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Oncotarget: Hereditary pancreatitis model by blastocyst complementation in mouse


FOR IMMEDIATE RELEASE
2020-06-10

Volume 11, Issue 22 of @Oncotarget reported that the application of pluripotent stem cells is expected to contribute to the elucidation of the unknown mechanism of human diseases.

To study the mechanism of human hereditary pancreatitis, the authors here performed the blastocyst complementation method.

In the BC method, mouse embryonic stem cells harboring CRISPR/CAS9-mediated mutations in the Prss1 gene were injected into blastocysts with a deficient Pdx1 gene, which is a critical transcription factor in the development of the pancreas.

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.

"The present study opens the possibility of investigating uncharacterized human diseases by utilizing the BC method"

Dr. Hideshi Ishii from Osaka University, as well as Dr. Takahiro Arai from Unitech Co., Ltd. also in Japan, said, "Pluripotent stem cells (PSCs)-applied technologies enable reprogramming of cells even harboring disease-specific germline mutations."

Although the reproduction of endocrine diseases such as pancreatic diseases was also studied, 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.

Moreover, other studies have reported the usefulness of patient-derived iPSCs as a screening tool of biomarkers for Alzheimer's disease and Behcet's disease.

Figure 7: Reproduction of HP by BC method. Mouse ES cells harboring mutations in the Prss1 were injected into the blastocysts with deficient Pdx1 gene. The blastocysts injected into the Prss1-mutant ES cells induced trypsin activation like human HP.

The blastocyst complementation method has attracted attention as a model that could reproduce human tissues and diseases in other animals and has been reported to be applied especially for the construction of pancreatic tissues.

Although the BC method using disease-specific PSCs had been suggested to reproduce hereditary diseases in vivo, its application on the study of hereditary diseases has been reported by only a few.

The substitution of amino acids due to mutations, which play a role in the activation of the trypsinogen precursor or the activated trypsin, was reported to result in pancreatitis.

The Ishii/Arai Research Team concluded in their Oncotarget Research Paper, "we applied to the BC method with Prss1-mutant ESCs to reproduce HP in mouse (Figure 7). The embryos derived from Prss1-mutant ESCs showed trypsin activation and autolysis, mimic to human HP. As the best of our knowledge, the present study is the first report for reproducing human disease by utilizing the BC method. Although the application of this method to human cells has ethical issues to be overcome, utilizing the BC method would be an attractive tool for the study of human diseases and can contribute to drug discovery and regenerative medicine."

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DOI - https://doi.org/10.18632/oncotarget.27595

Full text - https://www.oncotarget.com/article/27595/text/

Correspondence to - Hideshi Ishii - hishii@gesurg.med.osaka-u.ac.jp and Takahiro Arai - t.arai@unitech-op.com

Keywords - blastocyst complementation, hereditary pancreatitis, disease-specific pluripotent stem cells, PRSS1

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