Isolation and characterization of human mammary stem cells - PubMed (original) (raw)

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Isolation and characterization of human mammary stem cells

R B Clarke. Cell Prolif. 2005 Dec.

Abstract

Since stem cells are present throughout the lifetime of an organism, it is thought that they may accumulate mutations, eventually leading to cancer. In the breast, tumours are predominantly oestrogen and progesterone receptor-positive (ERalpha/PR+). We therefore studied the biology of ERalpha/PR-positive cells and their relationship to stem cells in normal human mammary epithelium. We demonstrated that ERalpha/PR-positive cells co-express the putative stem cell markers p21(CIP1/WAF1), cytokeratin (CK) 19 and Musashi-1 when examined using dual label immunofluorescence on tissue sections. Next, we isolated a Hoechst dye-effluxing 'side population' (SP) from the epithelium using flow cytometry and demonstrated them to be undifferentiated cells by lack of expression of myoepithelial and luminal cell-specific antigens such as CALLA and MUC1. Epithelial SP cells were shown to be enriched for the putative stem cell markers p21(CIP1/WAF1), Musashi-1 and ERalpha/PR-positive cells. Lastly, SP cells, compared to non-SP, were highly enriched for the capacity to produce colonies containing multiple lineages in 3D basement membrane (Matrigel) culture. We conclude that breast stem cells include two populations: a primitive ERalpha/PR-negative stem cell necessary for development and a shorter term ERalpha/PR-positive stem cell necessary for adult tissue homeostasis during menstrual cycling. We speculate these two basic stem cell types may therefore be the cells of origin for ERalpha-positive and -negative breast tumours.

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Figure 1

Figure 1

A model of the cellular hierarchies that may exist in the epithelium of the human breast lobule. Cells in an intermediate position include Hoechst dye‐effluxing SP cells and some of these express steroid receptors, p21CIP1, Msi1 and CK19. Msi1 and Delta/Notch signalling may regulate self‐renewal of the stem cell and production of the transit‐amplifying population through a process of asymmetric cell division. After a small number of cell divisions, transit‐amplifying cells exit from the cell cycle and differentiate into myo‐ or luminal epithelial cell lineages characterized by the markers CALLA and CK14 (myoepithelial) or MUC1 and CK18 (luminal).

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