Multipotent Basal Stem Cells, Maintained in Localized Proximal Niches, Support Directed Long-Ranging Epithelial Flows in Human Prostates

Moad, Mohammad; Hannezo, Édouard; Buczacki, Simon; Wilson, Laura; El-Sherif, A; Sims, David; Pickard, Robert; Wright, Nicholas A.; Williamson, Stuart C.; Turnbull, Doug M.; Taylor, Robert W.; Greaves, Laura C.; Robson, Craig; Simons, Benjamin D.; Heer, Rakesh

doi:10.1016/j.celrep.2017.07.061

Cited by 65 publications

(78 citation statements)

References 51 publications

(76 reference statements)

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“…As possible evidence that BPH is a reawakening of urethral budding and branching, we demonstrate that the identity of urethral luminal epithelia is established prior to prostate budding in the developing mouse and human ( Figure 4). Evidence from lineage tracing studies of mitochondrial mutations in humans demonstrates a clonal expansion of cells in the proximal urethra to the distal prostate in healthy adults (27,28), but needs confirmation in BPH specimens.…”

Section: Discussionmentioning

confidence: 99%

“…Several studies have identified cell populations characterized by expression of BMI1 (21), Sca-1 (22,23), TROP2 (24), LY6D (25), and KRT4 (26) that are enriched in the proximal region of the mouse prostate after castration, form spheroids at high frequency, and can act as facultative progenitors in prostate regeneration assays. A proximal to distal expansion of progenitors in human lineage tracing studies has also been demonstrated (27,28).…”

Section: Introductionmentioning

confidence: 88%

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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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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 88%

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

Joseph

Henry

Malewska

et al. 2020

Preprint

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“…The resulting mesenchyme cell population will include multiple mesenchymal cell types, i.e., mesenchymal stem cell-like cells, fibroblasts, endothelial cells, nerve cells, and immune cells. Isolation of mesenchymal cell subsets with fluorescence-activated cell sorting (FACS) or magnetic activated cell sorting (MACS), can be performed on the cells as described elsewhere (Kwon, Nelson, DeSantis, Morrissey, & Larsen, 2017;Lee et al, 2017;Moad et al, 2017;Yang, Adam, Ge, Hua, & Fuchs, 2017;Zepp et al, 2017;Zhao et al, 2017).…”

Section: Further Enrichment Of Mesenchymal Cellsmentioning

confidence: 99%

Generating Embryonic Salivary Gland Organoids

et al. 2018

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Organoids are important research tools for studying organ morphogenesis and differentiation because they recapitulate ex vivo the native 3D organization of cells that is essential for proper cell and organ function. The composition of organoids can be manipulated to incorporate specific cell types to facilitate molecular interrogation of cell-cell interactions during organoid formation. A method for generating organoids derived from both embryonic salivary gland epithelial progenitor cells and mesenchymal support cells is described. Methods for isolating enriched populations of the epithelial cells as clusters and the mesenchyme cells as single cells from mouse embryonic submandibular salivary glands are also provided. Separating the epithelial and mesenchymal cell populations allows for independent molecular manipulation of each cell type. In addition, methods for lentiviral transduction of the mesenchyme cells and quantitative image analysis of organoids are provided. The methods described here are useful for exploring mechanisms driving organ formation. C 2018 by John Wiley & Sons, Inc.Keywords: mesenchyme r organoid r proacinar r salivary

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“…Using one-dimensional mathematical models to infer stem cells and progenitor cells dynamics from lineage tracing experiments have been useful in modeling different tissues such as murine epithelial homeostasis of the skin (33), gut (34), human epithelial homeostasis of the epidermis (35) lung (36) prostate (37) and the cornea (38,39). Yet, while these models are insightful, the unique spatial organization in the cornea requires twodimensional models to encompass overall pattern changes.…”

Section: Introductionmentioning

confidence: 99%

The role of replication-removal spatial correlations and cellular replicative lifespan in corneal epithelium homeostasis

Strinkovsky

Havkin

Shalom-Feuerstein

et al. 2020

Preprint

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Homeostasis in adult tissues relies on the replication dynamics of stem cells, their progenitors and the spatial balance between them. This spatial and kinetic coordination is crucial to the successful maintenance of tissue size and its replenishment with new cells. However, our understanding of the role of cellular replicative lifespan and spatial correlation between cells in shaping tissue integrity is still lacking. We developed a mathematical model for the stochastic spatial dynamics that underlie the rejuvenation of corneal epithelium. Our model takes into account different spatial correlations between cell replication and cell removal. We derive the tradeoffs between replicative lifespan, spatial correlation length, and tissue rejuvenation dynamics. We determine the conditions that allow homeostasis and are consistent with biological timescales, pattern formation, and mutants phenotypes. Our results can be extended to any cellular system in which spatial homeostasis is maintained through cell replication.

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Multipotent Basal Stem Cells, Maintained in Localized Proximal Niches, Support Directed Long-Ranging Epithelial Flows in Human Prostates

Cited by 65 publications

References 51 publications

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

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

Generating Embryonic Salivary Gland Organoids

The role of replication-removal spatial correlations and cellular replicative lifespan in corneal epithelium homeostasis

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