Generation of a prostate from a single adult stem cell

Abstract

The existence of prostate stem cells (PSCs) was first postulated from the observation that normal prostate regeneration can occur after repeated cycles of androgen deprivation and replacement in rodents1. Given the critical role of PSCs in maintaining prostate tissue integrity and their potential involvement in prostate tumorigenesis2, it is important to define specific markers for normal PSCs. Several cell-surface markers have been reported to identify candidate PSCs, including stem cell antigen-1 (Sca-1, also known as Ly6a), CD133 (Prom1) and CD44 (refs 3—10). However, many non-PSCs in the mouse prostate also express these markers and thus identification of a more defined PSC population remains elusive. Here we identify CD117 (c-kit, stem cell factor receptor) as a new marker of a rare adult mouse PSC population, and demonstrate that a single stem cell defined by the phenotype Lin-Sca-1+CD133+CD44+CD117+ can generate a prostate after transplantation in vivo. CD117 expression is predominantly localized to the region of the mouse prostate proximal to the urethra and is upregulated after castration-induced prostate involution—two characteristics consistent with that of a PSC marker. CD117+ PSCs can generate functional, secretion-producing prostates when transplanted in vivo. Moreover, CD117+ PSCs have long-term self-renewal capacity, as evidenced by serial isolation and transplantation in vivo. Our data establish that single cells in the adult mouse prostate with multipotent, self-renewal capacity are defined by a Lin-Sca-1+CD133+CD44+CD117+ phenotype.

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Figure 1: CD117 is preferentially expressed in the proximal region of the mouse prostate.
Figure 2: The CD117 + population enriches for normal adult prostate stem cells.
Figure 3: A single adult stem cell with the phenotype Lin - Sca-1 + CD133 + CD44 + CD117 + can generate a secretion-producing prostate.
Figure 4: Human prostates contain a subpopulation of CD117 + cells that localize to the basal layer of the prostate epithelium.

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Acknowledgements

We thank J. Cupp, L. Gilmour and W. Tombo for FACS support, X.-D. Wang, R. Soriano and Z. Modrusan for microarray services, I. Kasman, L. Komuves and J. Eastham-Anderson for microscopy assistance, B. D. Tarlow for assistance with laser-capture microdissection and PCR-based genotyping, Genentech Laboratory Animal Resources for support services, L. Blocher and J. Simko for human clinical prostate specimens, and F. J. de Sauvage for valuable discussion, input and supervision of the project.

Author Contributions K.G.L. planned the project, designed and performed experiments, and prepared the manuscript. B.-E.W. assisted with ex vivo prostate studies. L.J. provided input and supervised the project. W.-Q.G. conceptualized the study, planned and supervised the project. All authors discussed the results and commented on the manuscript.

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Correspondence to Wei-Qiang Gao.

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Leong, K., Wang, BE., Johnson, L. et al. Generation of a prostate from a single adult stem cell. Nature 456, 804–808 (2008). https://doi.org/10.1038/nature07427

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