Assistant Investigator National Health Research Institutes Huwei Township, Yunlin, Taiwan
Abstract: Background Ca2+ is a ubiquitous intracellular signal regulating various stem cell types and niches. Our previous study indicated that Ca2+ signaling governs hair follicle (HF) morphogenesis and regeneration. Furthermore, treatment with Derinat, a transient receptor potential canonical channel (TRPC) inhibitor, altered hair growth patterns in BALB/c-nu and C57BL/6 mice by prolonging the anagen phase of the hair cycle. However, the specific mechanisms by which Ca2+ signaling influences HF stem cells and their niche to control the hair cycle phase remain unclear. Purpose This study elucidated the role of Ca²⁺ signaling in regulating the hair cycle, revealing that Ca²⁺ signals originating from TRPCs affect HF stem cells and their niche, thus controlling the phase of the hair cycle. Methods Vibrissae follicles (VFs) from mice were analyzed across the hair cycle for Ca2+ signaling, ROS accumulatinon, and DNA damage (TUNEL). Additionally, C57BL/6 female mice were treated with Derinat during telogen, from P49 (encompassing late catagen to telogen) to P59. Hair growth, cell proliferation (BrdU incorporation), TUNEL, and expression of bulge markers (K15), secondary hair germ (SHG) markers (P-cadherin), as well as CaMKII and β-catenin levels, were then evaluated. Results Our results indicated that Ca²⁺ signaling and intracellular ROS levels differ across the hair cycle phases of VFs. Specifically, middle and late catagen phases exhibit higher levels of Ca²⁺ signaling and intracellular ROS compared to the anagen phase. DNA damage was only observed in late catagen VFs. We further investigated the effect of the TRPC inhibitor, Derinat, on HFs. Our findings demonstrated that Derinat treatment during the telogen phase prematurely initiates the transition to the anagen phase. This is likely due to the blockage of Ca²⁺ signaling by Derinat, which activates HF stem cells in the bulge and SHG, as indicated by increased BrdU incorporation. Furthermore, we found that CaMKII and β-catenin signaling pathways are involved in Derinat-regulated hair cycle transition. Notably, Derinat treatment did not cause any alterations in body weight. Conclusion Inhibition of TRPC-mediated Ca²⁺ signaling by Derinat promotes premature anagen entry by activating hair follicle stem cells and modulating CaMKII and β-catenin pathways.
Funding Source: This work was funded by the National Science and Technology Council (NSTC) of Taiwan (NSTC 111-2314-B-400-042-MY2 and NSTC 113-2314-B-400-021-MY3)
