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

• Published in: Nature communications 2024-08, Vol.15 (1), p.7584-18, Article 7584
• Main Authors: Patel, Vaishali N., Aure, Marit H., Choi, Sophie H., Ball, James R., Lane, Ethan D., Wang, Zhangjie, Xu, Yongmei, Zheng, Changyu, Liu, Xibao, Martin, Daniel, Pailin, Jillian Y., Prochazkova, Michaela, Kulkarni, Ashok B., van Kuppevelt, Toin H., Ambudkar, Indu S., Liu, Jian, Hoffman, Matthew P.
• Format: Article
• Language: English
• Subjects: 13/1; 13/51; 14/19; 38; 38/22; 38/39; 38/91; 631/136/142; 631/136/2139; 631/80/221; 82/29; Animals; Basement Membrane - metabolism; Basement membranes; Basements; Cell Differentiation; Differentiation; Epithelial Cells - cytology; Epithelial Cells - metabolism; Exocrine glands; Fibroblast growth factor receptors; Fibroblast Growth Factors - metabolism; Gene expression; Growth factors; Heparan sulfate; Heparitin Sulfate - metabolism; Homeostasis; Humanities and Social Sciences; Male; Membranes; Metabolism; Mice; Mice, Knockout; multidisciplinary; Receptors, Fibroblast Growth Factor - genetics; Receptors, Fibroblast Growth Factor - metabolism; Regeneration; Salivary gland; Salivary glands; Salivary Glands - cytology; Salivary Glands - metabolism; Science; Science (multidisciplinary); Signal Transduction; Sulfates; Sulfotransferases - genetics; Sulfotransferases - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-51862-0

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. The use of heparan sulfate mimetics is an attractive target for organ regeneration. Here, the authors identify how highly 3- O -sulfated heparan sulfate domains regulate FGFR signaling and basement membrane metabolism to control epithelial differentiation.