Affiliation:
1. Stem Cell Biology Group, Waghmare Lab, Cancer Research Institute, Advanced Centre for Treatment Research and Education in Cancer (ACTREC), Tata Memorial Centre , Kharghar, Navi Mumbai, Maharashtra , India
2. Homi Bhabha National Institute, Training School Complex , Anushakti Nagar, Mumbai, Maharashtra , India
Abstract
Abstract
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.
Funder
Department of Biotechnology, India
ACTREC Fellowship
UGC Fellowship
Publisher
Oxford University Press (OUP)
Subject
Cell Biology,Developmental Biology,Molecular Medicine
Cited by
7 articles.
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