BMP-AKT-GSK3β Signaling Restores Hair Follicle Stem Cells Decrease Associated with Loss of Sfrp1

Wnt signaling plays a pivotal role in regulating activation, proliferation, stem cell renewal, and differentiation of hair follicle stem cells (HFSCs). Secreted frizzled-related protein 1 (Sfrp1), a Wnt antagonist is upregulated in the HFSCs; however, its role in the HFSCs regulation is still obscure. Here, we show that Sfrp1 loss showed a depletion of HFSCs, enhanced HFSC proliferation, and faster hair follicle cycle at PD21-PD28; HFSC markers, such as Lgr5 and Axin2, were decreased in both the Sfrp1+/- and Sfrp1-/- HFSCs. In addition, the second hair follicle cycle was also faster compared with WT. Importantly, Sfrp1-/- showed a restoration of HFSC by second telogen (PD49), whereas Sfrp1+/- did not show restoration with still having a decreased HFSC. In fact, restoration of HFSCs was due to a pronounced downregulation of β-catenin activity mediated through a cross-talk of BMP-AKT-GSK3β signaling in Sfrp1-/- compared with Sfrp1+/-, where downregulation was less pronounced. In cultured keratinocytes, Sfrp1 loss resulted in enhanced proliferation and clonogenicity, which were reversed by treating with either BMPR1A or GSK3β inhibitor thereby confirming BMP-AKT-GSK3β signaling involved in β-catenin regulation in both the Sfrp1+/- and Sfrp1-/- mice. Our study reveals a novel function of Sfrp1 by unraveling an in vivo molecular mechanism that regulates the HFSCs pool mediated through a hitherto unknown cross-talk of BMP-AKT-GSK3β signaling that maintains stem cell pool balance, which in turn maintains skin tissue homeostasis.