Stem cells tightly regulate dead cell clearance to maintain tissue fitness

• Published in: Nature (London) Vol. 633; no. 8029; pp. 407 - 5
• Main Authors: Stewart, Katherine S, Abdusselamoglu, Merve Deniz, Tierney, Matthew T, Gola, Anita, Hur, Yun Ha, Gonzales, Kevin A U, Yuan, Shaopeng, Bonny, Alain R, Yang, Yihao, Infarinato, Nicole R, Cowley, Christopher J, Levorse, John M, Pasolli, Hilda Amalia, Ghosh, Sourav, Rothlin, Carla V, Fuchs, Elaine
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group 12.09.2024
• Subjects: Apoptosis; Cell activation; Cell death; Degeneration; Dendritic cells; Flow cytometry; Follicles; Functionals; Gene regulation; Genes; Hair; Homeostasis; Immune clearance; Immune privilege; Lipids; Macrophages; Phagocytes; Phagocytosis; Progenitor cells; Proteins; Regeneration (physiology); Retinoid X receptor α; Retinoids; Stem cells; Tissue engineering; Tissues; Transcription activation
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1O38/s41586-O24-O7855-6

Billions of cells are eliminated daily from our bodies14. Although macrophages and dendritic cells are dedicated to migrating and engulfing dying cells and debris, many epithelial and mesenchymal tissue cells can digest nearby apoptotic corpses14. How these non-motile, non-professional phagocytes sense and eliminate dying cells while maintaining their normal tissue functions is unclear. Here we explore the mechanisms that underlie their multifunctionality by exploiting the cyclical bouts of tissue regeneration and degeneration during hair cycling. We show that hair follicle stem cells transiently unleash phagocytosis at the correct time and place through local molecular triggers that depend on both lipids released by neighbouring apoptotic corpses and retinoids released by healthy counterparts. We trace the heart of this dual ligand requirement to RARy-RXRa, whose activation enables tight regulation of apoptotic cell clearance genes and provides an effective, tunable mechanism to offset phagocytic duties against the primary stem cell function of preserving tissue integrity during homeostasis. Finally, we provide functional evidence that hair follicle stem cell-mediated phagocytosis is not simply redundant with professional phagocytes but rather has clear benefits to tissue fitness. Our findings have broad implications for other non-motile tissue stem or progenitor cells that encounter cell death in an immune-privileged niche.