Characteristic Features in the Intraislet Ductal Cells of Diabetic C414A-CRY1 Transgenic Mice

The transgenic mice ubiquitously expressing the zinc-binding site-mutant CRY1 (C414A-CRY1) show early onset diabetes mellitus similar to human MODY characterized by β-cell dysfunction. In the Tg mice with age, atypical ductal structures emerged inside islets, suggesting that islet cells can transdifferentiate to duct-like cells as we have reported at ADA Scientific Sessions in 2017 and 2018. To explore further molecular features of intra-islets ducts, we conducted staining experiments for Dolichos biflorus agglutinin (DBA) lectin in the pancreatic sections of well-matured mice. The results showed that high levels of staining for DBA lectin were observed in normal ducts of both wild type and Tg mice. In contrast, majority of intra-islet ductal structures especially still not fully developed small ones were weakly positive for DBA lectin, suggesting immaturity for ductal functions of the intra-islet ductal cells. Furthermore, the variation of the staining levels for DBA lectin in intra-islet ductal cells was evidently larger than that in other ductal cells, indicating heterogeneity in the cell functions among intra-islet ductal cells. We also found that remarkably high accumulation of FAM98A, an RNA-binding protein whose functions are still not decisive, was observed in the intra-islet ducts in the Tg mice. In normal ducts, moderate staining of FAM98A was observed. As for pancreatic endocrine cells, although as a whole the immunostaining levels were much weaker than those of acini and ductal cells, discernable staining of FAM98A is detected in both α and β cells of islets. Taken together, our results indicate that intra-islet ductal cells have unique feature distinct from normal ductal cells, and suggest that FAM98A may play important roles in the generation of atypical ductal cells from non-ductal cells in the islet. Disclosure S. Okano: None. A. Yasui: None. S. Kanno: None. K. Satoh: None. M. Igarashi: None. O. Nakajima: None. Funding Japan Society for the Promotion of Science; Tohoku University