Castration-resistant Lgr5⁺ cells are long-lived stem cells required for prostatic regeneration

The adult prostate possesses a significant regenerative capacity that is of great interest for understanding adult stem cell biology. We demonstrate that leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5) is expressed in a rare population of prostate epithelial progenitor cells, and a castration-resistant Lgr5⁺ population exists in regressed prostate tissue. Genetic lineage tracing revealed that Lgr5⁺ cells and their progeny are primarily luminal. Lgr5⁺ castration-resistant cells are long lived and upon regeneration, both luminal Lgr5⁺ cells and basal Lgr5⁺ cells expand. Moreover, single Lgr5⁺ cells can generate multilineage prostatic structures in renal transplantation assays. Additionally, Lgr5⁺ cell depletion revealed that the regenerative potential of the castrated adult prostate depends on Lgr5⁺ cells. Together, these data reveal insights into the cellular hierarchy of castration-resistant Lgr5+ cells, indicate a requirement for Lgr5⁺ cells during prostatic regeneration, and identify an Lgr5⁺ adult stem cell population in the prostate.