Generation of a functional mammary gland from a single stem cell

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Abstract
The existence of mammary stem cells has been inferred from genetic analysis of human breast tissue, and from the fact that mouse mammary gland can regenerate from tissue fragments. Two groups now report the isolation of mammary stem cells from mice. Shackleton et al. use a technique based on the introduction of a marker for stem-cell function. A single cell from this population then showed its potency by regenerating an entire mammary gland in vivo. This population of cells is expanded in a pre-malignant mammary tumour model, providing support for the concept of a mammary cancer stem cell. In a paper published online, Stingl et al. report the use of a powerful limiting dilution transplant procedure to purify to near homogeneity a rare subset of adult mouse mammary cells that can individually regenerate an entire mammary gland within six weeks. The existence of mammary stem cells (MaSCs) has been postulated from evidence that the mammary gland can be regenerated by transplantation of epithelial fragments in mice1,2,3. Interest in MaSCs has been further stimulated by their potential role in breast tumorigenesis4. However, the identity and purification of MaSCs has proved elusive owing to the lack of defined markers. We isolated discrete populations of mouse mammary cells on the basis of cell-surface markers and identified a subpopulation (Lin-CD29hiCD24+) that is highly enriched for MaSCs by transplantation. Here we show that a single cell, marked with a LacZ transgene, can reconstitute a complete mammary gland in vivo. The transplanted cell contributed to both the luminal and myoepithelial lineages and generated functional lobuloalveolar units during pregnancy. The self-renewing capacity of these cells was demonstrated by serial transplantation of clonal outgrowths. In support of a potential role for MaSCs in breast cancer, the stem-cell-enriched subpopulation was expanded in premalignant mammary tissue from MMTV-wnt-1 mice and contained a higher number of MaSCs. Our data establish that single cells within the Lin-CD29hiCD24+ population are multipotent and self-renewing, properties that define them as MaSCs.