Stem cells tightly regulate dead cell clearance to maintain tissue fitness

• 成果类型: Article
• 署名作者: 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
• 署名单位: Howard Hughes Medical Institute; Rockefeller University; Rockefeller University; Yale University; Yale University; Pohang University of Science & Technology (POSTECH); Memorial Sloan Kettering Cancer Center; Pennsylvania Commonwealth System of Higher Education (PCSHE); Temple University
• 刊物名称: Nature
• ISSN/ISSBN: 0028-6587
• DOI: 10.1038/s41586-024-07855-6
• 发表日期: 2024-09-12
• 关键词: 9-cis retinoic acid; hair follicle; apoptotic cells; x-receptor; arachidonic-acid; rxr heterodimers; nuclear receptor; rna-seq; expression; distinct

摘要

Billions of cells are eliminated daily from our bodies(1-4). 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 corpses(1-4). 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 RAR gamma-RXR alpha, 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.