Hereditary Pancreatitis Model by Blastocyst Complementation in Mouse

Abstract

The application of pluripotent stem cell is expected to contribute to the elucidation of the unknown mechanism of human diseases. However, in vitro induction of cells in several organs, such as the pancreas and liver, remains difficult; therefore, reproduction of those diseases in a model has not been feasible. To reproduce human hereditary pancreatitis (HP), which is most frequently caused by the mutations in the PRSS1 gene, we performed the blastocyst complementation (BC) method. In the BC method, mouse embryonic stem (ES) cells harboring CRISPR/CAS9-mediated mutations in the Prss1 were injected into the blastocysts of deficient Pdx1 gene mice, which is a critical transcription factor in the pancreas. The results showed that the blastocysts injected into the Prss1-mutant ES cells induced trypsin activation. This implied that the mouse phenotype mimics that of human HP and that the BC method was useful for the reproduction and study of pancreatic disorders. The present study opens the possibility of investigating uncharacterized human diseases by utilizing the BC method.