In vitro induction of prostate buds from murine urogenital epithelium in the absence of mesenchymal cells

The prostate is a male reproductive gland which secretes prostatic fluid that enhances male fertility. During development and instigated by fetal testosterone, prostate cells arise caudal to the bladder at the urogenital sinus (UGS), when the urogenital mesenchyme (UGM) secretes signals to the urogenital epithelium (UGE). These initial mesenchymal signals induce prostate-specific gene expression in the UGE, after which epithelial progenitor cells form prostatic buds. Although many important factors for prostate development have been described using UGS organ cultures, those necessary and sufficient for prostate budding have not been clearly identified. This has been in part due to the difficulty to dissect the intricate signaling and feedback between epithelial and mesenchymal UGS cells. In this study, we separated the UGM from the UGE and tested candidate growth factors to show that when FGF10 is present, testosterone is not required for initiating prostate budding from the UGE. Moreover, in the presence of low levels of FGF10, canonical WNT signaling enhances the expression of several prostate progenitor markers in the UGE before budding of the prostate occurs. At the later budding stage, higher levels of FGF10 are required to increase budding and retinoic acid is indispensable for the upregulation of prostate-specific genes. Lastly, we show that under optimized conditions, female UGE can be instructed towards a prostatic fate, and in vitro generated prostate buds from male UGE can differentiate into a mature prostate epithelium after in vivo transplantation. Taken together, our results clarify the signals that can induce fetal prostate buds in the urogenital epithelium in the absence of the surrounding, instructive mesenchyme.

Automated summary

The prostate is a male reproductive gland that secretes prostatic fluid to enhance male fertility. This study unravels the signaling events that drive the formation and development of prostate buds from the urogenital epithelium (UGE), independent of the surrounding mesenchyme. It shows that FGF10 and canonical WNT signaling play crucial roles in initiating and enhancing prostate budding, while retinoic acid is essential for the upregulation of prostate-specific genes. Moreover, it demonstrates that under optimized conditions, female UGE can be directed towards a prostatic fate, and male UGE-derived prostate buds can differentiate into mature prostate epithelium after transplantation.