Hs3st3-modified heparan sulfate controls KIT+ progenitor expansion by regulating 3-O-sulfotransferases.
Animals; Autocrine Communication; Blotting, Western; Cell Proliferation; Fetus; Fibroblast Growth Factor 10; Fluorescent Antibody Technique; Gene Expression Regulation, Enzymologic; Heparitin Sulfate; Immunoprecipitation; In Situ Hybridization; Mice; Organ Culture Techniques; Proto-Oncogene Proteins c-kit; RNA, Messenger; Real-Time Polymerase Chain Reaction; Receptor, Fibroblast Growth Factor, Type 2; Reverse Transcriptase Polymerase Chain Reaction; Salivary Glands; Stem Cells; Sulfotransferases
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.
Patel, V., Lombaert, I., Cowherd, S., Shworak, N., Xu, Y., Liu, J., & Hoffman, M. (2014). Hs3st3-modified heparan sulfate controls KIT+ progenitor expansion by regulating 3-O-sulfotransferases.. Developmental cell, 29 (6). Retrieved from https://hsrc.himmelfarb.gwu.edu/smhs_pharm_facpubs/276