Niche inflammatory signals control oscillating mammary regeneration and protect stem cells from cytotoxic stress

Abstract

Stem cells are known for their resilience and enhanced activity post-stress. The mammary gland undergoes frequent remodeling and is subjected to recurring stress during the estrus cycle, but it remains unclear how mammary stem cells (MaSCs) respond to the stress and contribute to regeneration. We discovered that cytotoxic stress-induced activation of CD11c⁺ ductal macrophages aids stem cell survival and prevents differentiation. These macrophages boost Procr⁺ MaSC activity through IL1β-IL1R1-NF-κB signaling during the estrus cycle in an oscillating manner. Deleting IL1R1 in MaSCs results in stem cell loss and skewed luminal differentiation. Moreover, under cytotoxic stress from the chemotherapy agent paclitaxel, ductal macrophages secrete higher IL1β levels, promoting MaSC survival and preventing differentiation. Inhibiting IL1R1 sensitizes MaSCs to paclitaxel. Our findings reveal a recurring inflammatory process that regulates regeneration, providing insights into stress-induced inflammation and its impact on stem cell survival, potentially affecting cancer therapy efficacy.

Keywords: CD11c(+) ductal macrophage; IL1β-IL1R1; NF-κB; Procr(+) MaSC; cytotoxic stress; estrus cycle; mammary gland.