The behavior of stem cells must be coordinated across the entirety of a tissue or organ for proper homeostasis. Clusters of stem cells (SCs) in individual hair follicles cycle between growth (anagen) and resting (telogen) phases, but little is known about how cycling is coordinated between hair follicles throughout the skin. Taking into account what is known about the cycling of individual hair follicles and the presence of diffusible signaling molecules, Plikus et al. constructed a cellular automaton (CA) model to describe the coordination of hair follicle SCs across the skin. The model, which treated individual SC clusters as automata, predicted that competence of an individual SC cluster to respond to different cues varies with the phase of the cycle and that individual hair follicles continuously integrate various intrinsic and extrinsic cues to coordinate cycling between neighboring follicles. Whereas bone morphogenetic protein (BMP) signaling promoted maintenance of telogen even in follicles in the path of a passing regenerative wave, Wnt ligands promoted follicle activation and were produced by hair follicles in anagen. Random, rare events of Wnt signaling in telogen follicles could trigger the transition to anagen if signaling were simultaneously activated in several adjacent follicles. Implantation of Wnt3a-coated beads initiated waves of follicle activation across the skin, whereas implantation of beads coated with the Wnt signaling inhibitor Dkk1 halted the progression of existing waves of activation. Overexpression of Wnt7a shortened the window during which SCs were refractory to signaling and increased SC activation, resulting in more frequent spontaneous transitions to anagen and faster propagation of waves. Similar patterns of activation and wave propagation were also observed in rabbits, which have compound follicles containing multiple SC clusters that behave as one automaton. This self-organizing behavior of hair follicles is thus effective in tissues that vary in the number and arrangement of SC clusters and enables coordination of SC populations across a large area.
M. V. Plikus, R. E. Baker, C.-C. Chen, C. Fare, D. de la Cruz, T. Andl, P. K. Maini, S. E. Millar, R. Widelitz, C.-M. Chuong, Self-organizing and stochastic behaviors during the regeneration of hair stem cells. Science 332, 586–589 (2011). [Abstract] [Full Text]