Alveolar progenitor cells develop in mouse mammary glands independent of pregnancy and lactation

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Abstract
We have previously described pluripotent, parity‐induced mammary epithelial cells (PI‐MEC) marked by Rosa26‐lacZ expression in the mammary glands of parous females. PI‐MEC act as lobule‐limited epithelial stem/progenitor cells. To determine whether parity is necessary to generate PI‐MEC, we incubated mammary explant cultures from virgin mice in vitro with insulin alone (I), hydrocortisone alone (H), prolactin alone (Prl), or a combination of these lactogenic hormones (IHPrl). Insulin alone activated the WAP‐Cre gene. Hydrocortisone and prolactin alone did not. Any combination of hormones that included insulin was effective. Only I, H and Prl together were able to induce secretory differentiation and milk protein synthesis. In addition, EGF, IGF‐2 and IGF‐1 added individually produced activated (lacZ+) PI‐MEC in explant cultures. Neither estrogen nor progesterone induced WAP‐Cre expression in the explants. None of these positive initiators of WAP‐Cre expression in PI‐MEC were effective in mammospheres or two‐dimensional cultures of mammary epithelium, indicating the indispensability of epithelial–stromal interaction in PI‐MEC activation. Like PI‐MEC, lacZ+ cells from virgin explants proliferated and contributed progeny to mammospheres in vitro and to epithelial outgrowths in vivo after transplantation. LacZ+ cells induced in virgin mouse mammary explants were multipotent (like PI‐MEC) in impregnated hosts producing lacZ+ mammary alveolar structures comprised of both myoepithelial and luminal progeny. These data demonstrate PI‐MEC, a mammary epithelial sub‐population of lobule‐limited progenitor cells, are present in nulliparous female mice before parity and, like the PI‐MEC observed following parity, are capable of proliferation, self‐renewal and the capacity to produce progeny of diverse epithelial cell fates. J. Cell. Physiol. 212:729–736, 2007.

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