Macrophages maintain mammary stem cell activity and mammary homeostasis via TNF-α-PI3K-Cdk1/Cyclin B1 axis.

Adult stem cell niche is a special environment composed of a variety stromal cells and signals, which cooperatively regulate tissue development and homeostasis. It is of great interest to study the role of immune cells in niche. Here, we show that mammary resident macrophages regulate mammary epithelium cell division and mammary development through TNF-α-Cdk1/Cyclin B1 axis. In vivo, depletion of macrophages reduces the number of mammary basal cells and mammary stem cells (MaSCs), while increases mammary luminal cells. In vitro, we establish a three-dimensional culture system in which mammary basal cells are co-cultured with macrophages, and interestingly, macrophage co-culture promotes the formation of branched functional mammary organoids. Moreover, TNF-α produced by macrophages activates the intracellular PI3K/Cdk1/Cyclin B1 signaling in mammary cells, thereby maintaining the activity of MaSCs and the formation of mammary organoids. Together, these findings reveal the functional significance of macrophageal niche and intracellular PI3K/Cdk1/Cyclin B1 axis for maintaining MaSC activity and mammary homeostasis.