Multipotent and unipotent progenitors contribute to prostate postnatal development

Abstract

The prostate is a glandular epithelium composed of basal, luminal and neuroendocrine cells that originate from the urogenital sinus during embryonic development. After birth, the prostate keeps developing until the end of puberty. Here, we used inducible genetic lineage tracing experiments in mice to investigate the cellular hierarchy that governs prostate postnatal development. We found that prostate postnatal development is mediated by basal multipotent stem cells that differentiate into basal, luminal and neuroendocrine cells, as well as by unipotent basal and luminal progenitors. Clonal analysis of basal cells revealed the existence of bipotent and unipotent basal progenitors as well as basal cells already committed to the luminal lineage with intermediate cells co-expressing basal and luminal markers associated with this commitment step. The existence of multipotent basal progenitors during prostate postnatal development contrasts with the distinct pools of unipotent basal and luminal stem cells that mediate adult prostate regeneration. Our results uncover the cellular hierarchy acting during prostate development and will be instrumental in defining the cellular origin and the mechanisms underlying prostate cancer initiation.

Symmetrical and asymmetrical division analysis provides evidence for a hierarchy of prostate epithelial cell lineages

“…Consistent with our results, such different cell division modes have been observed in neuroepithelial cells and neuroblasts of Drosophila in which neuroblasts undergo asymmetrical divisions with a parallel spindle orientation to the apical-basal axis, while neuroepithelial cells divide symmetrically, perpendicular to the apical-basal axis 44,45 . By cell division mode analysis, our findings strongly support the model proposed recently by Ousset et al 8 that there is a hierarchy of epithelial lineages containing multi-and unipotent stem cells in the developing prostate.…”

“…Furthermore, using a lineage-tracing approach, Choi et al 7 demonstrated that basal and luminal cells in adult mouse prostates are independent self-sustaining lineages during prostate regeneration. However, using the same approach, other groups reported that in addition to unipotent luminal cells, basal cells can act as multipotent stem cells during prostate development or regeneration [8][9][10] .…”

Multi-Drug Resistance ABC Transporter Inhibition Enhances Murine Ventral Prostate Stem/Progenitor Cell Differentiation

“…Luminal marker expression in sphere culture examines the differentiation potential of basal stem/progenitor cells, which may not be the case in vivo. The luminal cell compartment is regenerated from stem/progenitor cells in the luminal cell compartment, though a very small basal cell fraction has plasticity to differentiate into luminal cells during regeneration and in sphere culture [9]. Hence, lineage tracing of Abcg2 expressing cells would shed light on their in vivo differentiation potential during prostate development and regeneration.…”

“…Classic androgen deprivation and regeneration studies demonstrated that adult stem cells are present in the basal layer of the prostate gland [3][4][5]. However, the latest lineage tracing experiments during murine postnatal prostate development suggest that stem/ progenitor cells are present in both basal and luminal cell compartments [6][7][8][9][10]. Multi-drug resistance-ATP binding cassette (MDR-ABC) transporters potentially regulate prostate epithelial differentiation by mediating efflux of steroids [11,12].…”

A plethora of progenitors in the post‐natal prostate

“…In 2008, we demonstrated that basal stem cells expressing high levels of CD49f, Sca-1 and Trop2 isolated from a β-actin-DsRed transgenic mouse could regenerate glands containing basal, luminal and neuroendocrine cells, which all contained the label of the initial purified donor cell on transplantation into immune-deficient mice [6]. By following the progeny of labelled basal cells using the keratin 5 (K5) and keratin 14 (K14) promoters, Blanpain and co-workers have demonstrated that basal cells give rise to basal, luminal and neuroendocrine cells [5]. Although emerging data from epithelial tissues including the mammary gland, skin and sweat glands suggest that transplantation assays and lineage tracing do not yield identical results [7,8], here two approaches were used to confirm the presence of multipotent basal stem cells that give rise to all three lineages.…”