The Transcriptional Signatures of Cells from the Human Peyronie's Disease Plaque and the Ability of These Cells to Generate a Plaque in a Rat Model Suggest Potential Therapeutic Targets. (11th December 2014)

• Record Type: Journal Article
• Authors: Gelfand, Robert A.; Vernet, Dolores; Kovanecz, Istvan; Rajfer, Jacob; Gonzalez‐Cadavid, Nestor F.
• Is Part Of: Journal of sexual medicine. Volume 12:Number 2(2015:Feb.)
• Page Start: 313
• Page End: 327
• Publication Date: 2014-12-11
• Subjects: Sexual disorders -- Periodicals; Sex -- Periodicals; Sexual health -- Periodicals; 616.69005
• DOI: 10.1111/jsm.12760
• Languages: English
• ISSNs: 1743-6095

Abstract

<abstract abstract-type="main"> <title>Abstract</title> <sec id="jsm12760-sec-0001" sec-type="section"> <title>Introduction</title> <p>The success of medical therapies for Peyronie's disease (PD) has not been optimal, possibly because many of them went directly to clinical application without sufficient preclinical scientific research. Previous studies revealed cellular and molecular pathways involved in the formation of the PD plaque and in particular the role of the myofibroblast.</p> </sec> <sec id="jsm12760-sec-0002" sec-type="section"> <title>Aims</title> <p>The current work aimed to determine under normal and fibrotic conditions what differentiates PD cells from tunica albuginea (TA) and corpora cavernosa (CC) cells by defining their global transcriptional signatures and testing in vivo whether PD cells can generate a PD‐like plaque.</p> </sec> <sec id="jsm12760-sec-0003" sec-type="section"> <title>Methods</title> <p>Human TA, PD, and CC cells were grown with transforming growth factor beta 1 (TGFβ1; TA+, PD+, CC+) or without it (TA−, PD−, CC−) and assayed by (i) immunofluorescence, Western blot and RT‐PCR for myofibroblast, smooth muscle cell and stem cell markers; (ii) collagen content; and (iii) DNA microarray analysis. The ability of PD+ cells to induce a PD‐like plaque in an immuno‐suppressed rat model was assessed by Masson trichrome and Picrosirius Red stainings.</p> </sec> <sec id="jsm12760-sec-0004" sec-type="section"> <title>Main Outcomes Measures</title> <p>Fibroproliferative features of PD cells and identification of related key genes as novel targets to reduce plaque size.</p> </sec> <sec id="jsm12760-sec-0005" sec-type="section"> <title>Results</title> <p>Upon TGFβ1stimulation, collagen levels were increased by myofibroblasts in the PD+ but not in the CC+ cells. The transcriptional signature of the PD− cells identified fibroproliferative, myogenic (myofibroblasts), inflammatory, and collagen turnover genes that differentiate them from TA− or CC− cells and respond to TGFβ1 with a PD+ fibrotic phenotype, by upregulation of IGF‐1, ACTG2, MYF5, ACTC1, PSTN, COL III, MMP3, and others. The PD+ cells injected into the TA of the rat induce a PD‐like plaque.</p> </sec> <sec id="jsm12760-sec-0006" sec-type="section"> <title>Conclusions</title> <p>This suggests a novel combination therapy to eliminate a PD plaque by targeting the identified genes to (i) improve collagenase action by stimulating endogenous metalloproteinases specific to key collagen types and (ii) counteract fibromatosis by inhibiting myofibroblast generation, proliferation, and/or apoptosis. <bold>Gelfand RA, Vernet D, Kovanecz I, Rajfer J, and Gonzalez‐Cadavid NF. The transcriptional signatures of cells from the human Peyronie's disease plaque and the ability of these cells to generate a plaque in a rat model suggest potential therapeutic targets. J Sex Med 2015;12:313–327.</bold></p> </sec> </abstract>