Transient stimulation of TRPV4‐expressing keratinocytes promotes hair follicle regeneration in mice

Abstract

Background and Purpose: Hair follicle telogen to anagen transition results in a break in cellular quiescence of the hair follicle stem cells, which subsequently promotes hair follicle regeneration. Many critical molecules and signalling pathways are involved in hair follicle cycle progression. Transient receptor potential vanilloid 4 (TRPV4) is a polymodal sensory transducer that regulates various cutaneous functions under both normal and disease conditions. However, the role of TRPV4 in hair follicle regeneration in vivo remains incompletely understood. Experimental Approach: Using adult C57BL/6J mice, keratinocyte (K14 Cre ; Trpv4 f/f) and macrophage (Cx3cr1 Cre ; Trpv4 f/f) Trpv4 conditional knockout (cKO) mice, Trpv4 −/− mice, we investigated the effect of a single intradermal injection of GSK1016790A, a potent and selective small molecule TRPV4 activator, on hair follicle regeneration. Chemical cues and signal molecules involved in hair follicle cycle progression were measured by immunofluorescence staining, quantitative RT-PCR and western blotting. Key Results: Here, we show that a single intradermal injection of GSK1016790A is sufficient to induce telogen to anagen transition and hair follicle regeneration in mice by increasing the expression of the anagen-promoting growth factors and downregulating the expression of growth factors that inhibit anagen. The action of GSK1016790A relies largely on the function of TRPV4 in skin and involves activation of downstream ERK signalling. Conclusion and Implications: Our results suggest that transient chemical activation of TRPV4 in the skin induces hair follicle regeneration in mice, which might provide an effective therapeutic strategy for the treatment of hair loss and alopecia. 1 | INTRODUCTION The hair follicle is the most prominent mini-organ found in the skin. It is composed of three main components: the outer root sheath, the inner root sheath and the hair shaft. The hair follicle cyclically transforms from rapid growth (anagen), to apoptosis-driven regression (catagen) and last to relative quiescence (telogen) phases (Muller-Rover et al., 2001; Oshima, Rochat, Kedzia, Kobayashi, & Barrandon, 2001). Many critical molecules and signalling pathways are involved in these distinct phases of hair follicle cycle progression. The quiescence of hair follicle stem cells during telogen is largely maintained by bone morphogenetic proteins (BMPs) derived

TRPV Channels in Osteoarthritis: A Comprehensive Review

“…In the musculoskeletal system, TRPV4 is required for mechanical stress transduction [ 140 ]. In addition, TRPV4 protects the skin barrier [ 141 ], regulation of hair follicle growth [ 142 ], and pruritus in some pathologies [ 143 ]. Interestingly, TRPV4 −/− mice showed only slight changes in temperature response, while other physiological functions were significantly more affected [ 144 ].…”

Activation of TRPV4 Induces Exocytosis and Ferroptosis in Human Melanoma Cells

“…TRPV4 is widely distributed in both neuronal and non-neuronal tissues and organs, including brain, liver, intestine, olfactory epithelium, heart, lung, kidney, pancreas, bladder, testis, mammary gland, bone, and skeletal muscle [15]. Elevated TRPV4 expression has been noticed in certain tumors such as bladder, skin, stomach, and tuberous sclerosis [16][17][18][19]. Besides functioning in plasma membrane, TRPV4 also contributes to signaling in intracellular organelles.…”