Specific 3-O-sulfated heparan sulfate domains regulate salivary gland basement membrane metabolism and epithelial differentiation

Author:

Patel Vaishali N.ORCID,Aure Marit H.ORCID,Choi Sophie H.,Ball James R.,Lane Ethan D.ORCID,Wang Zhangjie,Xu Yongmei,Zheng Changyu,Liu Xibao,Martin DanielORCID,Pailin Jillian Y.,Prochazkova Michaela,Kulkarni Ashok B.,van Kuppevelt Toin H.,Ambudkar Indu S.,Liu Jian,Hoffman Matthew P.ORCID

Abstract

AbstractHeparan sulfate (HS) regulation of FGFR function, which is essential for salivary gland (SG) development, is determined by the immense structural diversity of sulfated HS domains. 3-O-sulfotransferases generate highly 3-O-sulfated HS domains (3-O-HS), and Hs3st3a1 and Hs3st3b1 are enriched in myoepithelial cells (MECs) that produce basement membrane (BM) and are a growth factor signaling hub. Hs3st3a1;Hs3st3b1 double-knockout (DKO) mice generated to investigate 3-O-HS regulation of MEC function and growth factor signaling show loss of specific highly 3-O-HS and increased FGF/FGFR complex binding to HS. During development, this increases FGFR-, BM- and MEC-related gene expression, while in adult, it reduces MECs, increases BM and disrupts acinar polarity, resulting in salivary hypofunction. Defined 3-O-HS added to FGFR pulldown assays and primary organ cultures modulates FGFR signaling to regulate MEC BM synthesis, which is critical for secretory unit homeostasis and acinar function. Understanding how sulfated HS regulates development will inform the use of HS mimetics in organ regeneration.

Funder

U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences

U.S. Department of Health & Human Services | NIH | National Institute of Dental and Craniofacial Research

Publisher

Springer Science and Business Media LLC

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