A collaborative signaling mechanism transforms standard cells into a highly effective cleanup crew.
Every day, billions of our cells perish to pave the way for new growth. Most of these dead cells are cleared away by phagocytes — mobile immune cells that travel to areas in need to engulf harmful substances. However, some dying or deceased cells are taken up by their neighboring natural tissue cells that have different primary functions. The way these neighboring cells detect nearby dying or dead cells has remained largely unclear.
Recent research from The Rockefeller University has unveiled how the sensing system functions within hair follicles, which undergo a well-recognized cycle of birth, decay, and regeneration driven by hair follicle stem cells (HFSCs). In a new article published in Nature, the researchers present evidence that two sensors work together to detect signals from both dying and healthy HFSCs, thus clearing away debris before it causes tissue damage and halting the process before healthy cells are harmed.
“The system seems to be spatially calibrated to the presence of dead cells and only activates when each sensor detects an appropriate signal,” remarks first author Katherine Stewart, a research associate in the Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development at Rockefeller. “If either of the sensors is missing, the mechanism ceases to function. It’s a remarkably elegant way to maintain cleanliness without consuming healthy cells.”
“By focusing on consuming their dying neighbors, HFSCs keep inflammation-causing immune cells at bay,” explains Elaine Fuchs, who leads the lab. “They likely gain extra energy from this, but once the debris is cleared, they need to quickly return to their main roles of maintaining the stem cell pool and producing hair for the body.”
The life cycle of hair follicles
Every hair follicle on your head experiences a specific cycle: growth, decay, rest, and — as you may observe in your shower — shedding.
The cycle begins when hair follicle stem cells (HFSCs), found in the “bulge” at the top of the follicle’s root sheath, signal neighboring epithelial and mesenchymal cells to kickstart growth. This growth phase is prolonged, lasting anywhere from two to six years.
The subsequent destructive phase, known as catagen, is short but aggressive, destroying around 80% of the hair follicle in just a few weeks. This process initiates at the base of the follicle and progresses upwards towards the HFSC niche. The outcome is a collection of dying and dead cells that must be removed to prevent the decay from inciting inflammatory or autoimmune responses.
Typically, phagocytes, including macrophages, would handle this cleanup. However, there are few macrophages present in the hair follicle, meaning that local epithelial cells are responsible for maintaining cleanliness. Stewart aimed to investigate the chemical communications that orchestrate this cleanup process.
The synergistic sensors
She and her team focused on the catagen phase in mouse hair follicles, which have a quick and synchronized hair cycle. It is only in the later catagen stage that death signals from the follicle base finally reach the area where undifferentiated stem cells reside. It had previously been believed that stem cells were immune to destruction, but unexpectedly, the team discovered that some do perish and are engulfed by their neighboring cells.
Stewart identified that the cleanup process can only initiate when both receptors are activated in healthy cells. The first, RXRα, detects the presence of lipids, a known “find me” signal released by dying cells. The second, RARγ, picks up on growth-promoting retinoic acid released by healthy cells.
Neither receptor can trigger the cleanup process on its own. “The demise of a cell allows the mechanism to start, and when there are no more dead cells remaining, the lipid signal fades away, leaving only the retinoic acid signal from healthy cells,” explains Stewart. “This indicates that the program should downregulate. It’s beautifully simple.”
The researchers also noted that macrophages took time to arrive in the area, appearing as much as four days after cell death. “It’s been commonly believed that professional phagocytes eventually arrive to handle the major cleanup, and that stationary cells were merely backup,” Stewart remarks. “I was quite surprised to find that hair follicle stem cells were the first responders, especially since mouse skin has a healthy number of macrophages nearby.”
They also observed that tissue damage occurred when HFSCs were unable to remove dying cells and left the cleanup to macrophages. This suggests that genetic issues in this clearing mechanism could contribute to skin conditions in humans, including inflammation and hair loss.
The effects of consumption
The HFSCs that engulfed neighboring dying cells — with some consuming as many as six of their neighbors — may gain nutritional benefits from the proteins, nucleic acids, solutes, and lipids contained in those cells. The exact nature of these benefits remains to be explored, which is something the Fuchs lab plans to investigate further.
“It’s possible that they can utilize that material to support their own growth or benefit from it in other ways,” speculates Stewart. “However, it’s also feasible that this might have adverse effects. Perhaps they’re too busy digesting all this material to fulfill their usual responsibilities.”
The implications of these findings extend beyond hair follicles, as they are just one of numerous body areas where professional phagocytes are scarce. For instance, in regions of the brain, breasts, and lungs, epithelial and mesenchymal tissue cells, including stem cells, act as substitute phagocytes.
“We often use the saying, ‘you are what you eat,’” Fuchs adds. “For our body’s stem cells, this may be their method of keeping tissues healthy by clearing away naturally dying cells and protecting against inflammation.”
