Urethral luminal epithelia are castration-insensitive progenitors of the proximal prostate

Abstract

Castration-insensitive epithelial progenitors capable of regenerating the prostate are concentrated in the proximal region close to the urethra, but the identification of these cells has been limited to individual cell surface markers. Here, we use single cell RNA sequencing (scRNA-seq) to obtain a cellular anatomy of the mouse prostate and urethra and create a comparative map with the human. These data reveal that previously identified facultative progenitors marked by TROP2, Sca-1, KRT4, and PSCA are actually luminal epithelia of the urethra that extend into the proximal prostate. These mouse urethral cells are the human equivalent of previously identified human club and hillock urethral cells. Castration decreases androgen-dependent prostate luminal epithelia as expected, but TROP2+ urethral luminal epithelia survive and expand into the prostate. Benign prostatic hyperplasia (BPH) has long been considered an 'embryonic reawakening', but the cellular origin of peri-urethral growth is unclear. We use scRNA-seq and flow cytometry to demonstrate an increase in PSCA+ urethral luminal epithelia within glandular nodules from patients with BPH, which are further enriched in patients treated with a 5 alpha reductase inhibitor. These data demonstrate that the putative prostate progenitors enriched by castration in the proximal prostate are an expansion of urethral luminal epithelia and that these cells may play an important role in the etiology of human BPH. Significance StatementThe prostate involutes after castration, but regrows to its original size with androgen replenishment. This observation prompted the search for a castration-insensitive prostate progenitor. Here, Joseph et al. produce a comparative cellular atlas of the prostate and urethra in the mouse vs. human, discovering an equivalent urethral luminal epithelial cell type that extends into the proximal prostatic ducts and expresses previously identified markers of facultative prostate progenitors. Urethral luminal epithelia are established before prostate budding in human and mouse development, and expand after castration in the mouse and after 3 5 alpha reductase inhibitor treatment in human BPH. These data suggest that luminal epithelia of the urethra are castration-insensitive cells of proximal ducts that may act as progenitors in human BPH.

A single-cell atlas of the mouse and human prostate reveals heterogeneity and conservation of epithelial progenitors

“…In the human prostate, the progenitor activity of LumP and/or PrU-like cells may have been observed by retrospective lineage tracing using mitochondrial mutations (Moad et al, 2017). In addition, the LumP and PrU populations may share some similarities with the "hillock" and "club" cells originally described in a cellular atlas of the mouse lung (Montoro et al, 2018) and reported in the human prostate (Henry et al, 2018;Joseph et al, 2020) and in benign human prostate organoids (McCray et al, 2019), but the precise relationship of these populations is unclear.…”

An immunohistochemical prostate cell identification key indicates that aging shifts procollagen 1A1 production from myofibroblasts to fibroblasts in dogs prone to prostate-related urinary dysfunction

“…We successfully stained dog prostate sections with the same antibodies and same antibody combinations previously used to identify mouse prostatic cell types, enabling future comparisons between these two model species. We also determined the abundance and distribution of individual cell types to enable comparisons to human prostate[13, 14] and address whether canine prostate has a homogeneous[5, 39] or heterogenous[38] composition. Our activities establish a baseline cellular map of the canine prostate that will be used to determine the impact of age, inflammation and other disease processes on prostatic cellular composition and to ultimately identify disease causing cell types.…”

“…[12] Careful histological and molecular analyses of human prostate have revolutionized our understanding of the cell types of the prostate, revealing a gland that contains at least five epithelial cell types and three fibroblast-like stromal cell types that are organized into three zones. [13, 14] Canine prostate cell types and their spatial distribution across the gland have not been extensively examined using modern molecular and multiplex immunohistochemical methods. This void of knowledge hinders the translational potential of canine prostate findings to human medicine in a model species that bolsters great benefit to the prostate research field.…”

An immunohistochemical prostate cell identification key indicates that aging shifts procollagen 1A1 production from myofibroblasts to fibroblasts in dogs prone to prostate-related urinary dysfunction

“…We successfully stained dog prostate sections with the same antibodies and same antibody combinations previously used to identify mouse prostatic cell types, enabling future comparisons between these two model species. We also determined the abundance and distribution of individual cell types to enable comparisons to human prostate [ 13 , 14 ] and address whether canine prostate has a homogeneous [ 5 , 39 ] or heterogenous [ 38 ] composition. Our activities establish a baseline cellular map of the canine prostate that will be used to determine the impact of age, inflammation and other disease processes on prostatic cellular composition and to ultimately identify disease causing cell types.…”

“…[ 12 ] Careful histological and molecular analyses of human prostate have revolutionized our understanding of the cell types of the prostate, revealing a gland that contains at least five epithelial cell types and three fibroblast-like stromal cell types that are organized into four zones. [ 13 , 14 ] Canine prostate cell types and their spatial distribution across the gland have not been extensively examined using modern molecular and multiplex immunohistochemical methods. This void of knowledge hinders the translational potential of canine prostate findings to human medicine in a model species that bolsters great benefit to the prostate research field.…”