title: Hs3st3-modified heparan sulfate controls KIT+ progenitor expansion by regulating 3-O-sulfotransferases.
abstract: The exquisite control of growth factor function by heparan sulfate (HS) is dictated by tremendous structural heterogeneity of sulfated modifications. How specific HS structures control growth factor-dependent progenitor expansion during organogenesis is unknown. We isolated KIT+ progenitors from fetal salivary glands during a stage of rapid progenitor expansion and profiled HS biosynthetic enzyme expression. Enzymes generating a specific type of 3-O-sulfated-HS (3-O-HS) are enriched, and fibroblast growth factor 10 (FGF10)/FGF receptor 2b (FGFR2b) signaling directly regulates their expression. Bioengineered 3-O-HS binds FGFR2b and stabilizes FGF10/FGFR2b complexes in a receptor- and growth factor-specific manner. Rapid autocrine feedback increases 3-O-HS, KIT, and progenitor expansion. Knockdown of multiple Hs3st isoforms limits fetal progenitor expansion but is rescued with bioengineered 3-O-HS, which also increases adult progenitor expansion. Altering specific 3-O-sulfated epitopes provides a mechanism to rapidly respond to FGFR2b signaling and control progenitor expansion. 3-O-HS may expand KIT+ progenitors in vitro for regenerative therapy.
authors: Matrix and Morphogenesis Section, Laboratory of Cell and Developmental Biology, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Vaishali N
authors: VN
authors: Patel
authors: Matrix and Morphogenesis Section, Laboratory of Cell and Developmental Biology, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Isabelle M A
authors: IM
authors: Lombaert
authors: Matrix and Morphogenesis Section, Laboratory of Cell and Developmental Biology, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Samuel N
authors: SN
authors: Cowherd
authors: Section of Cardiology, Department of Medicine, Geisel School of Medicine at Dartmouth, Hanover, NH 03756, USA.
authors: Nicholas W
authors: NW
authors: Shworak
authors: Division of Medicinal Chemistry and Natural Products, School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA.
authors: Yongmei
authors: Y
authors: Xu
authors: Division of Medicinal Chemistry and Natural Products, School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA.
authors: Jian
authors: J
authors: Liu
authors: Matrix and Morphogenesis Section, Laboratory of Cell and Developmental Biology, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: mhoffman@mail.nih.gov.
authors: Matthew P
authors: MP
authors: Hoffman
mesh_terms: D000818:Animals; D019898:Autocrine Communication; D015153:Blotting, Western; D049109:Cell Proliferation; D005333:Fetus / Q000166:cytology / Q000378:metabolism; D051526:Fibroblast Growth Factor 10 / Q000235:genetics / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D015971:Gene Expression Regulation, Enzymologic; D006497:Heparan Sulfate / Q000737:chemistry / Q000378:metabolism*; D047468:Immunoprecipitation; D017403:In Situ Hybridization; D051379:Mice; D009924:Organ Culture Techniques; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012469:Salivary Glands / Q000166:cytology / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism; D015238:Sulfotransferases / Q000235:genetics / Q000378:metabolism*
chemical_list: D051526:Fibroblast Growth Factor 10; D006497:Heparan Sulfate; D019009:Proto-Oncogene Proteins c-kit; D012333:RNA, Messenger; D051497:Receptor, Fibroblast Growth Factor, Type 2; D015238:Sulfotransferases; C496464:Fgf10 protein, mouse