The Role Of Wnt/?-catenin Signaling In Hair Follicle Dermal Sheath In Skin Homeostasis

Dermal sheath(DS),a layer of connective tissue sheath,is located between ORS and dermis.It harbors mesenchymal cells,called DS cells.Previous work considers DS cells as dermal stem cells that can long term self-renew.DS cells cellularly contribute to the new generated DP and DS during hair regeneration.Wnt/?-catenin signaling pathway is crucial in maintenance of stem cell quiescence,stem cell activation and tissue homeostasis.However,little is known about how Wnt/?-catenin signaling pathway regulates dermal sheath cells and progeny behaviors.In this study,we uncover that forced activation of ?-catenin disrupts bulge HFSC niche.Hair follicle epithelial cells undergo reprogramming to form ectopic hair follicles in the pre-existing hair follicles.The de novo DC cells of the ectopic hair follicle originate from DS and/or its progeny.The generation of the ectopic outgrowth resembles embryonic hair development.We also find progressive skin fibrosis occurs in mutant mice.Cell lineage tracing assays clearly show that DS cells are the main cellular origin of skin fibrosis.Gene expression profiling of FACS sorted dermal sheath cells was analyzed.We find expression of many DC/DP signature genes up-regulates and a general up-regulation of genes associated with GO terms ‘regulation of cell proliferation',‘cell migration' and ‘ECM organization' in ?-catenin activated dermal sheath cells.It indicates that DS cells per se are involved in the development of ectopic hair follicle and skin fibrosis.Wntless knock out experiment rule out the possiblity that secreted Wnt protein from DS promotes the initiation of the ectopic hair follicles.Gene expression analysis shows the significant elevation of Bmp,Fgf and Notch ligands,indicating that ?-catenin activated DS cells may induce ectopic hair follicles through these growth factors.Administration of BMPR inhibitor LDN-193189,FGFR inhibitor NVP-BGJ398 or Notch inhibitor DAPT attenuates ectopic hair follicle formation,which further validate that Wnt/?-catenin signaling pathway regulates the formation of ectopic hair follicles through Fgf,Bmp and Notch sigaling.Collectively,our work uncover that activation of ?-catenin in DS induce ectopic hair follicles via Bmp,Fgf and Notch signaling.?-catenin activated DS cells show elevated proliferation and differentiate into aberrant fibroblasts,which results in skin fibrosis.In summary,our findings advance the current knowledge of high plasticity of DS cells and provide an insight into understanding how Wnt/?-catenin signaling controls DS cells behaviors.