Differentiated prostate luminal cells acquire enhanced regenerative potential after androgen ablation

Cells in the prostate are postulated to have stem cell properties based on organ regeneration following castration. Through single cell RNA-seq (scRNA-Seq) analysis, we identify a rare luminal cell population in the mouse prostate that expresses stem-like markers (Sca1+, Psca+), as well as a larger population of more differentiated cells (Nkx3.1+, Pbsn+, CD133/Prom1+). Unexpectedly, both populations acquire enhanced organoid regeneration potential following castration and contribute equipotently to prostatic regeneration, as revealed by lineage tracing. Regeneration is mediated, in part, by androgen-driven expression of Nrg2, Igf1, Fgf10 and Rspo3 by distinct populations of mesenchymal cells acting in a paracrine fashion on luminal cells. Human prostate tissue contains similar differentiated and stem-like luminal subpopulations which also, collectively. acquire enhanced regenerative potential after androgen ablation therapy. Thus, nearly all luminal cells that persist post-castration contribute to prostate regeneration, not just rare stem cells.