Nicolazzi, G. A. | Search bioRxiv

bioRxiv2025

Multimerin1, not Galectin-8, Promotes Gastric Chief Cell Differentiation by Tempering WNT Signaling

Galectins are a family of proteins that bind galactose-containing glycans. One member, galectin-8, preferentially binds galactose that contains a terminal sulfate. Aberrant expression and secretion of sulfated glycosylation epitopes, such as 3-Sulfo-LeA/C, is a feature of high-risk human foregut metaplasias. In addition, recent work has demonstrated that 3-Sulfo-LeC is a marker of mature murine zymogenic chief cells of the stomach and that 3-Sulfo-LeC epitope is secreted via cathartocytosis during the cellular transition to a metaplastic state. Based on those findings, we used Lgals8-/-mice, to determine whether galectin-8 might play a role in chief cell homeostasis. We observed delayed gastric differentiation in the Lgals8-/-mice and discovered that this phenotype was due to an unappreciated deletion of Mmrn1 and Snca in the Lgals8-/- line. We show that multimerin-1 tempers WNT stimulation of the gastric corpus at an early age, as evidenced by nuclear beta-catenin staining and proliferation throughout the gland. Because multimerin-1 is synthesized and secreted from endothelial cells and not from the epithelial compartment, these data uncover a role for mesodermal cells in epithelial developmental and maturation of the mouse stomach. As prior studies have suggested galectin-8 and multimerin-1 have overlapping functions albeit, divergent with respect to bone, future studies using pure knockouts are necessary to refine these phenotypes.

developmental biology↗

bioRxiv2024

Cathartocytosis: How Cells Jettison Unwanted Material as They Reprogram

Injury can cause differentiated cells to undergo massive reprogramming to become proliferative to repair tissue via a cellular program called paligenosis. Gastric digestive-enzyme-secreting chief cells use paligenosis to reprogram into progenitor-like Spasmolytic-Polypeptide Expressing Metaplasia (SPEM) cells. Stage 1 of paligenosis is the downscaling of mature cell architecture via a process involving lysosomes. Here, we noticed that sulfated glycoproteins were not only digested during paligenosis but also excreted into the gland lumen. Various genetic and pharmacological approaches showed that endoplasmic reticulum membranes and secretory granule cargo were also excreted and that the process proceeded in parallel with, but was mechanistically independent of autophagy. 3-dimensional light and electron-microscopy demonstrated that excretion occurred via unique, complex, multi-chambered invaginations of the apical plasma membrane. As this lysosome-independent cell cleansing process does not seem to have been priorly described, we termed it "cathartocytosis". Cathartocytosis allows a cell to rapidly eject excess material without waiting for autophagic and lysosomal digestion. We speculate the ejection of sulfated glycoproteins would aid in downscaling and might also help bind and flush pathogens away from tissue.

cell biology↗