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Abstract
To combat organ shortage in transplantation medicine, a novel strategy has been proposed to generate human organs from exogenous pluripotent stem cells utilizing the developmental mechanisms of pig embryos/foetuses. Genetically modified pigs missing specific organs are key elements in this strategy. In this study, we demonstrate the feasibility of using a genome-editing approach to generate anephrogenic foetuses in a genetically engineered pig model. SALL1 knockout (KO) was successfully induced by injecting genome-editing molecules into the cytoplasm of pig zygotes, which generated the anephrogenic phenotype. Extinguished SALL1 expression and marked dysgenesis of nephron structures were observed in the rudimentary kidney tissue of SALL1-KO foetuses. Biallelic KO mutations of the target gene induced nephrogenic defects; however, biallelic mutations involving small in-frame deletions did not induce the anephrogenic phenotype. Through production of F1 progeny from mutant founder pigs, we identified mutations that could reliably induce the anephrogenic phenotype and hence established a line of fertile SALL1-mutant pigs. Our study lays important technical groundwork for the realization of human kidney regeneration through the use of an empty developmental niche in pig foetuses.
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Details
1 Meiji University International Institute for Bio-Resource Research, Kawasaki, Japan (GRID:grid.411764.1) (ISNI:0000 0001 2106 7990)
2 Meiji University, Laboratory of Developmental Engineering, Kawasaki, Japan (GRID:grid.411764.1) (ISNI:0000 0001 2106 7990)
3 Graduate School of Science, Hiroshima University, Department of Mathematical and Life Sciences, Hiroshima, Japan (GRID:grid.257022.0) (ISNI:0000 0000 8711 3200)
4 Biosignal Genome Resource Center, Institute for Molecular and Cellular Regulation, Gunma University, Laboratory of Genome Science, Gunma, Japan (GRID:grid.256642.1) (ISNI:0000 0000 9269 4097)
5 Institute of Molecular Embryology and Genetics, Kumamoto University, Department of Kidney Development, Kumamoto, Japan (GRID:grid.274841.c) (ISNI:0000 0001 0660 6749)
6 The Institute of Medical Science, The University of Tokyo, Division of Stem Cell Therapy, Tokyo, Japan (GRID:grid.26999.3d) (ISNI:0000 0001 2151 536X); Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Department of Genetics, Stanford, USA (GRID:grid.168010.e) (ISNI:0000000419368956)
7 Meiji University International Institute for Bio-Resource Research, Kawasaki, Japan (GRID:grid.411764.1) (ISNI:0000 0001 2106 7990); Meiji University, Laboratory of Developmental Engineering, Kawasaki, Japan (GRID:grid.411764.1) (ISNI:0000 0001 2106 7990)