Smad1 and 5 but Not Smad8 Establish Stem Cell Quiescence Which Is Critical to Transform the Premature Hair Follicle During Morphogenesis Toward the Postnatal State

Authors

  • Eve Kandyba,

    1. Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research and Department of Biochemistry and Molecular Biology, USC Norris Cancer Center, University of Southern California, Los Angeles, California, USA
    2. Department of Pathology, Department of Biochemistry and Molecular Biology, USC Norris Cancer Center, University of Southern California, Los Angeles, California, USA
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  • Virginia M. Hazen,

    1. Department of Biological Sciences, Neurobiology Section, Department of Biochemistry and Molecular Biology, USC Norris Cancer Center, University of Southern California, Los Angeles, California, USA
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  • Agnieszka Kobielak,

    1. Department of Otolaryngology-Head & Neck Surgery and Department of Biochemistry and Molecular Biology, USC Norris Cancer Center, University of Southern California, Los Angeles, California, USA
    2. Department of Biochemistry and Molecular Biology, USC Norris Cancer Center, University of Southern California, Los Angeles, California, USA
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  • Samantha J. Butler,

    1. Department of Biological Sciences, Neurobiology Section, Department of Biochemistry and Molecular Biology, USC Norris Cancer Center, University of Southern California, Los Angeles, California, USA
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  • Krzysztof Kobielak

    1. Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research and Department of Biochemistry and Molecular Biology, USC Norris Cancer Center, University of Southern California, Los Angeles, California, USA
    2. Department of Pathology, Department of Biochemistry and Molecular Biology, USC Norris Cancer Center, University of Southern California, Los Angeles, California, USA
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Correspondence: Krzysztof Kobielak, M.D, Ph.D., The Broad CIRM Center for Regenerative Medicine and Stem Cell Research, Department of Pathology, University of Southern California, 1425 San Pablo Street, BCC-513, Los Angeles, California 90033, USA. Telephone: +1-323-442-3208; Fax: +1-323-442-7832; e-mail: kkobiela@med.usc.edu

Abstract

Hair follicles (HFs) are regenerative miniorgans that offer a highly informative model system to study the regulatory mechanisms of hair follicle stem cells (hfSCs) homeostasis and differentiation. Bone morphogenetic protein (BMP) signaling is key in both of these processes, governing hfSCs quiescence in the bulge and differentiation of matrix progenitors. However, whether canonical or noncanonical pathways of BMP signaling are responsible for these processes remains unresolved. Here, we conditionally ablated two canonical effectors of BMP signaling, Smad1 and Smad5 during hair morphogenesis and postnatal cycling in mouse skin. Deletion of Smad1 and Smad5 (dKO) in the epidermis during morphogenesis resulted in neonatal lethality with lack of visible whiskers. Interestingly, distinct patterns of phospho-Smads (pSmads) activation were detected with pSmad8 restricted to epidermis and pSmad1 and pSmad5 exclusively activated in HFs. Engraftment of dKO skin revealed retarded hair morphogenesis and failure to differentiate into visible hair. The formation of the prebulge and bulge reservoir for quiescent hfSCs was precluded in dKO HFs which remained in prolonged anagen. Surprisingly, in postnatal telogen HFs, pSmad8 expression was no longer limited to epidermis and was also present in dKO bulge hfSCs and matrix progenitors. Although pSmad8 activity alone could not prevent dKO hfSCs precocious anagen activation, it sustained efficient postnatal differentiation and regeneration of visible hairs. Together, our data suggest a pivotal role for canonical BMP signaling demonstrating distinguished nonoverlapping function of pSmad8 with pSmad1 and pSmad5 in hfSCs regulation and hair morphogenesis but a redundant role in adult hair progenitors differentiation. Stem Cells 2014;32:534–547

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