2057-P: Atypical Trefoil Factor Family 2 Expressing ß-Cells of Diabetic Mutant CRY1 Transgenic Mice with Intraislet Ducts

We have demonstrated that cysteine414 (zinc-binding site of mCRY1)-alanine mutant mCRY1 transgenic mice (Tg mice) show diabetes characterized by the reduction of β-cell proliferation and by β-cell dysfunction due to SASP (senescence-associated secretory phenotype)-like characters of β-cells. In addition, our previous studies showed that mucinous pancreatic duct glands (PDGs) occur in exocrine areas of aged Tg mice. Further, we also showed that mucin-producing intra-islet ducts develope age-dependently in Tg mice (Okano S. et al., 2019). To explore the molecular mechanisms for developing the intra-islet ducts, we conducted DNA microarray analysis using RNA from islets of aged Tg mice. The islet samples were obtained by paraffin-embedded pancreas sections by laser-capture microdissection. The result showed that the mRNA expression of Trefoil factor family 2 (TFF2), which is reportedly expressed in PDGs, was up-regulated in the islet of aged Tg mice. Immunostaining experiments with TFF2 antibodies revealed that, inside of islet of aged Tg mice, TFF2 was expressed by considerable rate in β-cells. TFF2 was located in speckle-like granules in the cytoplasm in the β-cells. In wild type controls, no TFF2 was observed in β-cells. These results suggest that the atypical β-cells have both endocrine and ductal characteristics. In α-cells, essentially no TFF2 protein expression was observed in both wild type controls and Tg mice. Taken together, our results strongly suggest that β-cells are major sources for intra-islet ductal cells in Tg mice. Our results also suggest that direct trans-differentiation of β-cells to ductal cells is involved in the generation of the intra-islet ductal cells.