Genetically engineered pigs manifesting pancreatic agenesis with severe diabetes

• Main Authors: Eiji Kobayashi, Masaki Nagaya, Koki Hasegawa, Masahito Watanabe, Kazuaki Nakano, Kazutoshi Okamoto, Takeshi Yamada, Ayuko Uchikura, Kenji Osafune, Harumasa Yokota, Taiji Nagaoka, Hitomi Matsunari, Kazuhiro Umeyama, Hiromitsu Nakauchi, Hiroshi Nagashima
• Format: Article
• Language: English
• Published: BMJ Publishing Group 2020-12-01
• Series: BMJ Open Diabetes Research & Care
• Online Access: https://drc.bmj.com/content/8/2/e001792.full

Introduction Pancreatic duodenum homeobox 1 (Pdx1) expression is crucial for pancreatic organogenesis and is a key regulator of insulin gene expression. Hairy and enhancer of split 1 (Hes1) controls tissue morphogenesis by maintaining undifferentiated cells. Hes1 encodes a basic helix loop helix (bHLH) transcriptional repressor and functionally antagonizes positive bHLH genes, such as the endocrine determination gene neurogenin-3. Here, we generated a new pig model for diabetes by genetic engineering Pdx1 and Hes1 genes.Research design and methods A transgenic (Tg) chimera pig with germ cells carrying a construct expressing Hes1 under the control of the Pdx1 promoter was used to mate with wild-type gilts to obtain Tg piglets.Results The Tg pigs showed perinatal death; however, this phenotype could be rescued by insulin treatment. The duodenal and splenic lobes of the Tg pigs were slender and did not fully develop, whereas the connective lobe was absent. β cells were not detected, even in the adult pancreas, although other endocrine cells were detected, and exocrine cells functioned normally. The pigs showed no irregularities in any organs, except diabetes-associated pathological alterations, such as retinopathy and renal damage.Conclusion Pdx1-Hes1 Tg pigs were an attractive model for the analysis of pancreatic development and testing of novel treatment strategies for diabetes.