Billions of cells are eliminated daily from our bodies^1,2,3,4. 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^1,2,3,4. 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 RARγ–RXRα, 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.

每天有数十亿个细胞从我们的体内消失^1,2,3,4 。尽管巨噬细胞和树突细胞专门用于迁移和吞噬垂死的细胞和碎片，但许多上皮和间质组织细胞可以消化附近的凋亡尸体^1,2,3,4 。这些非活动性、非专业性的吞噬细胞如何感知并消除垂死的细胞，同时保持其正常的组织功能，目前尚不清楚。在这里，我们通过利用毛发循环过程中组织再生和退化的周期性发作来探索其多功能性背后的机制。我们表明，毛囊干细胞通过局部分子触发器在正确的时间和地点短暂地释放吞噬作用，这些分子触发器取决于邻近凋亡尸体释放的脂质和健康对应物释放的类维生素A。我们将这种双重配体需求的核心追溯到RARγ–RXRα，其激活能够严格调节凋亡细胞清除基因，并提供有效的、可调节的机制来抵消吞噬细胞对维持体内平衡期间组织完整性的初级干细胞功能的作用。最后，我们提供的功能证据表明，毛囊干细胞介导的吞噬作用不仅与专业吞噬细胞多余，而且对组织健康具有明显的益处。我们的研究结果对在免疫特权生态位中遭遇细胞死亡的其他非运动组织干细胞或祖细胞具有广泛的影响。