Understanding the cellular constituents of the prostate is essential for identifying the cell of origin for prostate adenocarcinoma. Here we describe a comprehensive single-cell atlas of the adult mouse prostate epithelium, which displays extensive heterogeneity. We observe distal lobe-specific luminal epithelial populations (LumA, LumD, LumL, and LumV), a proximally-enriched luminal population (LumP) that is not lobe-specific, and a periurethral population (PrU) that shares both basal and luminal features. Functional analyses suggest that LumP and PrU cells have multipotent progenitor activity in organoid formation and tissue reconstitution assays. Furthermore, we show that mouse distal and proximal luminal cells are most similar to human acinar and ductal populations, that a PrU-like population is conserved between species, and that the mouse lateral prostate is most similar to the human peripheral zone. Our findings elucidate new prostate epithelial progenitors, and help resolve long-standing questions about anatomical relationships between the mouse and human prostate.

Embryonic (ES) and trophoblast (TS) stem cells reflect the first, irrevocable cell fate decision in development that is reinforced by distinct epigenetic lineage barriers. Nonetheless, ES cells can seemingly acquire TS-like characteristics upon manipulation of lineage-determining transcription factors or activation of the extracellular signal-regulated kinase 1/2 (Erk1/2) pathway. Here we have interrogated the progression of reprogramming in ES cell models with regulatable Oct4 and Cdx2 transgenes or conditional Erk1/2 activation. Although trans-differentiation into TS-like cells is initiated, lineage conversion remains incomplete in all models, underpinned by the failure to demethylate a small group of TS cell genes. Forced expression of these non-reprogrammed genes improves trans-differentiation efficiency, but still fails to confer a stable TS cell phenotype. Thus, even ES cells in ground-state pluripotency cannot fully overcome the boundaries that separate the first cell lineages but retain an epigenetic memory of their ES cell origin.

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A single-cell atlas of the mouse and human prostate reveals heterogeneity and conservation of 3 epithelial progenitors 4 5 6 Summary 24 Understanding the cellular constituents of the prostate is essential for identifying the 25 cell of origin for benign prostatic hyperplasia and prostate adenocarcinoma. Here we 26 describe a comprehensive single-cell atlas of the adult mouse prostate epithelium, which 27 demonstrates extensive heterogeneity. We observe distinct lobe-specific luminal epithelial 28 populations (LumA, LumD, LumL, and LumV) in the distal region of the four prostate lobes, 29 a proximally-enriched luminal population (LumP) that is not lobe-specific, as well as a 30 periurethral population (PrU) that shares both basal and luminal features. Functional 31 analyses suggest that LumP and PrU cells have multipotent progenitor activity in organoid 32 formation and tissue reconstitution assays. Furthermore, we show that mouse distal and 33 proximal luminal cells are most similar to human acinar and ductal populations, that a PrU-34 like population is conserved between species, and that the mouse lateral prostate is most 35 similar to the human peripheral zone. Our findings elucidate new prostate epithelial 36 progenitors, and help resolve long-standing questions about the anatomical relationships 37 between the mouse and human prostate. 38 39 40 3