Microscopy image of a hair follicle shaft with clusters of orange debris surrounded by a group of green cells. Purple cells surround the hair root.
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Stem Cells Dine on Dying Neighbors to Keep Tissues Fit

In hair follicles, as nearby cells die, stem cells engage in phagocytosis to keep the hair cycle going.

Black and white photo of Danielle Gerhard
| 2 min read
Image creditKatherine Stewart; Stewart KS, et al. Nature. 2024; CC-BY 4.0.

Every day, the human body removes billions of dead cells.1 Professional phagocytes, such as macrophages and dendritic cells, do a lot of the heavy lifting, but some non-immune cells, the so-called nonprofessionals, dabble in the activity on a part-time basis. “This is something that's been widely appreciated but broadly overlooked when it comes to thinking about how tissues deal with dying cells,” said Katherine Stewart, a stem cell biologist in Elaine Fuchs’s group at the Rockefeller University

Hair follicles are the perfect system to study this. Not only do they regularly cycle through phases of regeneration and destruction, but they are also an immune-privileged niche, meaning professional phagocytes don’t actively patrol the area. Early in the destructive phase, nonprofessional phagocytic epithelial cells in the lower region of the hair follicle engulf their dying neighbors.2 However, little was known about how the cell death process unfolds as it progresses to the top of the hair shaft, where the stem cells reside.

In a recent paper in Nature, Stewart and her colleagues found that hair follicle stem cells (HFSCs) also moonlight as part-time phagocytes, clearing neighboring stem cell corpses.3 When she dug into the mechanisms orchestrating this transient behavior she found that apoptotic corpses released lysophosphatidylcholine (LPC), a common “find me” signal that lures in phagocytes. Meanwhile, healthy HFSCs express the retinoid X receptor alpha (RXRα), which binds the lipid. However, in vitro experiments revealed that LPC alone was insufficient to upregulate the phagocytic program.

As she dug deeper, she found that RXRα can form a heterodimer with retinoic acid receptor gamma which, as the name implies, binds retinoic acid. In mice, she found that, in the destructive phase, healthy HFSCs upregulate machinery to produce retinoic acid. Stewart returned to the in vitro experiment, this time adding retinoic acid alongside LPC. “Lo and behold, it recapitulated the phagocytic program to a degree that I was amazed at how well that actually worked,” she said. She added that this dual-ligand method for clearing cellular corpses “gives you exquisite spatial and temporal control.”

So, why are these stem cells taking on this extra labor? With professional phagocytes nowhere to be seen, Stewart said, “The duty almost falls on the stem cells by default.” By knocking out RXRα in mice, she interfered with the ability of HFSCs, depicted in green in the image, to clear apoptotic corpses. This led to debris build up, labeled in orange, causing secondary necrosis. A few days later, professional phagocytes, shown in purple, finally showed up to help. These findings highlight a key role for this stem cell population in maintaining the hair cycle and tissue fitness.