Notch ligand Dll1 mediates cross-talk between mammary stem cells and the macrophageal niche

• Published in: Science (American Association for the Advancement of Science) 2018-06, Vol.360 (6396)
• Main Authors: Chakrabarti, Rumela, Celià-Terrassa, Toni, Kumar, Sushil, Hang, Xiang, Wei, Yong, Choudhury, Abrar, Hwang, Julie, Peng, Jia, Nixon, Briana, Grady, John J, DeCoste, Christina, Gao, Jie, van Es, Johan H, Li, Ming O, Aifantis, Iannis, Clevers, Hans, Kang, Yibin
• Format: Article
• Language: English
• Subjects: Alveoli; Animal models; Animals; Breast cancer; Calcium-Binding Proteins; Cancer; Cell Count; Cell fate; Cell self-renewal; Clonal deletion; Coupling (molecular); Crosstalk; Enrichment; Epithelial cells; Feedback (Response); Feedback loops; Female; Fibroblasts; Gene Knockout Techniques; Homeostasis; Immune system; Individualized Instruction; Intercellular Signaling Peptides and Proteins - genetics; Intercellular Signaling Peptides and Proteins - metabolism; Lactation; Ligands; Macrophages; Macrophages - cytology; Macrophages - physiology; Mammary gland; Mammary Glands, Animal - cytology; Mammary Glands, Animal - growth & development; Mammary Glands, Animal - metabolism; Mice; Mice, Knockout; Molecular chains; Morphogenesis; Notch protein; Notch2 protein; Notch3 protein; Organs; Pharmacology; Populations; Pregnancy; Receptors; Receptors, Notch - metabolism; Regeneration; Signal Transduction; Signaling; Stem Cell Niche - physiology; Stem cell transplantation; Stem cells; Stem Cells - cytology; Stem Cells - physiology; Stromal Cells - cytology; Stromal Cells - physiology; Survival; Tissue engineering; Wnt protein; Wnt Proteins - metabolism
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.aan4153

The stem cell niche is a specialized environment that dictates stem cell function during development and homeostasis. We show that Dll1, a Notch pathway ligand, is enriched in mammary gland stem cells (MaSCs) and mediates critical interactions with stromal macrophages in the surrounding niche in mouse models. Conditional deletion of Dll1 reduced the number of MaSCs and impaired ductal morphogenesis in the mammary gland. Moreover, MaSC-expressed Dll1 activates Notch signaling in stromal macrophages, increasing their expression of Wnt family ligands such as Wnt3, Wnt10A, and Wnt16, thereby initiating a feedback loop that promotes the function of Dll1-expressing MaSCs. Together, these findings reveal functionally important cross-talk between MaSCs and their macrophageal niche through Dll1-mediated Notch signaling.