Study Provides Insights into Mechanisms Controlling Dead Cell Clearance

Recent research from The Rockefeller University has shed light on the intricate mechanisms governing the removal of dying cells, using hair follicle stem cells (HFSCs) as a key example. Published in Nature, the study reveals how HFSCs employ a sophisticated sensor system to detect and eliminate dead cells, thereby preventing potential tissue damage and inflammation.

Every day, billions of cells in the body die, necessitating an efficient cleanup process. While phagocytes, such as macrophages, typically handle this task, their limited presence in certain tissues means that neighboring cells often step in. The researchers focused on hair follicles, which undergo a well-defined cycle of growth, decay, and regeneration, driven by HFSCs. During the catagen phase, approximately 80% of the hair follicle is destroyed, leading to a buildup of dying cells that must be cleared.

The team discovered that HFSCs utilize a duo of receptors—RXRα and RARγ—to sense signals from both dying and healthy cells. RXRα identifies lipid signals from dying cells, while RARγ detects growth-promoting retinoic acid from healthy cells. This dual-sensing mechanism ensures that cleanup occurs only in the presence of dead cells, preventing the unnecessary removal of healthy ones.

The team also found that macrophages were slow to migrate to the region, showing up as much as four days after cell death. “It’s been pretty broadly thought that professional phagocytes eventually swoop in and do the heavy cleanup, and that non-motile cells were a sort of backup system,” first author Katherine Stewart explains. “I was very surprised to find that the hair follicle stem cells were actually the first responders, especially because mouse skin is fairly well-endowed with macrophages, so they’re not even that far away.”

The findings have applications beyond the hair follicle, because it is only one of several areas of the body where there are few professional phagocytes around. In regions of the brain, breasts, and lungs, for example, epithelial and mesenchymal tissue cells, including stem cells, moonlight as ersatz phagocytes.