A Quiescent Bcl11b High Stem Cell Population Is Required for Maintenance of the Mammary Gland

Stem cells in many tissues sustain themselves by entering a quiescent state to avoid genomic insults and to prevent exhaustion caused by excessive proliferation. In the mammary gland, the identity and characteristics of quiescent epithelial stem cells are not clear. Here, we identify a quiescent mammary epithelial cell population expressing high levels of Bcl11b and located at the interface between luminalandbasal cells. Bcl11b(high) cells are enriched for cells that can regenerate mammary glands in secondary transplants. Loss of Bcl11b leads to a Cdkn2a-dependent exhaustion of ductal epithelium and loss of epithelial cell regenerative capacity. Gain-and loss-of-function studies showthat Bcl11b induces cells to enter the G(0) phase of the cell cycle and become quiescent. Taken together, these results suggest that Bcl11b acts as a central intrinsic regulator of mammary epithelial stemcellquiescence and exhaustion and is necessary for long-term maintenance of the mammary gland.