Abstract
The application of pluripotent stem cells is expected to contribute to the elucidation of unknown mechanism of human diseases. However, in vitro induction of organ-specific cells, such as pancreas and liver, is still difficult and the reproduction of their disorders in a model has been unfeasible. To study the mechanism of human hereditary pancreatitis (HP), we here performed the blastocyst complementation (BC) method. In the BC method, mouse embryonic stem (ES) cells harboring CRISPR/CAS9-mediated mutations in the Prss1 gene were injected into blastocysts with deficient Pdx1 gene, which is a critical transcription factor in the development of pancreas. The results showed that trypsin was activated extremely in Prss1-mutant mice. 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.
Highlights
Pluripotent stem cells (PSCs)-applied technologies enable reprogramming of cells even harboring diseasespecific germline mutations
The present study showed that the blastocyst complementation (BC) methods with Prss1T29I embryonal stem cells (ESCs) can reproduce the phenotype of hereditary pancreatitis (HP) in a model
We investigated to reproduce HP using the BC method
Summary
Pluripotent stem cells (PSCs)-applied technologies enable reprogramming of cells even harboring diseasespecific germline mutations. Previous studies have used disease-specific PSCs from patients with hereditary disorders to clarify the pathogenesis of muscle dystrophy [3] and fibrodysplasia ossificans progressiva [4]. Reproduction of endocrine diseases such as pancreatic diseases were studied [5, 6], there has been no enough model to conclude consistent results between in vitro and in vivo, presumably due to the difficulty of cell differentiation in vitro and the complexity of the organ structures [7,8,9]. In order to reproduce the diseases that are derived from tissues, in which induction of differentiation is difficult, it is undoubtedly necessary to improve the efficiency of differentiation induction and to reconstruct the complexity of tissues in a model
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