Specific 3-O-sulfated heparan sulfate domains regulate salivary gland basement membrane metabolism and epithelial differentiation
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.
Authors
- Marit H. Aure (ORCID: https://orcid.org/0000-0002-2080-1740)
- Sophie H. Choi
- Yongmei Xu (ORCID: https://orcid.org/0000-0002-3756-581X)
- Daniel Martı́n (ORCID: https://orcid.org/0000-0002-8880-9087)
- Matthew P. Hoffman (ORCID: https://orcid.org/0000-0002-8293-5998)
- Ashok B. Kulkarni (ORCID: https://orcid.org/0000-0001-9849-3250)
- Ethan D. Lane (ORCID: https://orcid.org/0009-0005-1991-7243)
- James R. Ball
- Zhangjie Wang (ORCID: https://orcid.org/0000-0003-4301-953X)
- Xibao Liu (ORCID: https://orcid.org/0000-0002-9640-2850)
- Indu S. Ambudkar (ORCID: https://orcid.org/0000-0002-9559-8679)
- Vaishali N. Patel (ORCID: https://orcid.org/0000-0003-2914-7041)
- Toin H. Van Kuppevelt (ORCID: https://orcid.org/0000-0002-7028-6783)
- Jian Liu (ORCID: https://orcid.org/0000-0001-8552-1400)
- Jillian Y. Pailin
- Changyu Zheng
- Michaela Prochazkova
Institutions
- University of North Carolina at Chapel Hill (US)
- Radboud University Nijmegen (NL)
- Radboud University Medical Center (NL)
- National Institute of Dental and Craniofacial Research (US)
- NewGen Therapeutics (United States) (US)
- National Institute on Deafness and Other Communication Disorders (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-08-31
- DOI
- https://doi.org/10.1038/s41467-024-51862-0
- Citations
- 6
- Primary Topic
- Proteoglycans and glycosaminoglycans research
- Type
- article
- Field-Weighted Citation Impact
- 1.96
Funders
- National Institutes of Health
- National Institute on Deafness and Other Communication Disorders
- National Institute of General Medical Sciences
- National Institute of Dental and Craniofacial Research