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

Vaishali N. Patel (), Marit H. Aure, Sophie H. Choi, James R. Ball, Ethan D. Lane, Zhangjie Wang, Yongmei Xu, Changyu Zheng, Xibao Liu, Daniel Martin, Jillian Y. Pailin, Michaela Prochazkova, Ashok B. Kulkarni, Toin H. Kuppevelt, Indu S. Ambudkar, Jian Liu and Matthew P. Hoffman ()
Additional contact information
Vaishali N. Patel: DHHS
Marit H. Aure: DHHS
Sophie H. Choi: DHHS
James R. Ball: DHHS
Ethan D. Lane: DHHS
Zhangjie Wang: University of North Carolina
Yongmei Xu: University of North Carolina
Changyu Zheng: DHHS
Xibao Liu: DHHS
Daniel Martin: DHHS
Jillian Y. Pailin: DHHS
Michaela Prochazkova: DHHS
Ashok B. Kulkarni: DHHS
Toin H. Kuppevelt: Radboud University Medical Center
Indu S. Ambudkar: DHHS
Jian Liu: University of North Carolina
Matthew P. Hoffman: DHHS

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract Heparan 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.

Date: 2024
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DOI: 10.1038/s41467-024-51862-0

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