Compensation of Disabled Organogeneses in Genetically Modified Pig Fetuses by Blastocyst Complementation

• Published in: Stem cell reports Vol. 14; no. 1; pp. 21 - 33
• Main Authors: Matsunari, Hitomi, Watanabe, Masahito, Hasegawa, Koki, Uchikura, Ayuko, Nakano, Kazuaki, Umeyama, Kazuhiro, Masaki, Hideki, Hamanaka, Sanae, Yamaguchi, Tomoyuki, Nagaya, Masaki, Nishinakamura, Ryuichi, Nakauchi, Hiromitsu, Nagashima, Hiroshi
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 14.01.2020; Elsevier
• Subjects: Animals; Animals, Genetically Modified; Biomarkers; Blastocyst - cytology; Blastocyst - metabolism; blastocyst complementation; Cell Differentiation - genetics; cloned pig; Cloning, Organism; Fetus; Gene Expression Regulation, Developmental; Gene Knockout Techniques; Homeodomain Proteins; organ regeneration; organogenesis; Organogenesis - genetics; Pancreas - embryology; Phenotype; pluripotent stem cells; Pluripotent Stem Cells - cytology; Pluripotent Stem Cells - metabolism; Regeneration; Swine; Trans-Activators - deficiency; blastocyst complementation; pluripotent stem cells; organogenesis; cloned pig; organ regeneration
• ISSN: 2213-6711; 2213-6711
• DOI: 10.1016/j.stemcr.2019.11.008

We have previously established a concept of developing exogenic pancreas in a genetically modified pig fetus with an apancreatic trait, thereby proposing the possibility of in vivo generation of functional human organs in xenogenic large animals. In this study, we aimed to demonstrate a further proof-of-concept of the compensation for disabled organogeneses in pig, including pancreatogenesis, nephrogenesis, hepatogenesis, and vasculogenesis. These dysorganogenetic phenotypes could be efficiently induced via genome editing of the cloned pigs. Induced dysorganogenetic traits could also be compensated by allogenic blastocyst complementation, thereby proving the extended concept of organ regeneration from exogenous pluripotent cells in empty niches during various organogeneses. These results suggest that the feasibility of blastocyst complementation using genome-edited cloned embryos permits experimentation toward the in vivo organ generation in pigs from xenogenic pluripotent cells. [Display omitted] •Dysorganogenetic phenotypes induced via genome editing of cloned pigs•Apancreatic, anephrogenic, ahepatogenic, and vasculogenesis-disabled traits induced•Compensation of disabled organogenesis by allogenic blastocyst complementation•Use of genome-edited cloned pig embryos permits in vivo organ generation studies In this article, Nagashima and colleagues generated various cloned pig fetuses with dysorganogenetic phenotypes by editing master regulatory genes for pancreatogenesis, nephrogenesis, hepatogenesis, and vasculogenesis. They also demonstrate that these disabled organogeneses can be compensated by allogenic blastocyst complementation, thereby enabling use of the genetically modified pig fetuses for in vivo organ generation studies.