sexual Dysfunction in Diabetes (eds De Groot, L. J., Chrousos, G., Dungan, K. et al) (, Inc., 2000).

  96. 96.

    Gonzalez-Cadavid, N. F. & Rajfer, J. Mechanisms of disease: new insights into the cellular and molecular pathology of Peyronie’s disease. Nat. Clin. Pract. Urol. 2, 291–297 (2005).

  97. 97.

    Haglind, E. et al. Urinary incontinence and erectile dysfunction after robotic versus open radical prostatectomy: a prospective, controlled, nonrandomised trial. Eur. Urol. 68, 216–225 (2015).

  98. 98.

    Yafi, F. A. et al. Erectile dysfunction. Nat. Rev. Dis. Primers 2, 16003 (2016).

  99. 99.

    Ferrini, M. G. et al. Fibrosis and loss of smooth muscle in the corpora cavernosa precede corporal veno-occlusive dysfunction (CVOD) induced by experimental cavernosal nerve damage in the rat. J. Sex. Med. 6, 415–428 (2009).

  100. 100.

    Fode, M., Ohl, D. A., Ralph, D. & Sønksen, J. Penile rehabilitation after radical prostatectomy: what the evidence really says. BJU Int. 112, 998–1008 (2013).

  101. 101.

    Sopko, N. A. & Burnett, A. L. Erection rehabilitation following prostatectomy — current strategies and future directions. Nat. Rev. Urol. 13, 216–225 (2016).

  102. 102.

    Hannan, J. L. et al. Caspase-3 dependent nitrergic neuronal apoptosis following cavernous nerve injury is mediated via RhoA and ROCK activation in major pelvic ganglion. Sci. Rep. 6, 29416 (2016).

  103. 103.

    Albersen, M. et al. Pentoxifylline promotes recovery of erectile function in a rat model of postprostatectomy erectile dysfunction. Eur. Urol. 59, 286–296 (2011).

  104. 104.

    Chitaley, K. et al. Antagonism of Rho-kinase stimulates rat penile erection via a nitric oxide-independent pathway. Nat. Med. 7, 119–122 (2001).

  105. 105.

    Chitaley, K., Webb, R. C. & Mills, T. M. Rho-kinase as a potential target for the treatment of erectile dysfunction. Drug News Perspect. 14, 601–606 (2001).

  106. 106.

    Chitaley, K., Webb, R. & Mills, T. RhoA/Rho-kinase: a novel player in the regulation of penile erection. Int. J. Impot. Res. 13, 67–72 (2001).

  107. 107.

    Martínez-Salamanca, J. I. et al. α1A-adrenergic receptor antagonism improves erectile and cavernosal responses in rats with cavernous nerve injury and enhances neurogenic responses in human corpus cavernosum from patients with erectile dysfunction secondary to radical prostatectomy. J. Sex. Med. 13, 1844–1857 (2016).

  108. 108.

    Martínez-Salamanca, J. I., Mueller, A., Moncada, I., Carballido, J. & Mulhall, J. P. Penile prosthesis surgery in patients with corporal fibrosis: a state of the art review. J. Sex. Med. 8, 1880–1889 (2011).

  109. 109.

    Wang, X. et al. Hypoxia precondition promotes adipose-derived mesenchymal stem cells based repair of diabetic erectile dysfunction via augmenting angiogenesis and neuroprotection. PLOS ONE 10, e0118951 (2015).

  110. 110.

    Liu, T. et al. Hepatocyte growth factor-modified adipose tissue-derived stem cells improve erectile function in streptozotocin-induced diabetic rats. Growth Factors 33, 282–289 (2015).

  111. 111.

    Huang, Y.-C. et al. The effects of adipose-derived stem cells in a rat model of tobacco-associated erectile dysfunction. PLOS ONE 11, e0156725 (2016).

  112. 112.

    Kovanecz, I. et al. Separate or combined treatments with daily sildenafil, molsidomine, or muscle-derived stem cells prevent erectile dysfunction in a rat model of cavernosal nerve damage. J. Sex. Med. 9, 2814–2826 (2012).

  113. 113.

    Ying, C. et al. Erectile function restoration after repair of resected cavernous nerves by adipose-derived stem cells combined with autologous vein graft in rats. Cell. Mol. Neurobiol. 34, 393–402 (2014).

  114. 114.

    Chen, X. et al. 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, 1–12 (2016).

  115. 115.

    Albersen, M. 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. 7, 3331–3340 (2010).

  116. 116.

    Kim, I. G. et al. Effect of an adipose-derived stem cell and nerve growth factor-incorporated hydrogel on recovery of erectile function in a rat model of cavernous nerve injury. Tissue Eng. Part A 19, 14–23 (2013).

  117. 117.

    You, D. et al. Comparative study of autologous stromal vascular fraction and adipose-derived stem cells for erectile function recovery in a rat model of cavernous nerve injury. Stem Cells Transl Med. 4, 351–358 (2015).

  118. 118.

    Martínez-Salamanca, J. I. et al. Dual strategy with oral phosphodiesterase type 5 inhibition and intracavernosal implantation of mesenchymal stem cells is superior to individual approaches in the recovery of erectile and cavernosal functions after cavernous nerve injury in rats. J. Sex. Med. 13, 1–11 (2016).

  119. 119.

    Ryu, J.-K. et al. Intracavernous delivery of clonal mesenchymal stem cells rescues erectile function in the streptozotocin-induced diabetic mouse. Andrology 4, 172–184 (2016).

  120. 120.

    Qiu, X. 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. 62, 720–727 (2012).

  121. 121.

    Ryu, J. et al. Intracavernous delivery of clonal mesenchymal stem cells restores erectile function in a mouse model of cavernous nerve injury. J. Sex. Med. 11, 411–423 (2014).

  122. 122.

    Jeong, H. H. 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 81, 1108.e7–1108.e14 (2013).

  123. 123.

    Fandel, T. M. 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. 61, 201–210 (2012).

  124. 124.

    Ying, C., Yang, M., Zheng, X., Hu, W. & Wang, X. Effects of intracavernous injection of adipose-derived stem cells on cavernous nerve regeneration in a rat model. Cell. Mol. Neurobiol. 33, 233–240 (2013).

  125. 125.

    You, D. 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 81, 104–110 (2013).

  126. 126.

    You, D. et al. Bone marrow–derived mesenchymal stromal cell therapy in a rat model of cavernous nerve injury: preclinical study for approval. Cytotherapy 18, 870–880 (2016).

  127. 127.

    Zhu, J.-Q. et al. Therapeutic potential of human umbilical cord blood mesenchymal stem cells on erectile function in rats with cavernous nerve injury. Biotechnol. Lett. 37, 1515–1525 (2015).

  128. 128.

    Song, L. et al. BDNF-hypersecreting human umbilical cord blood mesenchymal stem cells promote erectile function in a rat model of cavernous nerve electrocautery injury. Int. Urol. Nephrol. 48, 37–45 (2016).

  129. 129.

    Gokce, A. et al. Adipose tissue-derived stem cell therapy for prevention and treatment of erectile dysfunction in a rat model of Peyronie’s disease. Andrology 2, 244–251 (2014).

  130. 130.

    Gokce, A. et al. Intratunical injection of genetically modified adipose tissue-derived stem cells with human interferon α-2b for treatment of erectile dysfunction in a rat model of tunica albugineal fibrosis. J. Sex. Med. 12, 1533–1544 (2015).

  131. 131.

    Castiglione, F. et al. Intratunical injection of human adipose tissue-derived stem cells prevents fibrosis and is associated with improved erectile function in a rat model of Peyronie’s disease. Eur. Urol. 63, 551–560 (2013).

  132. 132.

    Ouyang, B. 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 9, e92825 (2014).

  133. 133.

    Sangkum, P. et al. Effect of adipose tissue-derived stem cell injection in a rat model of urethral fibrosis. Can. Urol. Assoc. J. 10, E175–E180 (2016).

  134. 134.

    Levy, J. A., Marchand, M., Iorio, L., Cassini, W. & Zahalsky, M. P. Determining the feasibility of managing erectile dysfunction in humans with placental-derived stem cells. J. Am. Osteopath. Assoc. 116, e1 (2016).

  135. 135.

    Yang, Q. et al. 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. 25, 1987–2001 (2016).

  136. 136.

    Cengiz, T. et al. Intracavernous injection of human umbilical cord blood mononuclear cells improves erectile dysfunction in streptozotocin-induced diabetic rats. J. Sex. Med. 14, 50–58 (2017).

  137. 137.

    Shan, H.-T. et al. Combination of low energy shock wave therapy and bone marrow mesenchymal stem cell transplantation to improve the erectile function of diabetic rats. Asian J. Androl. 0, 0 (2016).

  138. 138.

    Wang, X. et al. Combination of mesenchymal stem cell injection with icariin for the treatment of diabetes-associated erectile dysfunction. PLOS ONE 12, e0174145 (2017).

  139. 139.

    Liu, G. 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 8, e72790 (2013).

  140. 140.

    Kovanecz, I. et al. Implanted muscle-derived stem cells ameliorate erectile dysfunction in a rat model of type 2 diabetes, but their repair capacity is impaired by their prior exposure to the diabetic milieu. J. Sex. Med. 13, 786–797 (2016).

  141. 141.

    Garcia, M. M. et al. Treatment of erectile dysfunction in the obese type 2 diabetic ZDF rat with adipose tissue-derived stem cells. J. Sex. Med. 7, 89–98 (2010).

  142. 142.

    Yun, Y.-R. et al. Fibroblast growth factors: biology, function, and application for tissue regeneration. J. Tissue Eng. 2010, 218142 (2010).

  143. 143.

    Matsuda, Y. et al. Intravenous infusion of bone marrow-derived mesenchymal stem cells reduces erectile dysfunction following cavernous nerve injury in rats. Sex. Med. 6, 49–57 (2018).

  144. 144.

    Yang, J. et al. Adipose-derived stem cells improve erectile function partially through the secretion of IGF-1, bFGF, and VEGF in aged rats. Andrology 6, 498–509 (2018).

  145. 145.

    Albersen, M., Weyne, E. & Bivalacqua, T. J. Stem cell therapy for erectile dysfunction: progress and future directions. Sex. Med. Rev. 1, 50–64 (2013).

  146. 146.

    Fang, J. et al. Combined transplantation of mesenchymal stem cells and endothelial progenitor cells restores cavernous nerve injury-related erectile dysfunction. J. Sex. Med. 15, 284–295 (2018).

  147. 147.

    Graziottin, T. M. The pathophysiology of Peyronie’s disease: beyond the Smith’s space. Int. Braz. J. Urol. 41, 1040–1042 (2015).

  148. 148.

    Ralph, D., Cellek, S. & Stebbeds, W. Solving a bottleneck in animal models of Peyronie’s disease. Asian J. Androl. 16, 639 (2014).

  149. 149.

    Cerruto, M. A. et al. Animal experimental model of Peyronie’s disease: a pilot study. Arch. Ital. Urol. Androl. 85, 28 (2013).

  150. 150.

    Chung, E., De Young, L. & Brock, G. B. Rat as an animal model for Peyronie’s disease research: a review of current methods and the peer-reviewed literature. Int. J. Impot. Res. 23, 235–241 (2011).

  151. 151.

    Zargooshi, J. Trauma as the cause of Peyronie’s disease: penile fracture as a model of trauma. J. Urol. 172, 186–188 (2004).

  152. 152.

    Acikgoz, A. et al. Relationship between penile fracture and Peyronie’s disease: a prospective study. Int. J. Impot. Res. 23, 165–172 (2011).

  153. 153.

    Mack, M. & Yanagita, M. Origin of myofibroblasts and cellular events triggering fibrosis. Kidney Int. 87, 297–307 (2015).

  154. 154.

    Bennett, M. R., Sinha, S. & Owens, G. K. Vascular smooth muscle cells in atherosclerosis. Circ. Res. 118, 692–702 (2016).

  155. 155.

    Vernet, D. et al. Evidence that osteogenic progenitor cells in the human tunica albuginea may originate from stem cells: implications for Peyronie disease. Biol. Reprod. 73, 1199–1210 (2005).

  156. 156.

    Tomasek, J. J., Gabbiani, G., Hinz, B., Chaponnier, C. & Brown, R. A. Myofibroblasts and mechano-regulation of connective tissue remodelling. Nat. Rev. Mol. Cell. Biol. 3, 349–363 (2002).

  157. 157.

    Jiang, H., Gao, Q., Che, X. & Zhu, L. Inhibition of penile tunica albuginea myofibroblasts activity by adipose — derived stem cells. Exp. Ther. Med. 14, 5149–5156 (2017).

  158. 158.

    Latini, J. M., McAninch, J. W., Brandes, S. B., Chung, J. Y. & Rosenstein, D. SIU/ICUD Consultation on urethral strictures: epidemiology, etiology, anatomy, and nomenclature of urethral stenoses, strictures, and pelvic fracture urethral disruption injuries. Urology 83, S1–S7 (2014).

  159. 159.

    Xie, H., Feng, C., Fu, Q., Sa, Y.-L. & Xu, Y.-M. Crosstalk between TGF-β1 and CXCR3 signaling during urethral fibrosis. Mol. Cell. Biochem. 394, 283–290 (2014).

  160. 160.

    de Kemp, V., de Graaf, P., Fledderus, J. O., Ruud Bosch, J. L. H. & de Kort, L. M. O. Tissue engineering for human urethral reconstruction: systematic review of recent literature. PLOS ONE 10, e0118653 (2015).

  161. 161.

    Sangkum, P. et al. Transforming growth factor-β1 induced urethral fibrosis in a rat model. J. Urol. 194, 820–827 (2015).

  162. 162.

    Marcos, R., Bragança, B. & Fontes-Sousa, A. P. Image analysis or stereology. J. Histochem. Cytochem. 63, 734–736 (2015).

  163. 163.

    Farris, A. B. et al. Morphometric and visual evaluation of fibrosis in renal biopsies. J. Am. Soc. Nephrol. 22, 176–186 (2011).

  164. 164.

    Huang, Y. et al. Image analysis of liver collagen using sirius red is more accurate and correlates better with serum fibrosis markers than trichrome. Liver Int. 33, 1249–1256 (2013).

  165. 165.

    Barrientos, S., Stojadinovic, O., Golinko, M. S., Brem, H. & Tomic-Canic, M. Perspective article: Growth factors and cytokines in wound healing. Wound Repair Regen. 16, 585–601 (2008).

  166. 166.

    Li, Y. et al. Severe lung fibrosis requires an invasive fibroblast phenotype regulated by hyaluronan and CD44. J. Exp. Med. 208, 1459–1471 (2011).

  167. 167.

    Wynn, T. A., Chawla, A. & Pollard, J. W. Macrophage biology in development, homeostasis and disease. Nature 496, 445–455 (2013).

  168. 168.

    Crotty, S. A brief history of T cell help to B cells. Nat. Rev. Immunol. 15, 185–189 (2015).

  169. 169.

    Novo, E. et al. Proangiogenic cytokines as hypoxia-dependent factors stimulating migration of human hepatic stellate cells. Am. J. Pathol. 170, 1942–1953 (2007).

  170. 170.

    Parola, M., Marra, F. & Pinzani, M. Myofibroblast-like cells and liver fibrogenesis: emerging concepts in a rapidly moving scenario. Mol. Aspects Med. 29, 58–66 (2008).

  171. 171.

    Fernández, M. et al. Angiogenesis in liver disease. J. Hepatol. 50, 604–620 (2009).

  172. 172.

    Novo, E. et al. Cellular and molecular mechanisms in liver fibrogenesis. Arch. Biochem. Biophys. 548, 20–37 (2014).

  173. 173.

    Trautwein, C., Friedman, S. L., Schuppan, D. & Pinzani, M. Hepatic fibrosis: concept to treatment. J. Hepatol. 62, S15–S24 (2015).

  174. 174.

    Lee, Y. A., Wallace, M. C. & Friedman, S. L. Pathobiology of liver fibrosis: a translational success story. Gut 64, 830–841 (2015).

  175. 175.

    Nelson, C. J. et al. The chronology of depression and distress in men with peyronie’s disease. J. Sex. Med. 5, 1985–1990 (2008).

  176. 176.

    Anaissie, J. et al. Peyronie’s Disease. Urology 100, 125–130 (2016).

  177. 177.

    Russo, G. I. et al. Clinical efficacy of injection and mechanical therapy for Peyronie’s disease: a systematic review of the literature. Eur. Urol. (2018).

  178. 178.

    Hinz, B. et al. The myofibroblast. Am. J. Pathol. 170, 1807–1816 (2007).

  179. 179.

    Hinz, B. et al. Recent developments in myofibroblast biology. Am. J. Pathol. 180, 1340–1355 (2012).

  180. 180.

    McAnulty, R. J. Fibroblasts and myofibroblasts: Their source, function and role in disease. Int. J. Biochem. Cell Biol. 39, 666–671 (2007).

  181. 181.

    Lamouille, S., Xu, J. & Derynck, R. Molecular mechanisms of epithelial–mesenchymal transition. Nat. Rev. Mol. Cell. Biol. 15, 178–196 (2014).

  182. 182.

    Zavadil, J. & Böttinger, E. P. TGF-β and epithelial-to-mesenchymal transitions. Oncogene 24, 5764–5774 (2005).

  183. 183.

    Kalluri, R. & Neilson, E. G. Epithelial-mesenchymal transition and its implications for fibrosis. J. Clin. Invest. 112, 1776–1784 (2003).

Download references


Reviewer information

Nature Reviews Urology thanks I. Kovanecz and other anonymous reviewer(s) for their contribution to the peer review of this work.

Author information


  1. Laboratory for Experimental Urology, Organ Systems, Department of Development and Regeneration, University of Leuven, Leuven, Belgium

    • Uros Milenkovic
    • , Maarten Albersen
    •  & Fabio Castiglione
  2. The Institute of Urology, University College of London Hospital (UCLH), London, UK

    • Fabio Castiglione
  3. Division of Oncology/Unit of Urology, Urological Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy

    • Fabio Castiglione


  1. Search for Uros Milenkovic in:

  2. Search for Maarten Albersen in:

  3. Search for Fabio Castiglione in:


All authors researched data for the article, made substantial contributions to the discussion of content, wrote the manuscript, and reviewed and edited the manuscript before submission.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Maarten Albersen.


Tunica albuginea

The connective tissue sheath surrounding the erectile tissue (corpora cavernosa) of the penis.

Corpora cavernosa

Sponge-like regions of the erectile tissue that contain most of the blood during a penile erection. (Singular: corpus cavernosum).


A condition whereby the penis remains in an erectile state without any stimulation, or after the stimulation has ended, for more than 4 hours.

Mesenchymal stem cells

(MSCs). Multipotent stromal cells with the ability to differentiate into several cell types within their germ layer (osteoblasts, chondrocytes, myocytes and adipocytes).

Corpus spongiosum

Spongy tissue surrounding the male urethra within the penis.

Totipotent stem cells

These stem cells have the capacity to divide and develop into cells from all three germ cell layers and into extra-embryonic tissues (for example, placenta). The zygote is an example of such a cell.

Pluripotent stem cells

These stem cells have the capacity to divide and develop into cells from all three germ cell layers, but not into extra-embryonic tissues (for example, placenta). Embryonic stem cells are examples of such cells.

Multipotent stem cells

These stem cells have the capacity to divide and develop into cells from a specific tissue or organ. Most adult stem cells are examples of such cells.


Temporary loss of motor and/or sensory function in a nerve from the peripheral nervous system as a result of impaired nerve conduction. Neuropraxia usually recovers fully after 6–8 weeks.

Wallerian degeneration

Active nerve degeneration resulting from a nerve being cut or crushed, whereby the axonal tail distal to the damage (furthest from the neuronal body) degenerates.

Space of Smith

A vascular, loose, areolar connective tissue sleeve that separates the corpus cavernosum from the tunica albuginea.

About this article

Publication history