Stem cells tightly regulate dead cell clearance to maintain tissue fitness [ATAC-seq]

Macrophages and dendritic cells have long been appreciated for their ability to migrate to and engulf dying cells and debris, including some of the billions of cells that are naturally eliminated from our body daily. However, a substantial amount of these dying cells are cleared by local tissue cells, so-called ‘non-professional phagocytes’, critical to preserve organismal fitness. How non-professional phagocytes are able to sense and digest nearby apoptotic corpses while still performing their normal tissue functions is unclear. Here, we explore the molecular mechanisms underlying this balancing act. Exploiting the cyclical bouts of tissue regeneration and degeneration during the hair cycle, we show that stem cells can transiently become non-professional phagocytes when confronted with dying cells. Adoption of this phagocytic state requires not only local lipids produced by apoptotic corpses, which are necessary for RXRα activation, but also tissue-specific retinoids able to activate RARg. The dual factor dependency enables tight regulation of the genes requisite to activate phagocytic apoptotic clearance. The tunable phagocytic program we describe here offers an attractive mechanism to offset phagocytic duties against the primary stem cell function of replenishing differentiated cells to preserve tissue integrity during homeostasis. Our findings have broad implications for other non-motile stem or progenitor cells which experience cell death in an immune-privileged niche. Hair follicle stem cells were FACS-sorted directly into PBS. ATAC-seq was performed as described before in Buenrostro et al., 2013. Briefly, FACS sorted HFSCs were lysed with ATAC lysis buffer on ice for 1 minute. Lysed cells were then tagmented with Tn5 transposase (Illumina) at 37C for 30min. Cleaned up fragments were PCR amplified (NEB) and size selected with 1.8X SPRI beads (Beckman Coulter). All libraries were sequenced on Illumina NextSeq 500 with 40-bp paired-end settings.