title: Skin Adipocyte Stem Cell Self-Renewal Is Regulated by a PDGFA/AKT-Signaling Axis.
abstract: Tissue growth and maintenance requires stem cell populations that self-renew, proliferate, and differentiate. Maintenance of white adipose tissue (WAT) requires the proliferation and differentiation of adipocyte stem cells (ASCs) to form postmitotic, lipid-filled mature adipocytes. Here we use the dynamic adipogenic program that occurs during hair growth to uncover an unrecognized regulator of ASC self-renewal and proliferation, PDGFA, which activates AKT signaling to drive and maintain the adipogenic program in the skin. Pdgfa expression is reduced in aged ASCs and is required for ASC proliferation and maintenance in the dermis, but not in other WATs. Our molecular and genetic studies uncover PI3K/AKT2 as a direct PDGFA target that is activated in ASCs during WAT hyperplasia and is functionally required for dermal ASC proliferation. Our data therefore reveal active mechanisms that regulate ASC self-renewal in the skin and show that distinct regulatory mechanisms operate in different WAT depots.
authors.affiliation: Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT 06520, USA.
authors.forename: Guillermo C
authors.initials: GC
authors.lastname: Rivera-Gonzalez
authors.affiliation: Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT 06520, USA.
authors.forename: Brett A
authors.initials: BA
authors.lastname: Shook
authors.affiliation: Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, 751 85 Uppsala, Sweden.
authors.forename: Johanna
authors.initials: J
authors.lastname: Andrae
authors.affiliation: Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT 06520, USA.
authors.forename: Brandon
authors.initials: B
authors.lastname: Holtrup
authors.affiliation: Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT 06520, USA.
authors.forename: Katherine
authors.initials: K
authors.lastname: Bollag
authors.affiliation: Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, 751 85 Uppsala, Sweden.
authors.forename: Christer
authors.initials: C
authors.lastname: Betsholtz
authors.affiliation: Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT 06520, USA; Section of Comparative Medicine, Yale University, New Haven, CT 06520, USA.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Rodeheffer
authors.affiliation: Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT 06520, USA; Department of Dermatology, Yale School of Medicine, Yale University, New Haven, CT 06520, USA. Electronic address: valerie.horsley@yale.edu.
authors.forename: Valerie
authors.initials: V
authors.lastname: Horsley
mesh_terms: D017667:Adipocytes / Q000166:cytology* / Q000201:enzymology*; D050156:Adipogenesis; D000818:Animals; D051927:CD24 Antigen / Q000378:metabolism; D049109:Cell Proliferation; D000066673:Cell Self Renewal; D020405:Dermis / Q000378:metabolism; D020869:Gene Expression Profiling; D006965:Hyperplasia; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000378:metabolism; D015398:Signal Transduction; D012867:Skin / Q000166:cytology*; D013234:Stem Cells / Q000166:cytology*
chemical_list: D051927:CD24 Antigen; D010982:Platelet-Derived Growth Factor; C075278:platelet-derived growth factor A; D019869:Phosphatidylinositol 3-Kinases; D020796:Receptor, Platelet-Derived Growth Factor alpha; D051057:Proto-Oncogene Proteins c-akt
keywords: PI3K/Akt signaling; Pdgfa; adipocyte stem cells; self-renewal; skin