Cell Kinetic Studies Fail to Identify Sequentially Proliferating Progenitors as the Major Source of Epithelial Renewal in the Adult Murine Prostate

Abstract

There is evidence that stem cells and their progeny play a role in the development of the prostate. Although stem cells are also considered to give rise to differentiated progeny in the adult prostate epithelium ex vivo, the cohort of adult prostate stem cells in vivo as well as the mechanisms by which the adult prostate epithelium is maintained and regenerated remain highly controversial. We have attempted to resolve this conundrum by performing in vivo tracing of serially replicating cells after the sequential administration of two thymidine analogues to mice. Our results show that, during normal prostate homeostasis, sequentially proliferating cells are detected at a rate that is consistent with a stochastic process. These findings indicate that in vivo, under steady-state conditions, most adult prostate epithelial cells do not represent the progeny of a small number of specialized progenitors that generate sequentially replicating transit-amplifying (TA) cells but are formed by stochastic cell division. Similarly, no rapidly cycling TA cells were detected during regeneration following one cycle of androgen-mediated involution/regeneration of the prostate epithelium. These findings greatly enhance our understanding of the mechanisms regulating prostate epithelial cell renewal and may have significant implications in defining the cell of origin of proliferative prostatic diseases.

The Sca-1+ and Sca-1− mouse prostatic luminal cell lineages are independently sustained

“…But it remains unclear whether in adults the prostate cells in the region adjacent to the urethra continue to substantially contribute to the epithelial cell lineages throughout the gland. Our study as well as others 16,52 showed that the homeostasis of the adult mouse prostate tissues can be sufficiently maintained by proliferation from distinct progenitors rather than a single stem/progenitor cell population. Considering that the human prostate is also a relatively small organ with a low turnover rate, it is possible that human prostate is also mostly maintained via cell duplication like mouse prostate, but this certainly does not exclude the possibility that there are fundamental differences between human and mouse regarding how the prostate homeostasis is maintained.…”

“…[48][49][50][51] In contrast, by sequentially labeling luminal cells with thymidine analogues, a study concluded that most adult prostate epithelial cells are formed by stochastic cell division. 52 Together, these studies question that the luminal cell lineage is maintained by only one rare population of specialized progenitor.…”

Prostate luminal progenitor cells: from mouse to human, from health to disease

“…33 ) or Luminal-B 32 ; TaBle 2) persisted after castration. In line with previous findings suggesting that most adult epithelial cells result from stochastic cell divisions 81 , a subsequent study used lineage tracing to show that Sca-1 + and Sca-1 neg luminal cell lineages (that is, LSC med -like and secretory cells, respectively) were independently sustained in castration-regeneration experiments, suggesting a progenitor-independent mechanism of luminal cell regeneration 44 . Accordingly, another study 33 showed that, at early stages of prostate regeneration induced by androgen replenishment, L1 secretory luminal cells were more proliferative than L2 luminal progenitor cells in situ, and their respective capacity to generate organoids in vitro no longer differed, in contrast to cells harvested from intact mice.…”

Intra‐epithelial non‐canonical Activin A signaling safeguards prostate progenitor quiescence

“…Recent single‐cell studies have confirmed the enrichment of a variety of epithelial progenitors—basal, luminal proximal (LumP), and periurethral (PrU) cells—in this anatomical district, though also present at low frequency in the distal compartment (Henry et al , 2018; Crowley et al , 2020; Guo et al , 2020; Joseph et al , 2020; Karthaus et al , 2020; Mevel et al , 2020). Such cells are known to be particularly quiescent during homeostasis (Pignon et al , 2015; Kwon et al , 2020), but also to exhibit extensive regenerative potential in ex vivo assays (Kwon et al , 2016b; Crowley et al , 2020).…”