Regenerated Luminal Epithelial Cells Are Derived from Preexisting Luminal Epithelial Cells in Adult Mouse Prostate

Liu, June; Pascal, Laura E.; Isharwal, Sudhir; Metzger, Daniel; Garcia, Raquel Ramos; Pilch, Ján; Kasper, Susan; Williams, Karin; Basse, Per H.; Nelson, Joel B.; Chambon, Pierre; Wang, Zhou

doi:10.1210/me.2011-1081

Cited by 75 publications

(72 citation statements)

References 23 publications

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“…One major difference between the two epithelial tissues, however, is that, whereas terminally differentiated epidermal cells are unable to proliferate and undergo apoptosis, prostate luminal cells are longlived and able to divide (32). Of note, recent lineage tracing studies in the adult prostate suggest that basal and luminal cells are largely self-sustaining cell lineages (6,8,9). Our data support a model in which during prostate development, luminal cells form from multipotent, ΔNp63-expressing stem/progenitor cells; subsequently, ΔNp63-positive basal cells (or a least some of them) transition to unipotency and luminal cells acquire self-renewal capacities.…”

Section: Discussionmentioning

confidence: 99%

“…Similarly, a subset of adult human prostate basal cells is able to reconstitute prostatic glands when engrafted with mouse urogenital mesenchyme under the renal capsule of murine hosts (5). However, recent in vivo lineage studies in the adult prostate gave conflicting results regarding basal cells' ability to give rise to luminal cells (6)(7)(8)(9). Knowledge about urothelial cell lineages is also uncertain and controversial (2,10).…”

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confidence: 99%

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p63-expressing cells are the stem cells of developing prostate, bladder, and colorectal epithelia

Pignon

Grisanzio

Geng

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

195

194

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The tumor protein p63 (p63), and more specifically the NH2-terminal truncated (ΔN) p63 isoform, is a marker of basal epithelial cells and is required for normal development of several epithelial tissues, including the bladder and prostate glands. Although p63-expressing cells are proposed to be the stem cells of the developing prostate epithelium and bladder urothelium, cell lineages in these endoderm-derived epithelia remain highly controversial, and rigorous lineage tracing studies are warranted. Here, we generated knock-in mice expressing Cre recombinase (Cre) under the control of the endogenous ΔNp63 promoter. Heterozygote ΔNp63 +/Cre mice were phenotypically normal and fertile. Cremediated recombination in ΔNp63 +/Cre ;ROSA26 EYFP reporter mice faithfully recapitulated the pattern of ΔNp63 expression and were useful for genetic lineage tracing of ΔNp63-expressing cells of the caudal endoderm in vivo. We found that ΔNp63-positive cells of the urogenital sinus generated all epithelial lineages of the prostate and bladder, indicating that these cells represent the stem/ progenitor cells of those epithelia during development. We also observed ΔNp63 expression in caudal gut endoderm and the contribution of ΔNp63-positive cells to the stem/progenitor compartment of adult colorectal epithelium. Because p63 is a master regulator of stratified epithelial development, this finding provides a unique developmental insight into the cell of origin of squamous cell metaplasia and squamous cell carcinoma of the colon.large intestine | hindgut | genitourinary tract

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

p63-expressing cells are the stem cells of developing prostate, bladder, and colorectal epithelia

Pignon

Grisanzio

Geng

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

195

194

View full text Add to dashboard Cite

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“…Two models have been used frequently in previous studies to investigate the prostate epithelial lineage hierarchy: the aging model and the model in which epithelial turnover is induced by alternate androgen ablation and replacement (14)(15)(16)(17)(18). A limitation of these models is that they do not consider some environmental factors, such as inflammation, that affect human prostate epithelial homeostasis.…”

Section: Discussionmentioning

confidence: 99%

“…A third type of epithelial cell, neuroendocrine cells, is rare and hence often is not investigated as intensively as the other two lineages (13). Using a lineage-tracing approach, we and several other groups showed that adult murine prostate basal and luminal cell lineages are largely self-sustained when residing in their native microenvironment, although in two of the studies basal cells were shown to generate luminal cells at an extremely rare frequency (14)(15)(16)(17)(18). In stark contrast, other studies have shown that basal cells are able to differentiate very efficiently into luminal cells and neuroendocrine cells in a dissociated prostate-cell regeneration assay (19)(20)(21)(22)(23)(24)(25).…”

mentioning

confidence: 98%

Prostatic inflammation enhances basal-to-luminal differentiation and accelerates initiation of prostate cancer with a basal cell origin

Kwon¹,

Zhang²,

Ittmann

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

171

154

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Chronic inflammation has been shown to promote the initiation and progression of diverse malignancies by inducing genetic and epigenetic alterations. In this study, we investigate an alternative mechanism through which inflammation promotes the initiation of prostate cancer. Adult murine prostate epithelia are composed predominantly of basal and luminal cells. Previous studies revealed that the two lineages are largely self-sustained when residing in their native microenvironment. To interrogate whether tissue inflammation alters the differentiation program of basal cells, we conducted lineage tracing of basal cells using a K14-CreER; mTmG model in concert with a murine model of prostatitis induced by infection from the uropathogenic bacteria CP9. We show that acute prostatitis causes tissue damage and creates a tissue microenvironment that induces the differentiation of basal cells into luminal cells, an alteration that rarely occurs under normal physiological conditions. Previously we showed that a mouse model with prostate basal cell-specific deletion of Phosphatase and tensin homolog (K14-CreER;Pten fl/fl ) develops prostate cancer with a long latency, because disease initiation in this model requires and is limited by the differentiation of transformation-resistant basal cells into transformation-competent luminal cells. Here, we show that CP9-induced prostatitis significantly accelerates the initiation of prostatic intraepithelial neoplasia in this model. Our results demonstrate that inflammation results in a tissue microenvironment that alters the normal prostate epithelial cell differentiation program and that through this cellular process inflammation accelerates the initiation of prostate cancer with a basal cell origin.prostate stem cells | cells-of-origin for cancer

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“…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].…”

Section: Introductionmentioning

confidence: 99%

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

Samant

Jackson

Felix

et al. 2015

Stem Cells and Development

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Multi-drug resistance (MDR)-ATP binding cassette (ABC) transporters, ABCB1, ABCC1, and ABCG2 participate in the efflux of steroid hormones, estrogens, and androgens, which regulate prostate development and differentiation. The role of MDR-ABC efflux transporters in prostate epithelial proliferation and differentiation remains unclear. We hypothesized that MDR-ABC transporters regulate prostate differentiation and epithelium regeneration. Prostate epithelial differentiation was studied using histology, sphere formation assay, and prostate regeneration induced by cycles of repeated androgen withdrawal and replacement. Embryonic deletion of Abcg2 resulted in a decreased number of luminal cells in the prostate and increased sphere formation efficiency, indicating an imbalance in the prostate epithelial differentiation pattern. Decreased luminal cell number in the Abcg2 null prostate implies reduced differentiation. Enhanced sphere formation efficiency in Abcg2 null prostate cells implies activation of the stem/progenitor cells. Prostate regeneration was associated with profound activation of the stem/progenitor cells, indicating the role of Abcg2 in maintaining stem/progenitor cell pool. Since embryonic deletion of Abcg2 may result in compensation by other ABC transporters, pharmacological inhibition of MDR-ABC efflux was performed. Pharmacological inhibition of MDR-ABC efflux enhanced prostate epithelial differentiation in sphere culture and during prostate regeneration. In conclusion, Abcg2 deletion leads to activation of the stem/progenitor cells and enhances differentiating divisions; and pharmacological inhibition of MDR-ABC efflux leads to epithelial differentiation. Our study demonstrates for the first time that MDR-ABC efflux transporter inhibition results in enhanced prostate epithelial cell differentiation.

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Regenerated Luminal Epithelial Cells Are Derived from Preexisting Luminal Epithelial Cells in Adult Mouse Prostate

Cited by 75 publications

References 23 publications

p63-expressing cells are the stem cells of developing prostate, bladder, and colorectal epithelia

p63-expressing cells are the stem cells of developing prostate, bladder, and colorectal epithelia

Prostatic inflammation enhances basal-to-luminal differentiation and accelerates initiation of prostate cancer with a basal cell origin

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

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