Stem cells tightly regulate dead cell clearance to maintain tissue fitness

Katherine S. Stewart (), Merve Deniz Abdusselamoglu, Matthew T. Tierney, Anita Gola, Yun Ha Hur, Kevin A. U. Gonzales, Shaopeng Yuan, Alain R. Bonny, Yihao Yang, Nicole R. Infarinato, Christopher J. Cowley, John M. Levorse, Hilda Amalia Pasolli, Sourav Ghosh, Carla V. Rothlin and Elaine Fuchs ()
Additional contact information
Katherine S. Stewart: The Rockefeller University
Merve Deniz Abdusselamoglu: The Rockefeller University
Matthew T. Tierney: The Rockefeller University
Anita Gola: The Rockefeller University
Yun Ha Hur: The Rockefeller University
Kevin A. U. Gonzales: The Rockefeller University
Shaopeng Yuan: The Rockefeller University
Alain R. Bonny: The Rockefeller University
Yihao Yang: The Rockefeller University
Nicole R. Infarinato: The Rockefeller University
Christopher J. Cowley: The Rockefeller University
John M. Levorse: The Rockefeller University
Hilda Amalia Pasolli: The Rockefeller University
Sourav Ghosh: Yale School of Medicine
Carla V. Rothlin: Yale School of Medicine
Elaine Fuchs: The Rockefeller University

Nature, 2024, vol. 633, issue 8029, 407-416

Abstract: Abstract Billions of cells are eliminated daily from our bodies1–4. 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 corpses1–4. 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.

Date: 2024
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DOI: 10.1038/s41586-024-07855-6

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