In vivo reprogramming of non-mammary cells to an epithelial cell fate is independent of amphiregulin signaling

Amphiregulin (AREG) -/- mice demonstrate impaired mammary development and form only rudimentary ductal epithelial trees; however, AREG -/- glands are still capable of undergoing alveologenesis and lactogenesis during pregnancy. Transplantation of AREG -/- mammary epithelial cells into cleared mouse mammary fat pads results in a diminished capacity for epithelial growth (∼15%) as compared to that of wild-type mammary epithelial cells. To determine whether estrogen receptor α (ERα, also known as ESR1) and/or AREG signaling were necessary for non-mammary cell redirection, we inoculated either ERα -/- or AREG -/- mammary cells with non-mammary progenitor cells (WAP-Cre/Rosa26LacZ+ male testicular cells or GFP-positive embryonic neuronal stem cells). ERα -/- cells possessed a limited ability to grow or reprogram non-mammary cells in transplanted mammary fat pads. AREG -/- mammary cells were capable of redirecting both types of non-mammary cell populations to mammary phenotypes in regenerating mammary outgrowths. Transplantation of fragments from AREG-reprogrammed chimeric outgrowths resulted in secondary outgrowths in six out of ten fat pads, demonstrating the self-renewing capacity of the redirected non-mammary cells to contribute new progeny to chimeric outgrowths. Nestin was detected at the leading edges of developing alveoli, suggesting that its expression may be essential for lobular expansion.