3-O-sulfated heparan sulfate expands the Kit+ epithelial progenitor pool via FGFR2b-dependent proliferation

Friday, November 08, 2013 — Poster Session IV
2:00 p.m. – 4:00 p.m.	FAES Academic Center (Upper-Level Terrace)	NIDCR	DEVBIO-6

Authors

VN Patel
IM Lombaert
Y Xu
J Liu
MP Hoffman

Abstract

During organogenesis a rapid expansion of the epithelial progenitor pool is required for growth and morphogenesis. Kit and Fgfr2b signaling maintain and expand the progenitor pool in branching epithelial organs. Elucidating the cellular mechanisms that induce rapid expansion of epithelial progenitors is crucial to understand organogenesis and expand progenitors for regeneration. Since heparan sulfate (HS) is required for Fgfr2b function we hypothesized that specific HS synthesized by Kit+ progenitors may control their expansion. Kit+ epithelial cells were isolated from fetal salivary glands and the HS biosynthetic enzymes were analyzed. Surprisingly, the enzymes that generate 3-O-sulfated heparan sulfate (3-O-HS) were specifically and highly expressed in Kit+ progenitors and Fgfr2b-signaling rapidly increases their expression. Using recombinant enzymes to specifically modify HS we show that 3-O-HS increases Fgfr2b signaling and the number of Kit+ progenitors. Alternatively, reducing Kit signaling decreases 3-O-sulfotransferase expression and organogenesis. Thus 3-O sulfated HS increases Fgfr2b and Kit signaling that feeds back to increase HS biosynthesis providing a rapid response mechanism to modify HS structures and control progenitor proliferation in response to a growth factor. The identification of specific HS structures that control localized progenitor cell proliferation will be useful to expand progenitor cells for use in regenerative therapy.