In a new study, Yale researchers are taking a unique approach to identifying the molecular signals that induce a critical trigger for hair follicle formation and regeneration.
The findings could prove crucial for developing new therapies to regrow hair – and provide a blueprint for unraveling other mysteries of tissue growth at the cellular level.
“This is a decades-old problem that is intractable because the formation of dermal condensate, the signaling center that induces hair follicle growth and differentiation, has been difficult to visualize and capture due to the how quickly they form,” said Dr. Peggy Myung, associate professor of dermatology at Yale School of Medicine and lead author of the new study in the journal Developmental Cell.
Dermal Condensates (DC) are clusters of dense cells, located under the outer layer of the skin. DCs act as the central commanders of hair follicle activity by sending signals to the outer layer of the skin, instructing it to form hair follicles and determining the size of the follicles.
Unraveling the steps that induce DC formation has been a major challenge for researchers, as the process is difficult to track over time and to disentangle experimentally. Overcoming this hurdle, the researchers say, could open the door to effective methods of replicating DCs to test new hair loss drugs and generate hair follicles in 3D culture models.
For the study, Myung and his colleagues, including Yuval Kluger, a Yale pathology professor who is affiliated with the university’s Applied Mathematics program, took a unique approach to studying DCs.
Using single-cell RNA sequencing data from mouse skin, they designed a computational approach to align a series of single-cell profile “snapshots” to reconstruct the time course of DC development. This provided a roadmap that describes how an immature dermal cell behaves in maturity. More importantly, the approach allowed the researchers to study the molecular signals that serve as drivers in the process. By combining their computational findings with in vivo genetic experiments, they were able to identify critical signals involved in DC formation.
“We show that there are two defining signals driving the process,” Myung said. “Interestingly, these are signals that are generally thought to oppose each other, but in this case they cooperate to induce the DC genesis process.”
One of the signals is known as Wnt and the other is called “sonic hedgehog” or SHH. Both signals are considered essential in the development of many types of tissues and play a role in the regulation of homeostasis and regeneration of adult tissues. They are also implicated in disease states such as cancer when aberrantly overactivated.
For the study, the researchers were able to genetically modulate these signals to reduce the rate of DC formation, effectively playing the DC formation process in slow motion.
“This work will help pave the way for the development of robust methods for recreating DCs in the laboratory and for regenerating adult hair follicles,” Myung said. “It also shows how computational methods can be used to understand cellular signals and behaviors that were previously impossible to capture.”
The first author of the study is Rihao Qu of Yale. The study’s co-authors are Danni Dong, Yiqun Jiang, Boris Landa, Charles Saez, Gwendolyn Strickland, and Pei-lun Weng, all of Yale; Khusali Gupta of the University of Massachusetts; Jonathan Levinsohn of Children’s Hospital of Pennsylvania; and Mr. Mark Taketo of Kyoto University.
Myung and Kluger are also affiliated with the Yale Cancer Center.
The research was supported by the National Institutes of Health and the American Cancer Society