UCSD BGGN 231 - Histocompatible Embryonic Stem Cells (6 pages)

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Histocompatible Embryonic Stem Cells



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Histocompatible Embryonic Stem Cells by Parthenogenesis Kitai Kim et al Science 315 482 2007 DOI 10 1126 science 1133542 The following resources related to this article are available online at www sciencemag org this information is current as of September 27 2007 Supporting Online Material can be found at http www sciencemag org cgi content full 1133542 DC1 This article cites 21 articles 10 of which can be accessed for free http www sciencemag org cgi content full 315 5811 482 otherarticles This article has been cited by 2 article s on the ISI Web of Science This article appears in the following subject collections Development http www sciencemag org cgi collection development Information about obtaining reprints of this article or about obtaining permission to reproduce this article in whole or in part can be found at http www sciencemag org about permissions dtl Science print ISSN 0036 8075 online ISSN 1095 9203 is published weekly except the last week in December by the American Association for the Advancement of Science 1200 New York Avenue NW Washington DC 20005 Copyright 2007 by the American Association for the Advancement of Science all rights reserved The title Science is a registered trademark of AAAS Downloaded from www sciencemag org on September 27 2007 Updated information and services including high resolution figures can be found in the online version of this article at http www sciencemag org cgi content full 315 5811 482 phenomenon called hybrid resistance that is particularly relevant to bone marrow transplantation 10 As compared with mismatched organs partial MHC antigen matching enhances allograft survival but full MHC matched tissues are the most favorable for transplant 11 The only certain strategy for avoiding immunologic complications is to transplant genetically identical tissues but this limits transplantation to autologous tissues transplants between monozygotic twins or cells created by somatic cell nuclear transfer Here we characterize pluripotent ES cell lines generated by parthenogenesis in which both of the maternal MHC loci have been maintained Differentiated tissues from such MHC matched ES cells can be transplanted into the oocyte donor strain without rejection suggesting that these cells could be a favorable source of histocompatible tissues for transplantation Recombinant MHC matched p MII ES cells We reasoned that during the isolation of p MII ES cells from hybrid F1 mice recombination events occurring between paired homologous chromosomes in meiosis I would produce cells that had restored heterozygosity at the MHC loci Fig 1B Recombination frequencies place the murine H 2 MHC locus at 18 5 centimorgans cM from the centromere on mouse chromosome 17 12 thus predicting that approximately one Histocompatible Embryonic Stem Cells by Parthenogenesis Kitai Kim 1 2 4 Paul Lerou 1 4 5 Akiko Yabuuchi 1 2 4 Claudia Lengerke 1 2 4 Kitwa Ng 1 2 4 Jason West 1 2 4 Andrew Kirby 6 Mark J Daly 6 George Q Daley1 2 3 4 Genetically matched pluripotent embryonic stem ES cells generated via nuclear transfer or parthenogenesis pES cells are a potential source of histocompatible cells and tissues for transplantation After parthenogenetic activation of murine oocytes and interruption of meiosis I or II we isolated and genotyped pES cells and characterized those that carried the full complement of major histocompatibility complex MHC antigens of the oocyte donor Differentiated tissues from these pES cells engrafted in immunocompetent MHC matched mouse recipients demonstrating that selected pES cells can serve as a source of histocompatible tissues for transplantation arthenogenesis entails the development of an embryo directly from an oocyte without fertilization Many animal and plant species reproduce via parthenogenesis but in mice parthenogenetic embryos develop only to the early limb bud stage because mammalian embryonic development requires gene expression from the paternal genome Parthenogenetic embryonic stem pES cells have been isolated from parthenogenetic blastocysts of mice and primates 1 2 Both mouse and primate pES cells undergo extensive differentiation in vitro 2 3 and pES cells contribute widely to adult tissues in chimeric mice 1 A human case of parthenogenetic chimerism has been described in which the hematopoietic system and skin were derived from parthenogenetic cells 4 In addition to pluripotent stem cells from fertilized embryos and embryos created by somatic cell nuclear transfer 5 parthenogenesis is another method for creating pluripotent stem cells that might serve as a source of tissue for transplantation Highly efficient methods of experimental murine parthenogenesis exist in which oocytes arrested at the second meiotic metaphase MII are chemically activated in the presence of cytochalasin a drug that prevents extrusion of the second polar body 6 Diploidy is maintained and the resulting pseudozygote can develop into a blastocyst from which ES cells can be isolated which we term p MII ES cells 7 In some cases pES cells harbor a duplication of a haploid genome and are thus believed to be P 1 Division of Pediatric Hematology Oncology Children s Hospital Boston and Dana Farber Cancer Institute Boston MA 02115 USA 2Department of Biological Chemistry and Molecular Pharmacology Harvard Medical School Boston MA 02115 USA 3Division of Hematology Brigham and Women s Hospital Boston MA 02115 USA 4Harvard Stem Cell Institute Cambridge MA 02138 USA 5Division of Newborn Medicine Brigham and Women s Hospital and Children s Hospital Harvard Medical School Boston MA 02115 USA 6Center for Human Genetic Research Massachusetts General Hospital Boston MA 02115 USA To whom correspondence should be addressed E mail george daley childrens harvard edu 482 predominantly homozygous 7 8 Because tissues derived from homozygous pES cells would express only one of two sets of parental histocompatibility antigens they can be more readily matched to patients and might pose less risk of tissue rejection 9 However in heterozygous recipients major histocompatibility complex MHC homozygous tissues may be rejected by natural killer NK cells that recognize the lack of one set of histocompatibility antigens a A hCG 0h 6h 12h fES 18h 1st PB 2nd PB 4n GV B hCG 0h 2n MI 1n MII 6h Recombination 12h p MII ES 18h CCB x No 2nd PB 4n GV C 2n MHC matched hCG 0h 2n MI 2n MII 2n MHC matched 6h Recombination 12h CCD 4n MI different centromere MHC p MI ES 2n MII 2n No 1st PB x 4n GV 18h


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