Castration-Resistant Lgr5+ Cells Are Long-Lived Stem Cells Required for Prostatic Regeneration

Abstract

SummaryThe 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.

Sox2 Expression Marks Castration-Resistant Progenitor Cells in the Adult Murine Prostate

“…The percentage of YFP+ cells in multiple rounds of castration‐regeneration hints at the existence of multiple progenitor pools. This is not entirely surprising, as recent reports have revealed castration‐resistant populations marked by Nkx3.1, Lgr5, and Bmi1 . Castration‐resistant cells expressing either Nkx3.1 (CARNs) or Bmi1 (CARBs), were shown to be distinct, nonoverlapping populations .…”

Identification, isolation and characterization of human LGR5-positive colon adenoma cells

“…Our study presents a blueprint for the identification, in vitro culture, isolation and experimental characterization of human LGR5(+) cells. We anticipate our methods can be readily adapted for the isolation and characterization of the LGR5(+) cell populations in other human tissues, including cochlea (McLean et al, 2017), hair (Jaks et al, 2008), kidney , liver (Huch et al, 2013), lung (Lee et al, 2017), mammary gland (de Visser et al, 2012), oral mucosa (Boddupally et al, 2016), prostate (Wang et al, 2015a) and stomach Simon et al, 2012). Additionally, we expect that the organoid culture methods described here will provide an experimental platform for the development of novel chemopreventive and chemotherapeutic agents that target LGR5(+) stem cells.…”

Prostate organogenesis: tissue induction, hormonal regulation and cell type specification

“…Notably, androgen deprivation by castration results in significant epithelial cell death in the prostate, whereas subsequent testosterone supplementation results in rapid tissue regeneration. During androgen-mediated regeneration, luminal castration-resistant Nkx3.1-expressing cells (CARNs) as well as basal cell populations can display bipotency and self-renewal indicative of stem cell activity (Lee et al, 2014;Wang et al, 2009Wang et al, , 2013bWang et al, , 2015. Furthermore, during tissue damage and repair, such as in mouse models of prostatitis or luminal-specific anoikis, basal cells show significant capability to replace lost luminal cells Toivanen et al, 2016).…”