Cell kinetic studies fail to identify sequentially proliferating progenitors as the major source of epithelial renewal in the adult murine prostate.

Jean-Christophe Pignon,Ingrid Carvo,Meredith Regan,Chiara Grisanzio,Lillian Werner,E Lynette Wilson,Sabina Signoretti,Lucia R Languino

doi:10.1371/journal.pone.0128489

Jean-Christophe Pignon, Ingrid Carvo + Show 6 more

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https://doi.org/10.1371/journal.pone.0128489

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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.

Highlights

It is widely accepted that cancer arises through a series of mutations that occur over a prolonged time period
We demonstrate for the first time that random duplication of prostate epithelial cells rather than serial division of a small pool of progenitor/TA cells is the dominant mechanism of epithelial cell replacement during normal homeostasis of the prostate epithelium
While these results raise the possibility that basal and luminal cell types might be independent of each other for renewal, recent cell-specific lineage tracing of basal and luminal cells performed in the mouse prostate have validated this hypothesis, convincingly demonstrating that basal cells do not contribute significantly to the pool of luminal cells and vice versa [6, 7, 23]

Summary

Introduction

It is widely accepted that cancer arises through a series of mutations that occur over a prolonged time period. This model is challenged by the evidence that, in contrast to rapidly proliferating epithelial cell compartments (e.g., epidermis and intestinal epithelium), slowly proliferating adult tissues (e.g., pancreatic epithelium and cardiac myocytes) can be maintained by random duplication of differentiated cells, with no significant contribution from stem/progenitor cells [1,2,3]. Recent lineage tracing studies in adult mice suggest that basal progenitor cells do not play a significant role in normal prostate homeostasis or androgen-mediated regeneration of the prostate epithelium [6, 7] While these novel findings suggest that the basal and luminal cell lineages become self-sustaining during adult life, it remains to be clarified whether each cell compartment (i.e. basal and luminal) is supported by a small pool of specialized progenitors that generate serially replicating transit amplifying (TA) cells, or by random duplication of adult epithelial cells. The fraction of CIdU-IdU-co-positive cells would be relatively small and would mirror the fraction predicted by the stochastic model (Fig 1C)

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