Distinct stem cells contribute to mammary gland development and maintenance

Abstract

The mammary epithelium is composed of several cell lineages including luminal, alveolar and myoepithelial cells. Transplantation studies have suggested that the mammary epithelium is maintained by the presence of multipotent mammary stem cells. To define the cellular hierarchy of the mammary gland during physiological conditions, we performed genetic lineage-tracing experiments and clonal analysis of the mouse mammary gland during development, adulthood and pregnancy. We found that in postnatal unperturbed mammary gland, both luminal and myoepithelial lineages contain long-lived unipotent stem cells that display extensive renewing capacities, as demonstrated by their ability to clonally expand during morphogenesis and adult life as well as undergo massive expansion during several cycles of pregnancy. The demonstration that the mammary gland contains different types of long-lived stem cells has profound implications for our understanding of mammary gland physiology and will be instrumental in unravelling the cells at the origin of breast cancers.

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Figure 1: All mammary epithelial lineages derive from embryonic K14-expressing progenitors.
Figure 2: K14-expressing stem cells ensure mammary myoepithelial lineage expansion and maintenance during puberty, adult life and pregnancy.
Figure 3: K8-expressing stem cells ensure mammary luminal lineage expansion and maintenance during puberty, adult life and pregnancy.
Figure 4: Myoepithelial and luminal stem cells maintain their unipotent fate in mammary reconstitution assay when co-transplanted in non-limiting conditions.
Figure 5: Myoepithelial but not luminal stem cells can be forced to adopt a multipotent fate in mammary reconstitution assays.

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Acknowledgements

We thank our colleagues who provided us with reagents, which are cited in the text, and B. Hogan for sharing unpublished mice. We thank our colleagues from the Blanpain laboratory and C. Govaerts for their comments on the manuscript. We thank J. Rosen for discussion and M. Van Lohuizen and K. Nacerddine for their help with the transplantation assay. We thank F. Bollet-Quivogne and J.-M. Vanderwinden for their help with confocal imaging. C.B. and A.V.K. are chercheur qualifié, B.B. is chargé de recherche and M.O. is a collaborateur scientifique of the FRS/FNRS. A.S.R. is supported by TELEVIE and the Portuguese Science Foundation (FCT). N.S. is supported by the Fondation Contre le Cancer. J.R. is supported by the grant F32HL102920. C.B. is an investigator of Welbio. This work was supported by the FNRS, TELEVIE, the program d’excellence CIBLES of the Wallonia Region, a research grant from the Fondation Contre le Cancer, the ULB fondation, the fond Gaston Ithier, a starting grant of the European Research Council (ERC) and the EMBO Young Investigator Program.

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C.B., A.V.K, A.S.R. designed the experiments and performed data analysis. AV.K., A.S.R. and M.O. performed most of the experiments, J.R. generated the K5-CreER knockin mice, B.B., S.D. and A.V.K. performed the FACS analysis and cell sorting. G.B. and N.S. provided technical support. C.B. wrote the manuscript.

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Correspondence to Cédric Blanpain.

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The authors declare no competing financial interests.

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Van Keymeulen, A., Rocha, A., Ousset, M. et al. Distinct stem cells contribute to mammary gland development and maintenance. Nature 479, 189–193 (2011). https://doi.org/10.1038/nature10573

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