Histone 2B-GFP Label-Retaining Prostate Luminal Cells Possess Progenitor Cell Properties and Are Intrinsically Resistant to Castration

Zhang, Dingxiao; Jeter, Collene; Gong, Shuai; Tracz, Amanda; Lu, Yue; Shen, Jianjun; Tang, Dean G.

doi:10.1016/j.stemcr.2017.11.016

Cited by 37 publications

(42 citation statements)

References 53 publications

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“…Considering previous reports of heterogeneity within prostate epithelial lineages, we next determined lineage‐specific expression of Sox2 . We observed endogenous Sox2 expression in CK5+ basal cells of both proximal and distal regions.…”

Section: Resultsmentioning

confidence: 99%

Sox2 Expression Marks Castration-Resistant Progenitor Cells in the Adult Murine Prostate

et al. 2019

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Identification of defined epithelial cell populations with progenitor properties is critical for understanding prostatic development and disease. Here, we demonstrate that Sox2 expression is enriched in the epithelial cells of the proximal prostate adjacent to the urethra. We use lineage tracing of Sox2-positive cells during prostatic development, homeostasis, and regeneration to show that the Sox2 lineage is capable of self-renewal and contributes to prostatic regeneration. Persisting luminal cells express Sox2 after castration, highlighting a potential role for Sox2 in cell survival and castration-resistance. In addition to revealing a novel progenitor population in the prostate, these data implicate Sox2 as a regulatory factor of adult prostate epithelial stem cells.

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Section: Resultsmentioning

confidence: 99%

Sox2 Expression Marks Castration-Resistant Progenitor Cells in the Adult Murine Prostate

et al. 2019

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“…LGR5 (41), BMI1 (21), Sca-1 (22,31), TROP2 (24), CD133 (23), LY6D (25), and KRT4 (26) have been described using lineage tracing, flow cytometry, and facultative regeneration assays. Label retention by slow cycling cells after multiple rounds of castration has also been proposed as a characteristic of stemness, and a transcriptional profile of labeled cells demonstrates survival of a luminal cell population after androgen deprivation (43). Castration-insensitive luminal epithelia that display many of these individual characteristics are shown to be enriched in the proximal region of the prostate, but defining a cell type as prostate based on 'luminal' (e.g.…”

Section: Discussionmentioning

confidence: 99%

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

Joseph

Henry

Malewska

et al. 2020

Preprint

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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.

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“…(From Shibata and Shen 2015; adapted, with permission, from the authors.) of newly synthesized DNA with BrdU (Tsujimura et al 2002) or of nucleosomes with histones fused with green fluorescent protein (GFP) (Zhang et al 2018). However, studies in other tissues have shown that label retention is not an inherent property of stem cell populations (e.g., Kiel et al 2007), and thus the interpretation of label-retention assays are fraught with potential difficulties.…”

Section: Assays For Identifying Normal and Tumorigenic Progenitor Cellsmentioning

confidence: 99%

Prostate Stem Cells and Cancer Stem Cells

Shen

2018

Cold Spring Harb Perspect Med

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Stem/progenitor cells play central roles in processes of organogenesis and tissue maintenance, whereas cancer stem cells (CSCs) are thought to drive tumor malignancy. Here, we review recent progress in the identification and analysis of normal prostate stem/progenitor cells as well as putative CSCs in both genetically engineered mouse models as well as in human tissue. We also discuss studies that have investigated the cell type of origin for prostate cancer. In addition, we provide a critical assessment of methodologies used in stem cell analyses and outline directions for future research.

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Histone 2B-GFP Label-Retaining Prostate Luminal Cells Possess Progenitor Cell Properties and Are Intrinsically Resistant to Castration

Cited by 37 publications

References 53 publications

Sox2 Expression Marks Castration-Resistant Progenitor Cells in the Adult Murine Prostate

Sox2 Expression Marks Castration-Resistant Progenitor Cells in the Adult Murine Prostate

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

Prostate Stem Cells and Cancer Stem Cells

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