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Intratunical injection of autologous adipose stromal vascular fraction reduces collagen III expression in a rat model of chronic penile fibrosis

Abstract

Previous studies have shown that the injection of adipose stem cells and stromal vascular fraction(SVF) into the tunica albuginea (TA) during the inflammatory phase in a rat model of Peyronie’s disease(PD) prevented the development of TA fibrosis. Our aim was to investigate whether local injection of SVF can reduce established fibrosis in a rat model of chronic phase of PD. Eighteen-male 12-wk-old Sprague-Dawley rats were divided in three equal groups: sham, PD without treatment (PD) and PD treated with SVF(PD-SVF). Sham rats underwent 2 injections of vehicle into the TA one month apart. PD rats underwent TGF-β1 injection and injection of vehicle one month later. PD-SVF rats underwent TGF-β1 injection followed by SVF (1-million cells) one month later. One month after the last treatment, the animals, n = 6 rats per group, underwent measurement of intracorporal and mean arterial pressure during electrostimulation of the cavernous nerve. Following euthanasia, penises were harvested for in-vitro study. Erectile function was not statistically significantly different between groups. PD animals developed subtunical areas of fibrosis and elastosis with upregulation of collagen III protein. These fibrotic changes were reversed after injection of SVF. We provide evidence that local injection of SVF reverses TA fibrosis in a rat model of chronic phase of PD.

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References

  1. Milenkovic U, Albersen M, Castiglione F. The mechanisms and potential of stem cell therapy for penile fibrosis. Nat Rev Urol. 2019;16:79–97

  2. Wynn Ta. Mechanism of fibrosis: therapeutic transplation for fibrotic disease. Nat Med. 2013;18:1028–40.

    Google Scholar 

  3. Vannella KM, Wynn TA. Mechanisms of organ injury and repair by macrophages. Annu Rev Physiol. 2017;79:593–617.

    CAS  PubMed  Google Scholar 

  4. Wynn TA. Cellular and molecular mechanisms of fibrosis. J Pathol. 2008;214:199–210.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Garaffa G, Trost LW, Serefoglu EC, Ralph D, Hellstrom WJ. Understanding the course of Peyronie’s disease. Int J Clin Pr. 2013;67:781–8.

    CAS  Google Scholar 

  6. Abdel-Hamid IA, Anis T. Peyronie’s disease: perspectives on therapeutic targets. Expert Opin Ther Targets. 2011;15:913–29.

    CAS  PubMed  Google Scholar 

  7. Dellis A, Papatsoris A. Stem cell therapy for the treatment of Peyronie’s disease. Expert Opin Biol Ther. 2017;17:407–13.

    PubMed  Google Scholar 

  8. Goldring CE, Duffy PA, Benvenisty N, Andrews PW, Ben-David U, Eakins R, et al. Assessing the safety of stem cell therapeutics. Cell Stem Cell. 2011;8:618–28.

    CAS  PubMed  Google Scholar 

  9. Aronowitz JA, Lockhart RA, Hakakian CS. Mechanical versus enzymatic isolation of stromal vascular fraction cells from adipose tissue. + . 2015;4:713.

    PubMed  PubMed Central  Google Scholar 

  10. Gentile P, De Angelis B, Pasin M, Cervelli G, Curcio CB, Floris M, et al. Adipose-derived stromal vascular fraction cells and platelet-rich plasma: basic and clinical evaluation for cell-based therapies in patients with scars on the face. J Craniofac Surg. 2014;25:267–72.

    PubMed  Google Scholar 

  11. Gumucio JP, Flood MD, Roche SM, Sugg KB, Momoh AO, Kosnik PE, et al. Stromal vascular stem cell treatment decreases muscle fibrosis following chronic rotator cuff tear. Int Orthop. 2016;40:759–64.

    PubMed  Google Scholar 

  12. Han S, Sun HM, Hwang KC, Kim SW. Adipose-derived stromal vascular fraction cells: update on clinical utility and efficacy. Crit Rev Eukaryot Gene Expr. 2015;25:145–52.

    PubMed  Google Scholar 

  13. Mazo M, Cemborain A, Gavira JJ, Abizanda G, Arana M, Casado M, et al. Adipose stromal vascular fraction improves cardiac function in chronic myocardial infarction through differentiation and paracrine activity. Cell Transpl. 2012;21:1023–37.

    Google Scholar 

  14. 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;62:720–7.

    PubMed  PubMed Central  Google Scholar 

  15. Haahr MK, Jensen CH, Toyserkani NM, Andersen DC, Damkier P, Sorensen JA, et al. Safety and potential effect of a single intracavernous injection of autologous adipose-derived regenerative cells in patients with erectile dysfunction following radical prostatectomy: an open-label phase I clinical trial. EBioMedicine . 2016;5:204–10.

    PubMed  PubMed Central  Google Scholar 

  16. Guillaume-Jugnot P, Daumas A, Magalon J, Jouve E, Nguyen PS, Truillet R, et al. Autologous adipose-derived stromal vascular fraction in patients with systemic sclerosis: 12-month follow-up. Rheumatol . 2016;55:301–6.

    Google Scholar 

  17. Bivalacqua TJ, Diner EK, Novak TE, Vohra Y, Sikka SC, Champion HC, et al. A rat model of Peyronie’s disease associated with a decrease in erectile activity and an increase in inducible nitric oxide synthase protein expression. J Urol. 2000;163:1992–8.

    CAS  PubMed  Google Scholar 

  18. Castiglione F, Hedlund P, Weyne E, Hakim L, Montorsi F, Salonia A, et al. Intratunical injection of stromal vascular fraction prevents fibrosis in a rat model of Peyronie’s disease. BJU Int. 2018. https://doi.org/10.1111/bju.14570. [Epub ahead of print].

  19. Albersen M, Kendirci M, Van der Aa F, Hellstrom WJ, Lue TF, Spees JL. Multipotent stromal cell therapy for cavernous nerve injury-induced erectile dysfunction. J Sex Med. 2012;9:385–403.

    CAS  PubMed  Google Scholar 

  20. Castiglione F, Hedlund P, Van der Aa F, Bivalacqua TJ, Rigatti P, Van Poppel H, 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. 2013;63:551–60.

    CAS  PubMed  Google Scholar 

  21. Castiglione F, Dewulf K, Hakim L, Weyne E, Montorsi F, Russo A, et al. Adipose-derived stem cells counteract urethral stricture formation in rats. Eur Urol. 2016;70:1032–41.

    PubMed  Google Scholar 

  22. Castiglione F, Hedlund P, Van der Aa F, Bivalacqua TJ, Rigatti P, Van Poppel H, 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. 2013;63:551–60.

    CAS  PubMed  Google Scholar 

  23. Castiglione F, Bergamini A, Albersen M, Hannan JL, Bivalacqua TJ, Bettiga A, et al. Pelvic nerve injury negatively impacts female genital blood flow and induces vaginal fibrosis-implications for human nerve-sparing radical hysterectomy. Bjog. 2015;122:1457–65.

    CAS  PubMed  Google Scholar 

  24. De la Peyronie F. Sur quelques obstacles quis’opposent à l’éjaculation naturelle de la semence. Mem Acad R Chir. 1743;1:423–34.

    Google Scholar 

  25. Sommer F, Schwarzer U, Wassmer G, Bloch W, Braun M, Klotz T, et al. Epidemiology of Peyronie’s disease. Int J Impot Res. 2002;14:379–83.

    CAS  PubMed  Google Scholar 

  26. Gonzalez-Cadavid NF, Rajfer J. Mechanisms of disease: new insights into the cellular and molecular pathology of Peyronie’s disease. Nat Clin Pr Urol. 2005;2:291–7.

    CAS  Google Scholar 

  27. Vernet D, Nolazco G, Cantini L, Magee TR, Qian A, Rajfer J, et al. Evidence that osteogenic progenitor cells in the human tunica albuginea may originate from stem cells: implications for peyronie disease. Biol Reprod. 2005;73:1199–210.

    CAS  PubMed  Google Scholar 

  28. Gonzalez-Cadavid NF. Mechanisms of penile fibrosis. J Sex Med. 2009;6(Suppl 3):353–62.

    PubMed  Google Scholar 

  29. Wynn TA, Ramalingam TR. Mechanisms of fibrosis: therapeutic translation for fibrotic disease. Nat Med. 2012;18:1028–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Caplan AI, Correa D. The MSC: an injury drugstore. Cell Stem Cell. 2011;9:11–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Caplan AI, Dennis JE. Mesenchymal stem cells as trophic mediators. J Cell Biochem. 2006;98:1076–84.

    CAS  PubMed  Google Scholar 

  32. Yu FX, Su LF, Dai CL, Wang Y, Teng YY, Fu JH, et al. Inhibition of pancreatic stellate cell activity by adipose-derived stem cells. Hepatobiliary Pancreat Dis Int. 2015;14:215–21.

    CAS  PubMed  Google Scholar 

  33. Caplan AI, Correa D. The MSC: an injury drugstore. Cell Stem Cell. 2011;9:11–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Sorrell JM, Caplan AI. Topical delivery of mesenchymal stem cells and their function in wounds. Stem Cell Res Ther. 2010 ;1:30.

    PubMed  PubMed Central  Google Scholar 

  35. Castiglione F, Hedlund P, Weyne E, Hakim L, Montorsi F, Bivalacqua TJ, et al. Intratunical injection of human adipose tissue-derived stem cells restores collagen III/I ratio in a rat model of chronic Peyronie’s disease. Sex Med. 2018;7:94-103. https://doi.org/10.1016/j.esxm.2018.09.003.

  36. 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;12:1533–44.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Gokce A, Abd Elmageed ZY, Lasker GF, Bouljihad M, Kim H, Trost LW, et al. Adipose tissue-derived stem cell therapy for prevention and treatment of erectile dysfunction in a rat model of Peyronie’s disease. Andrology. 2014;2:244–51.

    CAS  PubMed  Google Scholar 

  38. Wynn TA. Common and unique mechanisms regulate fibrosis in various fibroproliferative diseases. J Clin Invest. 2007;117:524–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Duffield JS, Lupher M, Thannickal VJ, Wynn TA. Host responses in tissue repair and fibrosis. Annu Rev Pathol. 2013;8:241–76.

    CAS  PubMed  Google Scholar 

  40. El Sherif A, Yano F, Mittal S, Filipi CJ. Collagen metabolism and recurrent hiatal hernia: cause and effect? Hernia . 2006;10:511–20.

    PubMed  Google Scholar 

  41. Wynn TA, Vannella KM. Macrophages in tissue repair, regeneration, and fibrosis. Immunity . 2016;44:450–62.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Lockhart RA, Aronowitz JA, Dos-Anjos Vilaboa S. Use of freshly isolated human adipose stromal cells for clinical applications. Aesthet Surg J. 2017;37(suppl_3):S4–s8.

    PubMed  Google Scholar 

  43. Aronowitz JA, Lockhart RA, Hakakian CS, Birnbaum ZE. Adipose stromal vascular fraction isolation: a head-to-head comparison of 4 cell separation systems #2. Ann Plast Surg. 2016;77:354–62.

    CAS  PubMed  Google Scholar 

  44. Conde-Green A, Kotamarti VS, Sherman LS, Keith JD, Lee ES, Granick MS, et al. Shift toward mechanical isolation of adipose-derived stromal vascular fraction: review of upcoming techniques. Plast Reconstr Surg Glob Open. 2016;4:e1017.

    PubMed  PubMed Central  Google Scholar 

  45. Tremp M, Menzi N, Tchang L, di Summa PG, Schaefer DJ, Kalbermatten DF. Adipose-derived stromal cells from lipomas: isolation, characterisation and review of the literature. Pathobiology . 2016;83:258–66.

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Arianna Bettiga, Fabio Benigni, Giorgia Colciago, Rita Van Bree, Catherien Luyten, Goedlieve Verbist, and Petra Steven for their technical contributions to the experiments in this study. This study was funded by the European Society for Sexual Medicine (ESSM) grant for basic medical research 2011 awarded to Fabio Castiglione and Maarten Albersen and by European Urological Scholarship Programme (EUSP) awarded to Fabio Castiglione Asif Muneer is supported by the NIHR Biomedical Research Centre UCLH.

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Correspondence to Maarten Albersen.

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Hakim, L., Fiorenzo, S., Hedlund, P. et al. Intratunical injection of autologous adipose stromal vascular fraction reduces collagen III expression in a rat model of chronic penile fibrosis. Int J Impot Res 32, 281–288 (2020). https://doi.org/10.1038/s41443-019-0136-9

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