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

Stem cells are known to survive stress and reemerge with enhanced activity. The mammary gland undergoes active remodeling and is subjected to recurring stress during the estrus cycle, but it remains unclear how mammary stem cells (MaSCs) respond to the stress in the niche and contribute to regeneration. We found that cytotoxic stress-induced activation of CD11c+ ductal macrophages promotes stem cell survival and prevents its differentiation. These macrophages enhance Procr+ MaSC activity in an oscillating manner through IL1β-IL1R1-NF-κB signaling during the estrus cycle. IL1R1 deletion in MaSCs leads to 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. Importantly, inhibiting IL1R1 sensitizes MaSCs to Paclitaxel. Our findings reveal a recurring inflammatory process that regulates regeneration in an oscillating manner, providing insights into stress-induced inflammation and its influence on stem cell survival, with potential implications for cancer therapy efficacy.

20 2024-06-21

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