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Proc Natl Acad Sci U S A. 2014 May 20;111(20):7260-5. doi: 10.1073/pnas.1406376111. Epub 2014 May 5.

Engraftment of human iPS cells and allogeneic porcine cells into pigs with inactivated RAG2 and accompanying severe combined immunodeficiency.

Author information

  • 1Division of Animal Science.
  • 2Department of Animal Biotechnology, Konkuk University, Seoul 143-701, Korea;
  • 3Division of Animal Science,Bond Life Sciences Center, Departments of.
  • 4Veterinary Pathobiology and.
  • 5Division of Animal Science,National Swine Resource and Research Center, University of Missouri, Columbia, MO 65211;
  • 6Division of Animal Science,Department of Animal Science and Technology, Sunchon National University, Suncheon, Jeonnam 540-742, Korea.
  • 7Department of Biomedical Science, College of Life Science, CHA University, Seongnam-si, Gyeonggi-Do 463-836, Korea; and.
  • 8Division of Animal Science,Bond Life Sciences Center, Departments ofVeterinary Pathobiology andBiochemistry, and robertsrm@missouri.edu PratherR@Missouri.edu jhkim541@konkuk.ac.kr.
  • 9Division 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.
  • 10Department of Animal Biotechnology, Konkuk University, Seoul 143-701, Korea; robertsrm@missouri.edu PratherR@Missouri.edu jhkim541@konkuk.ac.kr.

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.

PMID:
24799706
[PubMed - indexed for MEDLINE]
PMCID:
PMC4034252
Free PMC Article
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