A University of Colorado Boulder research team, in collaboration with a researcher at the University of Colorado School of Medicine, has discovered how skin stem cells know when to stop dividing. The findings, published as the cover story in the Feb 5th issue of the journal Science, could point to new avenues for controlling stem cells in regenerative medicine, and should further our understanding of how stem cells may go awry in cancer, says Rui Yi, associate professor of molecular, cellular, and developmental biology at CU-Boulder, who led the study along with first author Li Wang, who recently completed his PhD in Yi’s lab.
By some estimates, Yi says, adults replace all the cells in their skin every month. To maintain such constant cell turnover, the skin has to exert tight controls over which cells may divide and when any particular cell divides. Fortunately, Yi says, most cells within our body do not divide, or we would grow unrestrained. But stem cells, such as those responsible for replenishing skin, have the potential to divide unlimited times if given the opportunity. How does a stem cell know when to divide and when to stop? That question, Yi says, is important, not only for understanding how skin controls its normal growth, but to develop strategies to combat skin cancer, the unfettered tissue growth that ensues when these controls run amuk.
Yi says that biologists understand many of the details of how molecular signals secreted by surrounding skin tissue communicate with stem cells to stimulate them to divide. For example, when the skin suffers a cut, it musters stem cells in the area to divide and repair the injury. But until now, not much has been known about whether a stem cell, itself, has any internal sense of when to divide or when it should lay in wait.
Using genetically engineered mice provided by co-author Julie Siegenthaler, an assistant professor in the department of pediatrics at CU Denver, the researchers discovered that a transcription factor called Foxc1 acts within hair follicle stem cells to forestall them from dividing until the appropriate time. A transcription factor is a protein that controls when genes are turned on or off, and the Colorado team identified more than a hundred genes that Foxc1 turns on. Enforcing a two-pronged control strategy, Foxc1 activates genes that prevent stem cells from dividing, and as a result also turns off genes that stem cells need to divide.
When Yi’s team inactivated Foxc1 in hair follicle stem cells, the cells lost their inhibition toward dividing, allowing them to divide prematurely. In addition, Yi’s team noticed that Foxc1 is also turned on in the stem cell niche, a cluster of neighboring cells that supports the stem cells. When the researchers inactivated Foxc1 in the niche, it led to hair loss. “It seems,” Yi says, “that this factor has different roles in the stem cells and in the niche.”
The most intriguing finding about Foxc1, Yi notes, is that it only appears in a stem cell once the cell has divided. In effect, he says, Foxc1 serves as a switch that notifies a stem cell that it has divided and should stop dividing until further notice. This way, he explains, every hair follicle stem cell gets to divide at least one time so that it can replenish itself, but once that happens, Foxc1 in the newly divided daughter cells contols whole networks of genes to keep the cells from dividing further unless absolutely necessary. What turns on Foxc1 in newly divided stem cells? Yi says that question is still a mystery remaining to be solved.
Now that Yi’s team has pinpointed Foxc1 as the key control point for hair follicle skin stem cell division, they are eager to learn how the dozens of Foxc1’s target genes carry out its orders to prevent cell division. This is a profoundly important question, Yi says, because it is now widely accepted that skin cancers originate from stem cells. And hair follicle stem cells in particular, he adds, are more prone to develop into invasive cancers, such as basal cell carcinoma and squamous cell carcinoma. In addition to Wang, Yi, and Siegenthaler, MCDB assistant professor Robin Dowell co-authored the Science paper and supervised bioinformatics analyses.