Deficiency in Metabolic Regulators PPARγ and PTEN Cooperates to Drive Keratinizing Squamous Metaplasia in Novel Models of Human Tissue Regeneration

Hindgut-derived endoderm can differentiate into rectal, prostatic, and bladder phenotypes. Stromal-epithelial interactions are crucial for this development; however, the precise mechanisms by which epithelium responds to stromal cues remain unknown. We have previously reported ectopic expression of peroxisome proliferator-activated receptor-gamma 2 (PPAR gamma 2) increased androgen receptor expression and promoted differentiation of mouse prostate epithelium. PPAR gamma is also implicated in urothelial differentiation. Herein we demonstrate that knockdown of PPAR gamma 2 in benign human prostate epithelial cells (BHPrEs) promotes urothelial transdifferentiation. Furthermore, in vitro and in vivo heterotypic tissue regeneration models with embryonic bladder mesenchyme promoted urothelial differentiation of PPAR gamma 2-deficient BHPrE cells, and deficiency of both PPAR gamma isoforms 1 and 2 arrested differentiation. Because PTEN deficiency is cooperative in urothelial pathogenesis, we engineered BHPrE cells with combined knockdown of PPAR gamma and PTEN and performed heterotypic recombination experiments using embryonic bladder mesenchyme. Whereas PTEN deficiency alone induced latent squamous differentiation in BHPrE cells, combined PPAR gamma and PTEN deficiency accelerated the development of keratinizing squamous metaplasia (KSM). We further confirmed via immunohistochemistry that gene expression changes in metaplastic recombinants reflected human urothelium undergoing KSM. In summary, these data suggest that PPAR gamma isoform expression provides a molecular basis for observations that adult human epithelium can be transdifferentiated on the basis of heterotypic mesenchymal induction. These data also implicate PPAR gamma and PTEN inactivation in the development of KSM. (Am J Pathol 2013, 182: 449-459; http://dx.doi.org/10.1016/j.ajpath.2012.10.007)