Unusual Duct-Like Cells in the Islet of Diabetic C414A-CRY1 Transgenic Mice

Abstract

Cryptochrome (CRY) proteins play indispensable roles in the mammalian circadian clock. We previously generated transgenic mice ubiquitously expressing mCRY1 with a mutation in cysteine414 (the zinc-binding site of CRY1). The Tg mice overexpressing the mutant CRY1 (C414A-CRY1) showed early onset diabetes mellitus characterized by β-cell dysfunction in addition to unusual circadian rhythms in locomotor activities. We have already shown that the decrease of insulin secretion from β-cells along with the lowered proliferation of β-cells due to the senescence-associated secretory phenotype (SASP)-like changes in the Tg mice (Okano S., 2016). We have also demonstrated that, atypical duct-like structures having some common morphological characters to pancreatic intraepithelial neoplasias (PanINs) that can cause pancreatic ductal adenocarcinoma, frequently appeared in the aged Tg mice. In this study, to explore the relation between the unique features of β-cells and the generation of PanIN-like structures, we further performed detailed studies of the pancreases of Tg mice. We found that unusual duct-like structures producing mucin emerged not only in the exocrine areas but also in the inside islets in the Tg mice frequently with age. These results may suggest that islet cells in the Tg mice can transdifferentiate to duct-like cells, thereby contributing to generate PanIN-like lesions in the Tg mice. In addition, the extent of fibrosis in the islet increased in the Tg mice compared with wild type controls. Taken together, our results suggest the SASP-like microenvironment in the islet play some roles to modify the integrity of endocrine cells as well as the architecture of the islet. Disclosure S. Okano: None. A. Yasui: None. S. Kanno: None. K. Satoh: None. M. Igarashi: None. O. Nakajima: None.