title: Engraftment of human iPS cells and allogeneic porcine cells into pigs with inactivated RAG2 and accompanying severe combined immunodeficiency.
abstract: Pigs with severe combined immunodeficiency (SCID) may provide useful models for regenerative medicine, xenotransplantation, and tumor development and will aid in developing therapies for human SCID patients. Using a reporter-guided transcription activator-like effector nuclease (TALEN) system, we generated targeted modifications of recombination activating gene (RAG) 2 in somatic cells at high efficiency, including some that affected both alleles. Somatic-cell nuclear transfer performed with the mutated cells produced pigs with RAG2 mutations without integrated exogenous DNA. Biallelically modified pigs either lacked a thymus or had one that was underdeveloped. Their splenic white pulp lacked B and T cells. Under a conventional housing environment, the biallelic RAG2 mutants manifested a "failure to thrive" phenotype, with signs of inflammation and apoptosis in the spleen compared with age-matched wild-type animals by the time they were 4 wk of age. Pigs raised in a clean environment were healthier and, following injection of human induced pluripotent stem cells (iPSCs), quickly developed mature teratomas representing all three germ layers. The pigs also tolerated grafts of allogeneic porcine trophoblast stem cells. These SCID pigs should have a variety of uses in transplantation biology.
authors.affiliation: Division of Animal Science.
authors.forename: Kiho
authors.initials: K
authors.lastname: Lee
authors.affiliation: Department of Animal Biotechnology, Konkuk University, Seoul 143-701, Korea;
authors.forename: Deug-Nam
authors.initials: DN
authors.lastname: Kwon
authors.affiliation: Division of Animal Science,Bond Life Sciences Center, Departments of.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Ezashi
authors.affiliation: Department of Animal Biotechnology, Konkuk University, Seoul 143-701, Korea;
authors.forename: Yun-Jung
authors.initials: YJ
authors.lastname: Choi
authors.affiliation: Department of Animal Biotechnology, Konkuk University, Seoul 143-701, Korea;
authors.forename: Chankyu
authors.initials: C
authors.lastname: Park
authors.affiliation: Veterinary Pathobiology and.
authors.forename: Aaron C
authors.initials: AC
authors.lastname: Ericsson
authors.affiliation: Division of Animal Science.
authors.forename: Alana N
authors.initials: AN
authors.lastname: Brown
authors.affiliation: Division of Animal Science,National Swine Resource and Research Center, University of Missouri, Columbia, MO 65211;
authors.forename: Melissa S
authors.initials: MS
authors.lastname: Samuel
authors.affiliation: Division of Animal Science,Department of Animal Science and Technology, Sunchon National University, Suncheon, Jeonnam 540-742, Korea.
authors.forename: Kwang-Wook
authors.initials: KW
authors.lastname: Park
authors.affiliation: Division of Animal Science,National Swine Resource and Research Center, University of Missouri, Columbia, MO 65211;
authors.forename: Eric M
authors.initials: EM
authors.lastname: Walters
authors.affiliation: Veterinary Pathobiology and.
authors.forename: Dae Young
authors.initials: DY
authors.lastname: Kim
authors.affiliation: Department of Biomedical Science, College of Life Science, CHA University, Seongnam-si, Gyeonggi-Do 463-836, Korea; and.
authors.forename: Jae-Hwan
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Veterinary Pathobiology and.
authors.forename: Craig L
authors.initials: CL
authors.lastname: Franklin
authors.affiliation: Division of Animal Science.
authors.forename: Clifton N
authors.initials: CN
authors.lastname: Murphy
authors.affiliation: Division of Animal Science,Bond Life Sciences Center, Departments ofVeterinary Pathobiology andBiochemistry, and robertsrm@missouri.edu PratherR@Missouri.edu jhkim541@konkuk.ac.kr.
authors.forename: R Michael
authors.initials: RM
authors.lastname: Roberts
authors.affiliation: Division of Animal Science,National Swine Resource and Research Center, University of Missouri, Columbia, MO 65211; robertsrm@missouri.edu PratherR@Missouri.edu jhkim541@konkuk.ac.kr.
authors.forename: Randall S
authors.initials: RS
authors.lastname: Prather
authors.affiliation: Department of Animal Biotechnology, Konkuk University, Seoul 143-701, Korea; robertsrm@missouri.edu PratherR@Missouri.edu jhkim541@konkuk.ac.kr.
authors.forename: Jin-Hoi
authors.initials: JH
authors.lastname: Kim
mesh_terms: D000483:Alleles; D000818:Animals; D001483:Base Sequence; D004268:DNA-Binding Proteins / Q000235:genetics*; D005347:Fibroblasts / Q000378:metabolism; D005838:Genotype; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000637:transplantation*; D008969:Molecular Sequence Data; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D010641:Phenotype; D012038:Regeneration; D016511:Severe Combined Immunodeficiency / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D013552:Swine; D013556:Swine, Miniature; D013950:Thymus Gland / Q000378:metabolism; D014183:Transplantation, Heterologous; D014470:Umbilical Cord / Q000166:cytology
chemical_list: D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C499311:RAG2 protein, human