Молекулярная характеристика и генетические особенности плюрипотентных клеток человека и их производных тема диссертации и автореферата по ВАК РФ 03.02.07, доктор биологических наук Лагарькова, Мария Андреевна

• Лагарькова, Мария Андреевна
• доктор биологических наук
• 2010

Оглавление диссертации доктор биологических наук Лагарькова, Мария Андреевна

СОДЕРЖАНИЕ.

БЛАГОДАРНОСТИ.

СПИСОК ИСПОЛЬЗОВАННЫХ СОКРАЩЕНИЙ.

ВВЕДЕНИЕ.

ОБЗОР ЛИТЕРАТУРЫ.

ЭКСПЕРИМЕНТАЛЬНАЯ ЧАСТЬ

МАТЕРИАЛЫ И МЕТОДЫ

РЕЗУЛЬТАТЫ И ОБСУЖДЕНИЕ

ВЫВОДЫ

Заключение диссертации по теме «Генетика», Лагарькова, Мария Андреевна

выводы.

1. Создана коллекция и проведена подробная характеристика линий ЭСК человека, в том числе получены, поддерживаются и доступны для исследований линии ЭСК в культуральной среде с полностью охарактеризованными компонентами (потенциальные «терапевтические» линии ЭСК).

2. Впервые обнаружены эпигенетические различия в разных линиях ЭСК человека Впервые показано, что экспрессия транскрипционного фактора Nanog в ходе дифференцировки ЭСК человека сопровождается изменением уровня метилирования его регуляторного района, а уровень метилирования регуляторных районов генов ОРРА-З и ОРРА-5 различается между линиями ЭСК человека и не отражается на уровне экспрессии этих генов во время дифференцировки,

3. Доказано, что длительное культивирование ЭСК человека в стандартизованных условиях и криоконсервация клеток не приводит к кариотипическим изменениям. Разработаны рекомендации по мониторингу кариотипа ЭСК человека в процессе культивирования.

4. Впервые продемонстрировано, что рецептор семейства ФНО СБЗО является новым маркером плюрипотентных стволовых клеток, а не маркером трансформированных ЭСК человека.

5. Показана высокая диффузионная связь через щелевые контакты между плюрипотентными клетками в культурах ЭСК. Впервые продемонстрировано, что на ранних этапах детерминации, сопровождающихся потерей экспрессии ОсХЗ/А, между недифференцированными и дифференцированными клетками в колонии ЭСК полностью нарушается диффузионная связь.

6. Разработан новый протокол дифференцировки ЭСК человека в функциональные клетки эндотелия. Показано влияние транскрипционного фактора НОХВ4 на дифференцировку эндотелия из ЭСК. Показана способность ЭСК к дифференцировке in vivo и in vitro, в том числе в кардиомиоциты, фибробласты, сетчатку глаза, клетки крови, нейроны и глию. С использованием протокола дифференцировки ЭСК человека по нейрональному пути обнаружено, что транскрипты anti-NOS2A и NOS2A изменяют свой профиль экспрессии при дифференцировке ЭСК в нейросферы.

7. Впервые показано, что повышение экспрессии генов транскрипционных факторов, участвующих в дифференцировке в эндотелий, GATA-2, GATA-3 и гена eNOS при дифференцировке ЭСК человека в клетки эндотелия сопровождается деметилированием регуляторных районов этих генов.

Список литературы диссертационного исследования доктор биологических наук Лагарькова, Мария Андреевна, 2010 год

1. Гилберт СФ: Биология развития. Издательство «Мир», Москва (1993).

2. Лебедев ИН, Никитина ТВ, Суханова НН, Назаренко СА: Ранняя эмбриональная гибель: реальные масштабы мозаичных форм аномалий кариотипа. Молекулярно-биологические технологии в медицинской практике. Вып. I стр. 49-57 (2001).

3. Agarwal S, Holton KL, Lanza R.Efficient differentiation of functional hepatocytes from human embryonic stem cells. Stem Cells. 2008 May;26(5):l 117-27.

4. Albrecht, E.W., Stegeman, C.A., Heeringa, P., Henning, R.H., van Goor, H„ Protective role of endothelial nitric oxide synthase. J Pathol. 2003, 199, 8-17.

5. Amit M, Shariki C, Margulets V, Itskovitz-Eldor J: Feeder layer- and serum-free culture of human embryonic stem cells. Biol Reprod 70:837-845 (2004).

6. Aoi T, Yae K, Nakagawa M, Ichisaka T, Okita K, Takahashi K, Chiba T, Yamanaka S. Generation of pluripotent stem cells from adult mouse liver and stomach cells. Science. 2008 Aug l;321(5889):699-702.

7. Arney, K.L., Bao, S., Bannister, A.J., Kouzarides, T., Surani, M.A. Histone methylation defines epigenetic asymmetry in the mouse zygote. Int J Dev Biol. 2002, 46: 317320.

8. Asahara, T., Murohara, T., Sullivan, A., Silver, M., van der Zee, R., Li, T., Witzenbichler, B., Schatteman, G., Isner, J.M. Isolation of putative progenitor endothelial cells for angiogenesis. Science. 1997, 275, 964-967.

9. Aubert, J., Dunstan, H., Chambers, I., and Smith, A. (2002). Functional gene screening in embryonic stem cells implicates Wnt antagonism in neural differentiation. Nat. Biotechnol. 20, 1240-1245.

10. Avilion, A.A., Nicolis, S.K., Pevny, L.H., Perez, L., Vivian, N., Lovell-Badge, R. Multipotent cell lineages in early mouse development depend on SOX2 function. Genes Dev. 2003, 17, 126-140.

11. Azuara V, Perry P, Sauer S, Spivakov M, Jorgensen HF, John RM, Gouti M, Casanova M,Warnes G, Merkenschlager M, Fisher AG. 2006. Chromatin signatures of pluripotent cell lines. Nat Cell Biol 8:532-538.

12. Baharvand, H., Jafary, H., Massumi, M., Ashtiani, S.K. Generation of insulin-secreting cells from human embryonic stem cells. Dev Growth Differ. 2006, 48: 323-332.

13. Bain, G., Kitchens, D., Yao, M., Huettner, J.E., and Gottlieb, D.I. (1995). Embryonic stem cells express neuronal properties in vitro. Dev. Biol. 168, 342-357.

14. Baker DE, Harrison NJ, Maltby E, Smith K, Moore HD, Shaw PJ, Heath PR, Holden H, Andrews PW: Adaptation to culture of human embryonic stem cells and oncogenesis in vivo. Nat Biotechnol 25:207-215 (2007).

15. Barski, A., Cuddapah, S., Cui, K.R., Roh, T.Y., Schones, D.E., Wang, Z.B., Wei, G., Chepelev, I., and Zhao, K.J. (2007). High-resolution profiling of histone methylations in the human genome. Cell 129, 823-837.

16. Beaujean, N., Hartshorne, G., Cavilla, J., Taylor, J., Gardner, J., Wilmut, I., Meehan, R., Young, L. Non-conservation of mammalian preimplantation methylation dynamics. Curr Biol. 2004, 14: 266-267.

17. Becskei, A., Seraphin, B. and Serrano, L. (2001). Positive feedback in eukaryotic gene networks: cell differentiation by graded to binary response conversion. EMBO J. 20, 25282535.

18. Beddington, R. S. and Robertson, E. J. (1989). An assessment of the developmental potential of embryonic stem cells in the midgestation mouse embryo. Development 105, 733-73

19. Belham C., Roig J., Caldwell J. A., Aoyama Y., Kemp B. E., Comb M. and Avruch J. 2003. A mitotic cascade of NIMA family kinases. Nerccl/Nek9 activates the Nek6 and Nek7 kinases. J. Biol. Chem. 278: 34897-34909.

20. Ben-Hur, T., Idelson, M., Khaner, H., Pera, M., Reinhartz, E., Itzik, A., and Reubinoff, B.E. (2004). Transplantation of human embryonic stem cell-derived neural progenitors improves behavioral deficit in Parkinsonian rats. Stem Cells 22, 1246-1255.

21. Bestor TH. The DNA methyltransferases of mammals. Hum Mol Genet. 2000 0ct;9(16):2395-402.

22. Bird, A. DNA methylation patterns and epigenetic memory. Genes Dev. 2002, 16: 621.

23. Blum B, Benvenisty N. Clonal analysis of human embryonic stem cell differentiation into teratomas. Stem Cells. 2007 Aug;25(8): 1924-30.

24. Blume-Jensen P. and Hunter, T. 2001. Oncogenic kinase signalling. Nature. 411: 355365.

25. Boiani & Scholer, Regulatory networks in embryo-derived pluripotent stem cells, Nature V 6, P 872, 2005

26. Bortvin, A., Eggan, K., Skaletsky, H., Akutsu, H., Berry, D.L., Yanagimachi, R., Page, D.C., Jaenisch, R. Incomplete reactivation of Oct4-related genes in mouse embryos cloned from somatic nuclei. Development. 2003, 130: 1673-1680.

27. Bouwman, P., Gollner, H., Elsasser, H.P., Eckhoff, G., Karis, A., Grosveld, F., Philipsen, S., Suske, G. Transcription factor Sp3 is essential for post-natal survival and late tooth development. EMBO J. 2000, 19: 655-661.

28. Brandenberger R, Khrebtukova I, Thies RS, Miura T, Jingli C, Puri R, Vasicek T, Lebkowski J, Rao M: Mpss profiling of human embryonic stem cells. BMC Dev Biol 4:10 (2004).

29. Brenin D, Look J, Bader M, Hubner N, Levan G, and Iannaccone P. Rat embryonic stem cells: a progress report. Transplant Proc 29: 1761-1765, 1997

30. Brustle, O., Jones, K.N., Learish, R.D., Karram, K., Choudhary, K., Wiestler, O.D., Duncan, I.D., and McKay, R.D. (1999). Embryonic stem cell-derived glial precursors: a source of myelinating transplants. Science 285, 754-756.

31. Bruzzone R., White T.W., Paul D.L. Connections with connexins: the molecular basis of direct intercellular signaling. // Europ. J. Bio-chem. 1996. V. 238. P. 1-27.

32. Burch, J.B. Regulation of GATA gene expression during vertebrate development. Semin Cell Dev Biol. 2005, 16: 71-81.

33. Burdon, T., Stracey, C., Chambers, I., Nichols, J. & Smith, A. Suppression of SHP-2 and ERK signalling promotes selfrenewal of mouse embryonic stem cells. Dev. Biol. 210, 30-43 (1999)

34. Butler A. A., Yakar S., Gewolb I. H., Karas M., Okubo Y. and Leroith D. 1998. Insulin-like growth factor-I receptor signal transduction: at the interface between physiology and cell biology. Comp. Biochem. Physiol. B. Biochem. Mol. Biol. 121: 19-26.

35. Buzzard J., Gough N., Crook J. Karyotype of human ES cells during extended culture //Nat Biotechnol. 2004 Apr;22(4):381-2;

36. Caisander G, Park H, Frej K, Lindqvist J, Bergh C, Lundin K, Hanson C: Chromosomal integrity maintained in five human embryonic stem cell lines after prolonged in vitro culture. Chromosome Res. 14(2): 131-7 (2006).

37. Carpenter MK, Rosier ES, Fisk GJ, Brandenberger R, Ares X, Miura T, Lucero M, Rao MS: Properties of four human embryonic stem cell lines maintained in a feeder-free culture system. Dev Dyn 229:243-258 (2004).

38. Carter, M. G., Sharov, A. A., VanBuren, V., Dudekula, D. B., Carmack, C. E., Nelson, C. and Ko, M. S. (2005). Transcript copy number estimation using a mouse whole-genome oligonucleotide microarray. Genome Biol. 6, R61.

39. Cartwright P, McLean C, Sheppard A, Rivett D, Jones K, Dalton S. 2005. LIF/STAT3 controls ES cell self-renewal and pluripotency by a Myc-dependent mechanism.

40. Chadwick, K., Wang, L., Li, L., Menendez, P., Murdoch, B., Rouleau, A., and Bhatia, M. (2003). Cytokines and BMP-4 promote hematopoietic differentiation of human embryonic stem cells. Blood 102, 906-915.

41. Chailakhyan L.M. Ligand-receptor and junction-mediated cell-cell interactions: comparison of the two principles // Differentiation. 1990. V. 45. № l.P. 1-6.

42. Chan, Y., Fish, J.E., D'Abreo, C. The cell-specific expression of endothelial nitric-oxide synthase: a role for DNA methylation. J Biol Chem. 2004, 279: 35087-35100.

43. Charron, F., Nemer, M. GATA transcription factors and cardiac development. Semin Cell Dev Biol. 1999, 10: 85-91.

44. Choi, K., Kennedy, M., Kazarov, A., Papadimitriou, J.C., and Keller, G. (1998). A common precursor for hematopoietic and endothelial cells. Development 125, 725-732.

45. Chung, Y.S., Zhang, W.J., Arentson, E., Kingsley, P.D., Palis, J., Choi, K. Lineage analysis of the hemangioblast as defined by FLK1 and SCL expression. Development. 2002, 129, 5511-5520.

46. Cowan CA, Klimanskaya I, McMahon J, Atienza J, Witmyer J, Zucker JP, Wang S, Morton CC, McMahon AP, Powers D, Melton DA: Derivation of embryonic stem-cell lines from human blastocysts. N Engl J Med 350:1353-1356 (2004).

47. Cowan, P.J., Tsang, D., Pedic, C.M. The human ICAM-2 promoter is endothelial cell-specific in vitro and in vivo and contains critical Spl and GATA binding sites. J Biol Chem. 1998, 273: 11737-11744.

48. Cumano, A., and Godin, I. (2007). Ontogeny of the hematopoietic system. Annu. Rev. Immunol. 25, 745-785.

49. Conley BJ, Trounson AO, Mollard R. Human embryonic stem cells form embryoid bodies containing visceral endoderm-like derivatives.Fetal Diagn Ther. 2004 May-Jun;19(3):218-23

50. D'Amour, K.A., Agulnick, A.D., Eliazer, S., Kelly, O.G., Kroon, E., and Baetge, E.E. (2005). Efficient differentiation of human embryonic stem cells to definitive endoderm. Nat. Biotechnol. 23, 1534-1541.

51. D'Achille P., Seymour J.F., Campbell L.J. Translocation (14; 18)(q32;q21) in acute lymphoblastic leukemia: a study of 12 cases and review of the literature.Cancer Genet Cytogenet. 2006 Nov;171(l):52-6.

52. Daheron, L., Opitz, S.L., Zaehres, H., Lensch, W.M., Andrews, P.W., Itskovitz-Eldor, J., Daley, G.Q. LIF/STAT3 signaling fails to maintain self-renewal of human embryonic stem cells. Stem Cells. 2004,22: 770-778.

53. De Santa, F., Totaro, M.G., Prosperini, E., Notarbartolo, S., Testa, G., and Natoli, G. (2007). The histone H3 lysine-27 demethylase Jmjd3 links inflammation to inhibition of poly comb-mediated gene silencing. Cell 130, 1083-1094.

54. Di Agostino S., Rossi P., Geremia R. and Sette C. 2002. The MAPK pathway triggers activation of Nek2 during chromosome condensation in mouse spermatocytes. Development. 129: 1715-1727.

55. Dodge, J.E., Kang, Y.K., Beppu, H., Lei, H., Li, E. Histone H3-K9 methyltransferase ESET is essential for early development. Mol Cell Biol. 2004,24: 2478-2486.

56. Doetschman T, Williams P, and Maeda N. Establishment of hamster blastocyst-derived embryonic stem (ES) cells. Dev Biol 127: 224-227, 1988

57. Dorfman, D.M., Wilson, D.B., Bruns, G.A., Orkin, S.H. Human transcription factor GATA-2. Evidence for regulation of preproendothelin-1 gene expression in endothelial cells. J Biol Chem. 1992, 267: 1279-1285.

58. Draper JS, Smith K, Gokhale P, Moore HD, Maltby E, Johnson J, Meisner L, Zwaka TP, Thomson JA, Andrews PW: Recurrent gain of chromosomes 17q and 12 in cultured human embryonic stem ceils. Nat Biotechnol 22:53-54 (2004).

59. Dravid G, Ye Z, Hammond H, et al. Defining the role of Wntfaetacatenin signaling in the survival, proliferation, and self-renewal of human embryonic stem cells. Stem Cells 2005; 23:1489-1501.

60. D'Souza, F.M., Sparks, R.L., Chen, H., Kadowitz, P.J., Jeter, J.R. Jr. Mechanism of eNOS gene transfer inhibition of vascular smooth muscle cell proliferation. Am J Physiol Cell Physiol. 2003,284: 191-199.

61. Dzierzak, E. (2005). The emergence of definitive hematopoietic stem cells in the mammal. Curr. Opin. Hematol. 12, 197-202.

62. Doetschman T, Williams P, and Maeda N. Establishment of hamster blastocyst-derived embryonic stem (ES) cells. Dev Biol 127:224-227, 1988

63. Doetschman TC, Eistetter H, Katz M, Schmidt W, Kemler R. The in vitro development of blastocyst-derived embryonic stem cell lines: formation of visceral yolk sac, blood islands and myocardium.J Embryol Exp Morphol. 1985 Jun;87:27-45.

64. Eivers E., McCarthy K., Glynn C., Nolan C.M., Byrnes L. 2004. Insulin-like growth factor (IGF) signalling is required for early dorso-anterior development of the zebrafish embryo. Int J Dev Biol. 48: 1131-40.

65. Evans MJ 1972, The isolation and properties of a clonal tissue culture strain of pluripotent mouse teratoma cells. J.Embryol. Exp. Morphol. 28:163-176

66. Evans MJ, Kaufman MH: Establishment in culture of pluripotential cells from mouse embryos. Nature 292:154-156 (1981).

67. Fan, J.B., Chee, M.S., and Gunderson, K.L. (2006). Highly parallel genomic assays. Nat. Rev. Genet. 7, 632-644.

68. Fish, J.E., Marsden, P.A. Endothelial nitric oxide synthase: insight into cell-specific gene regulation in the vascular endothelium. Cell Mol Life Sci. 2006, 63: 144-162.

69. Fish, J.E., Matouk, C.C., Rachlis, A., Lin, S., Tai, S.C., D'Abreo, C., Marsden, P.A. The expression of endothelial nitric-oxide synthase is controlled by a cell-specific histone code. J Biol Chem. 2005, 280: 24824-24838.

70. Fujikawa T, Oh SH, Pi L, Hatch HM, Shupe T, Petersen BE. Teratoma formation leads to failure of treatment for type I diabetes using embryonic stem cell-derived insulin-producing cells.Am J Pathol. 2005 Jun; 166(6): 1781-91.

71. Fuks F, Burgers WA, Godin N, Kasai M, Kouzarides T. Dnmt3a binds deacetylases and is recruited by a sequence-specific repressor to silence transcription. EMBO J. 2001 May 15;20(10):2536-44.

72. Fuks F, Hurd PJ, Deplus R, Kouzarides T. The DNA methyltransferases associate with HP1 and the SUV39H1 histone methyltransferase. Nucleic Acids Res. 2003 May 1;31(9):2305-12.

73. Gadue, P., Huber, T.L., Nostro, M.C., Kattman, S., and Keller, G.M. (2005). Germ layer induction from embryonic stem cells. Exp. Hematol. 33, 955-964.

74. Galic, Z., Kitchen, S.G., Kacena, A., Subramanian, A., Burke, B., Cortado, R., and Zack, J.A. (2006). T lineage differentiation from human embryonic stem cells. Proc. Natl. Acad. Sei. USA 103, 11742-11747.

75. Garlanda, C., Dejana, E. Heterogeneity of endothelial cells. Specific markers. Arterioscler Thromb Vase Biol. 1997, 17, 1193-1202.

76. Geiman TM, Sankpal UT, Robertson AK, Zhao Y, Zhao Y, Robertson KD. DNMT3B interacts with hSNF2H chromatin remodeling enzyme, HDACs 1 and 2, and components of the histone methylation system. Biochem Biophys Res Commun. 2004 May 28;318(2):544-55.

77. George, K.M., Leonard, M.W., Roth, M.E. Embryonic expression and cloning of the murine GATA-3 gene. Development. 1994, 120: 2673-2686.

78. Gerami-Naini, B., Dovzhenko, O. V., Durning, M., Wegner, F. H., Thomson, J. A. and Golos, T. G. (2004). Trophoblast differentiation in embryoid bodies derived from human embryonic stem cells. Endocrinology 145, 1517-1524.

79. Gerecht-Nir, S., Ziskind, A., Cohen, S., Itskovitz-Eldor, J. Human embryonic stem cells as an in vitro model for human vascular development and the induction of vascular differentiation. Lab Invest. 2003, 83: 1811-1820.

80. German, Z., Chambliss, K.L., Pace, M.C., Arnet, U.A., Lowenstein, C.J., Shaul, P.W. Molecular basis of cell-specific endothelial nitric-oxide synthase expression in airway epithelium. J Biol Chem. 2000, 275: 8183-8189.

81. Gleiberman AS, Sharovskaya YuYu, Chailakhjan LM. Contact inhibition" of alpha-fetoprotein synthesis and junctional communication in adult mouse hepatocyte culture. Exp Cell Res. 1989 Sep;184(l):228-34.

82. Grass, J.A., Boyer, M.E., Pal, S., Wu, J., Weiss, M.J., Bresnick, E.H. GATA-1-dependent transcriptional repression of GATA-2 via disruption of positive autoregulation and domain-wide chromatin remodeling. Proc Natl Acad Sei USA. 2003, 100: 8811-8816.

83. Guenther, M.G., Levine, S.S., Boyer, L.A., Jaenisch, R., and Young, R.A. (2007). A chromatin landmark and transcription initiation at most promoters in human cells. Cell 130, 7788.

84. Guerette, B., Skuk, D., Celestin, F., Huard, C., Tardif, F., Asselin, I., Roy, B.,Goulet, M., Roy, R., Entman, M., et al. (1997). Prevention by anti-LFA-1 of acute myoblast death following transplantation. J. Immunol. 159, 2522-2531.

85. Guillot, P.V., Liu, L., Kuivenhoven, J.A., Guan, J., Rosenberg, R.D., Aird, W.C. Targeting of human eNOS promoter to the Hprt locus of mice leads to tissue-restricted transgene expression. Physiol Genomics. 2000, 2: 77-83.

86. Hanna, L.A., Foreman, R.K., Tarasenko, I.A., Kessler, D.S., Labosky, P.A. Requirement for Foxd3 in maintaining pluripotent cells of the early mouse embryo. Genes Dev. 2002, 16, 2650-2661.

87. Hardie G. and Hanks S. 1995. The Protein Kinase FactsBook: Protein-Serine Kinases. Academic Press. San Diego. CA. 418.

88. Harrison NJ, Baker D, Andrews PW: Culture adaptation of embryonic stem cells echoes germ cell malignancy. Int J Androl 30:275-281; (2007).

89. Hatano, S. Y., Tada, M., Kimura, H., Yamaguchi, S., Kono, T., Nakano, T., Suemori, H., Nakatsuji, N. and Tada, T. (2005). Pluripotential competence of cells associated with Nanog activity. Mech. Dev. 122, 67-79.

90. Heard E. (2004) Recent advances in X-chromosome inactivation Current Opinion in Cell Biology 2004, 16:247-255

91. Heng, B.C., Haider, H.Kh., Sim, E.K., Cao, T., Ng, S.C. Strategies for directing the differentiation of stem cells into the cardiomyogenic lineage in vitro. Cardiovasc Res. 2004, 62:

92. Herrler A, Krusche C.A., Beier H.M. 1998. Insulin and insulin-like growth factor-1 promote rabbit blastocyst development and prevent apoptosis. Biol Reprod. 59:1302-1310.

93. Hoffman LM, Hall L, Batten JL, Young H, Pardasani D, Baetge EE, Lawrence J, Carpenter MK: X-inactivation status varies in human embryonic stem cell lines. Stem Cells 23:1468-1478 (2005).

94. Hook SS, Lin JJ, Dutta A: Mechanisms to control rereplication and implications for cancer. Curr Opin Cell Biol 19:663-671 (2007).

95. Houghton F.D. Role of gap junctions during early embryo development. Reproduction. 2005. V. 129. P. 129-135.

96. Howlett SK, Reik W. Methylation levels of maternal and paternal genomes during preimplantation development. Development. 1991 Sep;l 13(1): 119-27.

97. Huber, T.L., Kouskoff, V., Fehling, H.J., Palis, J., and Keller, G. (2004).Haemangioblast commitment is initiated in the primitive streak of the mouse embryo. Nature 432, 625-630.

98. Huettner JE, Lu A, Qu Y, Wu Y, Kim M, McDonald JW. Gap junctions and connexon hemichannels in human embryonic stem cells. Stem Cells. 2006 Jul;24(7): 1654-67

99. Ivanova, N., Dobrin, R., Lu, R., Kotenko, I., Levorse, J., DeCoste, C., Schafer, X., Lun, Y. and Lemischka, I. R. (2006). Dissecting self-renewal in stem cells with RNA interference. Nature 442, 533-538.

100. Jackson-Grusby L, Beard C, Possemato R, Tudor M, Fambrough D, Csankovszki G, Dausman J, Lee P, Wilson C, Lander E, Jaenisch R.Loss of genomic methylation causes p53-dependent apoptosis and epigenetic deregulation. Nat Genet. 2001 Jan;27(l):31-9.

101. Jaenisch, R., Bird, A. Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat Genet. 2003, 33: 245-254.

102. Jenuwein T, Allis CD Translating the histone code. Science. 2001 Aug l0;293(5532):1074-80.

103. Jeppesen P. Immunofluorescence in cytogenetic analysis: method and applications. Genet Mol Biol 2000; 23:1107-14.

104. Jiang, W., Shi, Y., Zhao, D., Chen, S., Yong, J., Zhang, J., Qing, T., Sun, X., Zhang, P., Ding, M., et al. (2007b). In vitro derivation of functional insulin-producing cells from human embryonic stem cells. Cell Res. 17, 333-344.

105. Jones J.I. and Clemmons D.R. 1995. Insulin-like growth factors and their binding proteins: biological actions. Endocr. Rev. 16: 3-34.

106. Jones, P.L., Veenstra, G.J., Wade, P.A., Vermaak, D., Kass, S.U., Landsberger, N., Strouboulis, J., Wolffe, A.P. Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription. Nat Genet. 1998, 19: 187-191.

107. Josephson R, Sykes G, Liu Y, Ording C, Xu W, Zeng X, Shin S, Loring J, Maitra A, Rao MS, Auerbach JM: A molecular scheme for improved characterization of human embryonic stem cell lines. BMC Biol 4:28 (2006).

108. Kandli M., Feige E., Chen A., Kilfin G. and Motro B. 2000. Isolation and characterization of two evolutionarily conserved murine kinases (Nek6 and nek7) related to the fungal mitotic regulator, NIMA. Genomics 68: 187-196.

109. Kantaputra PN, Limwongse C, Tochareontanaphol C, Mutirangura A, Mevatee U, Praphanphoj V: Contiguous gene syndrome of holoprosencephaly and hypotrichosis simplex: Association with an ISpl 1.3 deletion. Am J Med Genet A 140:2598-2602 (2006).

110. Katsuyama, K., Shichiri, M., Marumo, F., Hirata, Y. NO inhibits cytokine-induced iNOS expression and NF-kappaB activation by interfering with phosphorylation and degradation of IkappaB-alpha. Arterioscler Thromb Vase Biol. 1998, 18: 1796-1802.

111. Kaufman, D.S., Hanson, E.T., Lewis, R.L., Auerbach, R., and Thomson, J.A. (2001). Hematopoietic colony-forming cells derived from human embryonic stem cells. Proc. Natl. Acad. Sci. USA 98, 10716-10721.

112. Kawasaki, H., Mizuseki, K., Nishikawa, S., Kaneko, S., Kuwana, Y., Nakanishi,S., Nishikawa, S.I., and Sasai, Y. (2000). Induction of midbrain dopaminergic neurons from ES cells by stromal cell-derived inducing activity. Neuron 28,31-40.

113. Keller, G. (2005). Embryonic stem cell differentiation: emergence of a new era in biology and medicine. Genes Dev. 19, 1129-1155.

114. Kennedy, M., D'Souza, S.L., Lynch-Kattman, M., Schwantz, S., and Keller, G.(2007). Development of the hemangioblast defines the onset of hematopoiesis in human ES cell differentiation cultures. Blood 109, 2679-2687.

115. Kikyo, N„ Wade, P.A., Guschin, D., Ge, H., Wolffe, A.P. Active remodeling of somatic nuclei in egg cytoplasm by the nucleosomal ATPase ISWI. Science. 2000, 289: 23602362.

116. Kim D, Gu Y, Ishii M, Fujimiya M, Qi M, Nakamura N, Yoshikawa T, Sumi S, Inoue K. In vivo functioning and transplantable mature pancreatic islet-like cell clusters differentiated from embryonic stem cell.Pancreas. 2003 Aug;27(2):e34-41

117. Kim, D.S., Kim, J.Y., Kang, M., Cho, M.S., and Kim, D.W. (2007). Stem cellbased cell therapy for spinal cord injury. Cell Transplant. 16, 117-123.

118. Kim, T.H., and Ren, B. (2006). Genome-wide analysis of protein-DNA interactions. Annu. Rev. Genomics Hum. Genet. 7, 81-102

119. Kimura F., Florl A.R., Seifert H.H., Louhelainen J., Maas S., Knowles M.A., Schulz W.A. Destabilization of chromosome 9 in transitional cell carcinoma of the urinary bladder. Br J Cancer. 2001 Dec 14;85(12):1887-93

120. Kishimoto T. 2003. Distinct regulators for Plkl activation in starfish meiotic and early embryonic cycles. EMBO Journal. 22: 5633-5642.

121. Kleinsmith LJ, Pierce GB Jr. Multipotentiality of single embryonal carcinoma cells.Cancer Res. 1964 Oct;24:1544-51.

122. Klug, M.G., Soonpaa, M.H., and Field, L.J. (1995). DNA synthesis and multinucleation in embryonic stem cell-derived cardiomyocytes. Am. J. Physiol. 269, 19131921.

123. Kohda, T., Inoue, K., Ogonuki, N., Miki, H., Naruse, M., Kaneko-Ishino, T., Ogura, A., Ishino, F. Variation in gene expression and aberrantly regulated chromosome regions in cloned mice. Biol Reprod. 2005, 73: 1302-1311.

124. Korobko E.V., Smirnova E.V., Kiselev S.L, Georgiev G.P., Korobko I.V. 2000. Identification of a new alternative-splicing transcript of Rabaptin-5 interacting with protein kinase MAK-V. Dokl Biochem. 370: 1-3.

125. Korobko I.V., Korobko E.V., Kiselev S.L. 2000.The MAK-V protein kinase regulates endocytosis in mouse. Mol Gen Genet. 264: 411-418.

126. Kumar N.M., GilulaNJB The gap junction communication channel. Cell. 1996. V. 84. №3. P. 381-388.

127. Kyba, M., Perlingeiro, R.C., and Daley, G.Q. (2002). HoxB4 confers definitive lymphoid-myeloid engraftment potential on embryonic stem cell and yolk sac hematopoietic progenitors. Cell 109, 29-37.

128. Lacaud, G., Keller, G., Kouskoff, V. Tracking mesoderm formation and specification to the hemangioblast in vitro.Trends Cardiovasc Med. 2004, 14, 314-317.

129. Laflamme, M.A., Gold, J., Xu, C., Hassanipour, M., Rosler, E., Police, S., Muskheli, V., and Murry, C.E. (2005). Formation of human myocardium in the rat heart from human embryonic stem cells. Am. J. Pathol. 167, 663-671.

130. Lagarkova MA, Shutova MV, Bogomazova AN, Vassina EM, Glazov EA, Zhang P, Rizvanov AA, Chestkov IV, Kiselev SL Induction of pluripotency in human endothelial cells resets epigenetic profile on genome scale Cell Cycle. 2010 Mar 6;9(5).

131. Lee, M.G., Villa, R., Trojer, P., Norman, J., Yan, K.P., Reinberg, D., Di Croce, L.,and Shiekhattar, R. (2007). Demethylation of H3K27 regulates polycomb recruitment and H2A

132. Lees JG, Tuch BE. Conversion of embryonic stem cells into pancreatic beta-cell surrogates guided by ontogeny.Regen Med. 2006 May;l(3):327-36. Review.

133. Lei, H., Oh, S.P., Okano, M., Juttermann, R., Goss, K.A., Jaenisch, R., Li, E. De novo DNA cytosine methyltransferase activities in mouse embryonic stem cells. Development. 1996, 122:3195-31205.

134. Lepikhov, K., Walter, J. Differential dynamics of histone H3 methylation at positions K4 and K9 in the mouse zygote. BMC Dev Biol. 2004, 4: 12.

135. Lichter P., Cremer T., Borden J.,Manuelidis L., Ward D.C. 1988. Delineation of individual human chromosomes in metaphase and interphase cells by in situ supression hybridization using recombinant DNA libraries. Hum Genet. 80:224-234.

136. Lighten A.D., Moore G.E., Winston R.M., Hardy K. 1998. Routine addition of human insulin-like growth factor-1 ligand could benefit clinical invitro fertilization culture. Hum Reprod. 13:3144-3150.

137. Lin T.C., Yen J.M., Gong K.B., Hsu T.T., Chen L.R. 2003. IGF-1/1GFBP-1 increases blastocyst formation and total blastocyst cell number in mouse embryo culture and facilitates the establishment of a stem-cell line. BMC Cell Biol. 19:14-28.

138. Lindsley, R.C., Gill, J.G., Kyba, M., Murphy, T.L., and Murphy, K.M. (2006). Canonical Wnt signaling is required for development of embryonic stem cell derived mesoderm. Development 133, 3787-3796.

139. Liu J.P., Baker J., Perkins A.S., Robertson E.J. and Efstratiadis A. 1993. Micc carrying null mutations of the genes encoding insulin-like growth factor I (Igf-I) and type 1 IGF receptor (Igflr). Cell. 75: 59-72.

140. Lowry WE, Richter L, Yachechko R, Pyle AD, Tchieu J, Sridharan R, Clark AT, Plath K. Generation of human induced pluripotent stem cells from dermal fibroblasts. Proc Natl Acad Sci USA. 2008 Feb 26;105(8):2883-8.

141. Ludwig TE, Levenstein ME, Jones JM, Berggren WT, Mitchen ER, Frane JL, Crandall LJ, Daigh CA, Conard KR, Piekarczyk MS, Lianas RA, Thomson JA: Derivation of human embryonic stem cells in defined conditions. Nat Biotechnol 24:185-187 (2006).

142. Lugus, J.J., Chung, Y.S., Mills, J.C., Kim, S.I., Grass, J.A., Kyba, M., Doherty, J.M., Bresnick, E.H., Choi, K. GATA2 functions at multiple steps in hemangioblast development and differentiation. Development. 2007, 134: 393-405.

143. Lumelsky N, Blondel O, Laeng P, Velasco I, Ravin R, and McKay R. Differentiation of embryonic stem cells to insulin-secreting structures similar to pancreatic islets. Science 292: 1389-1394, 2001

144. Loebel DA, Watson CM, De Young RA, Tam PP. Lineage choice and differentiation in mouse embryos and embryonic stem cells.Dev Biol. 2003 Dec 1;264(1):1-14.

145. Maitra, A., Arking, D.E., Shivapurkar, N., Ikeda, M., Stastny, V., Kassauei, K., Sui, G., Cutler, D.J., Liu, Y., Brimble, S.N., et al. (2005). Genomic alterations in cultured human embryonic stem cells. Nat. Genet. 37, 1099-1103.

146. Manes, C., Menzel, P. Demethylation of CpG sites in DNA of early rabbit trophoblast. Nature. 1981, 293,: 589-590.

147. Martin G. Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Proc Natl Acad Sci USA. 1981 Dec;78(12):7634-8

148. Martin GR, Evans MJ. Differentiation of clonal lines of teratocarcinoma cells: formation of embryoid bodies in vitro.Proc Natl Acad Sci USA. 1975 Apr;72(4):1441-5.

149. Martin, M.J., Muotri, A., Gage, F., Varki, A., Human embryonic stem cells express an immunogenic nonhuman sialic acid. Nature Medicine 2005, 11: 228 232.

150. Matsuda, T., Nakamura, T., Nakao, K., Arai, T., Katsuki, M., Heike, T., and Yokota, T. (1999) EMBO J.

151. Mayer, W., Niveleau, A., Walter, J., Fundele, R., and Haaf, T. (2000). Demethylation of the zygotic paternal genome. Nature 403, 501-502

152. McDevitt, T.C., Laflamme, M.A., and Murry, C.E. (2005). Proliferation of cardiomyocytes derived from human embryonic stem cells is mediated via the IGF/PI 3-kinase/Akt signaling pathway. J. Mol. Cell. Cardiol. 39, 865-873.

153. Meshorer E, Yellajoshula D, George E, Scambler PJ, Brown DT, Misteli T. Hyperdynamic plasticity of chromatin proteins in pluripotent embryonic stem cells. Dev Cell. 2006 Jan;10(l):105-16.

154. Mesnil M Connexins and cancer. Biol. Cell. 2002. V. 94. № 7/8. P. 493-500.

155. Mikkelsen, T.S., Ku, M., Jaffe, D.B., Issac, B., Lieberman, E., Giannoukos, G., Alvarez, P., Brockman, W., Kim, T.K., Koche, R.P., et al. (2007). Genome-wide maps of chromatin state in pluripotent and lineage-committed cells. Nature 448, 553-560.

156. Mikkola M, Olsson C, Palgi J, Ustinov J, Palomaki T, Horelli-Kuitunen N, Knuutila S, Lundin K, Otonkoski T, Tuuri T: Distinct differentiation characteristics of individual human embryonic stem cell lines. BMC Dev Biol 6:40 (2006).

157. Miller S. L., DeMaria J. E., Freier D. O., Riegel A. M. and Clevenger C. V. 2005. Novel association of Vav2 and Nek3 modulates signaling through the human prolactin receptor. Mol. Endocrino. 19: 939-949.

158. Minoguchi S., Minoguchi M. and Yoshimura A. 2003. Differential control of the NIMA-related kinases, Nek6 and Nek7, by serum stimulation. Biochem. Biophys. Res. Commun. 301: 899-906.

159. Mitalipova MM, Rao RR, Hoyer DM, Johnson JA, Meisner LF, Jones KL, Dalton S, Stice SL: Preserving the genetic integrity of human embryonic stem cells. Nat Biotechnol 23:1920 (2005).

160. Mitsui K, Tokuzawa Y, Itoh H, et al. The homeoprotein Nanog is required for maintenance of pluripotency in mouse epiblast and ES cells. Cell 2003; 113:631-642.

161. Monk M, Boubelik M, Lehnert S. Temporal and regional changes in DNA methylation in the embryonic, extraembryonic and germ cell lineages during mouse embryo development. Development. 1987

162. Moreira F, Paula-Lopes F.F., Hansen P.J., Badinga L., Thatcher W.W. 2002. Effects of growth hormone and insulin-like growth factor-1 on development of in vitro derived bovine embryos. Theriogenology. 57:895-907.

163. Murry CE, Keller G. Differentiation of embryonic stem cells to clinically relevant populations: lessons from embryonic development. Cell. 2008 Feb 22;132(4):661-80.

164. Musaro, A., McCullagh, K.J., Naya, F.J., Olson, E.N., Rosenthal, N. IGF-1 induces skeletal myocyte hypertrophy through calcineurin in association with GATA-2 and NF-ATcl. Nature. 1999,400: 581-585.

165. Nagy A, Rossant J, Nagy R, Abramow-Newerly W, Roder JC. Derivation of completely cell culture-derived mice from early-passage embryonic stem cells.Proc Natl Acad SciUSA. 1993 Sep 15;90(18):8424-8.

166. Nakagawa M, Koyanagi M, Tanabe K, Takahashi K, Ichisaka T, Aoi T, Okita K, Mochiduki Y, TakizawaN, Yamanaka S.Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nat Biotechnol. 2008 Jan;26(l): 101-6.

167. Nakajima, F., Tokunaga, K., and Nakatsuji, N. (2007). Human leukocyte antigen matching estimations in a hypothetical bank of human embryonic stem cell lines in the Japanese population for use in cell transplantation therapy Stem Cells 25, 983-985

168. Nakano, T., Kodama, H., and Honjo, T. (1994). Generation of lymphohematopoietic cells from embryonic stem cells in culture. Science 265, 1098-1101.

169. Nan, X., Campoy, F.J., Bird, A. MeCP2 is a transcriptional repressor with abundant binding sites in genomic chromatin. Cell. 1997, 88: 471-481.

170. Nan, X., Ng, H.H., Johnson, C.A., Laherty, C.D., Turner, B.M., Eisenman, R.N., Bird, A. Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature. 1998, 393: 386-389.

171. Narlikar GJ, Fan HY, Kingston RE. Cooperation between complexes that regulate chromatin structure and transcription. Cell. 2002 Feb 22;108(4):475-87

172. Ng, E.S., Davis, R.P., Azzola, L., Stanley, E.G., and Elefanty, A.G. (2005b). Forced aggregation of defined numbers of human embryonic stem cells into embryoid bodies fosters robust, reproducible hematopoietic differentiation.Blood 106, 1601-1603.

173. Ng, H.H., Zhang, Y., Hendrich, B., Johnson, C.A., Turner, B.M., Erdjument-Bromage, H., Tempst, P., Reinberg, D., Bird, A. MBD2 is a transcriptional repressor belonging to the MeCPl histone deacetylase complex. Nat Genet. 1999, 23: 58-61.

174. Nichols, J., Chambers, I., Taga, T., Smith, A. Physiological rationale for responsiveness of mouse embryonic stem cells to gpl30 cytokines. Development. 2001, 128: 2333-2339.

175. Nichols, J., Zevnik, B., Anastassiadis, K., Niwa, H., Klewe-Nebenius, D., Chambers, I., Scholer, H. and Smith, A. (1998). Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4. Cell 95, 379-391.

176. Nistor, G.I., Totoiu, M.O., Haque, N., Carpenter, M.K., and Keirstead, H.S. (2005). Human embryonic stem cells differentiate into oligodendrocytes in high purity and myelinate after spinal cord transplantation. Glia 49, 385-396

177. Niwa H How is pluripotency determined and maintained? Development. 2007 Feb;134(4):635-46.

178. Okabe, S., Forsberg-Nitsson, K., Spiro, A.C., Segal, M., and McKay, R.D. (1996). Development of neuronal precursor cells and functional postmitotic neurons from embryonic stem cells in vitro. Mech. Dev. 59, 89-102.

179. Okano, M„ Bell, D.W., Haber, D.A., and Li, E. (1999). DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 99, 247-257.

180. Okano, M., Xie, S., Li, E. Dnmt2 is not required for de novo and maintenance methylation of viral DNA in embryonic stem cells. Nucleic Acids Res. 1998, 26: 2536-2540.

181. Okano-Uchida T, Okumura E, Iwashita M, Yoshida H, Tachibana K, Kishimoto T Distinct regulators for Plkl activation in starfish meiotic and early embryonic cycles. EMBO J. 2003 Oct 15;22(20):5633-42.

182. Okita K, Ichisaka T, Yamanaka S. Generation of germlinecompetent induced pluripotent stem cells. Nature 2007 6 Jun; doi:10.1038/nature05934.

183. Pain B, Clark ME, Shen M, Nakazawa H, Sakurai M, Samarut J, and Etches RJ. Long-term in vitro culture and characterisation of avian embryonic stem cells with multiple morphogenetic potentialities. Development 122: 2339-2348, 1996

184. Pan G, Thomson JA. Nanog and transcriptional networks in embryonic stem cell pluripotency. Cell Res. 2007 Jan;17(l):42-9.

185. Pan, G., Li, J., Zhou, Y., Zheng, H., Pei, D. A negative feedback loop of transcription factors that controls stem cell pluripotency and self-renewal. FASEB J. 2006, 20: 1730-1732.

186. Pan, J., McEver, R.P. Characterization of the promoter for the human P-selectin gene. J Biol Chem. 1993,268: 22600-22608.

187. Pan, X., Minegishi, N., Harigae, H. Identification of human GATA-2 gene distal IS exon and its expression in hematopoietic stem cell fractions. Journal of biochemistry 2000, 127: 105-112.

188. Pata, I., Studer, M., van Doorninck, J.H. The transcription factor GATA3 is a downstream effector of Hoxbl specification in rhombomere 4. Development. 1999, 126: 55235531.

189. Peng, Y., Jahroudi, N. The NFY transcription factor inhibits von Willebrand factor promoter activation in non-endothelial cells through recruitment of histone deacetylases. J Biol Chem. 2003, 278: 8385-8394.

190. Pera E.M., Wessely О., LI S. Y. and De Robertis E.M. 2001. Neural and head induction by insulin-like growth factor signals. Dev. Cell. 1: 655-665.

191. Pera MF, Reubinoff B, Trounson A. Human embryonic stem cells. J Cell Sci. 2000 Jan; 113 ( Pt 1):5-10.

192. Perkins, K.J., Davies, K.E. Ets, Ap-1 and GATA factor families regulate the utrophin В promoter: potential regulatory mechanisms for endothelial-specific expression. FEBS Lett. 2003, 538: 168-172.

193. Perrier, A.L., Tabar, V., Barberi, Т., Rubio, M.E., Bruses, J., Topf, N., Harrison,N.L., and Studer, L. (2004). Derivation of midbrain dopamine neurons from human embryonic stem cells. Proc. Natl. Acad. Sci. USA 101, 12543-12548.

194. Prokhortchouk A, Hendrich B, Jorgensen H, Ruzov A, Wilm M, Georgiev G, Bird A, Prokhortchouk E. The pi20 catenin partner Kaiso is a DNA methylation-dependent transcriptional repressor. Genes Dev. 2001 Jul l;15(13):1613-8.

195. Qiu, C., Olivier, E.N., Velho, M., and Bouhassira, E.E. (2008). Globin switches in yolk-sac-like primitive and fetal-like definitive red blood cells produced from human embryonic stem cells. Blood 111, 2400-2408.

196. Rafii, S., Lyden, D. Therapeutic stem and progenitor cell transplantation for organ vascularization and regeneration. Nat Med. 2003, 9, 702-712.

197. Rajagopal J, Anderson WJ, Kume S, Martinez OI, and Melton DA. Insulin staining of ES cell progeny from insulin uptake. Science 299: 363, 2003

198. Reubinoff, В. E., Itsykson, P., Turetsky, Т., Pera, M. F., Reinhartz, E., Itzik, A. and Ben-Hur, T. Neural progenitors from human embryonic stem cells. Nat. Biotechnol. 2001, 19, 1134-1140.

199. Reubinoff, B.E., Pera, M.F., Fong, C.Y., Trounson, A., and Bongso, A. (2000). Embryonic stem cell lines from human blastocysts: somatic differentiation in vitro. Nat. Biotechnol. 18, 399-404.

200. Richard-Parpaillon L., Heligon C., Chesnel F., Boujard D. and Philpott A. 2002. The IGF pathway regulates head formation by inhibiting Wnt signalling in Xenopus. Dev. Biol. 244: 407-417.

201. Richards M, Tan S, Fong CY, Biswas A, Chan WK, Bongso A: Comparative evaluation of various human feeders for prolonged undifferentiated growth of human embryonic stem cells. Stem Cells 21:546-556 (2003).

202. Richards M, Tan SP, Tan JH, Chan WK and Bongso A: The transcriptome profile of human embryonic stem cells as defined by SAGE Stem Cells 22:51-64 (2004).

203. Rideout WM 3rd, Hochedlinger K, Kyba M, Daley GQ, Jaenisch R. Cell. 2002 Apr 5; 109( 1): 17-27.Correction of a genetic defect by nuclear transplantation and combined cell and gene therapy.

204. Rodda, D. J., Chew, J. L., Lim, L. H., Loh, Y. H., Wang, B., Ng, H. H. and Robson, P. (2005). Transcriptional regulation of nanog by OCT4 and SOX2. J. Biol. Chem. 280, 2473124737.

205. Rosier ES, Fisk GJ, Ares X, Irving J, Miura T, Rao MS and Carpenter MK: Long-term culture of human embryonic stem cells in feeder-free conditions Dev Dyn 229:259-274 (2005)

206. Rowland, B.D., Bernards, R., and Peeper, D.S. (2005). The KLF4 tumour suppressor is a transcriptional repressor of p53 that acts as a context-dependent oncogene. Nat. Cell Biol. 7, 1074-1082.

207. Royston, B.D., Royston, D., Pearson, J.D. Aprotinin inhibits platelet adhesion to endothelial cells. Blood Coagul Fibrinolysis. 1992, 3: 737-742.

208. Ruthenburg, A.J., Allis, C.D., and Wysocka, J. (2007). Methylation of lysine 4 on histone H3: intricacy of writing and reading a single epigenetie mark. Mol. Cell 25, 15-30.

209. Ruzov AS, Mertsalov IB, Meehan R, Kiselev SL, Buchman VL, Korobko IV. 2004. Cloning and developmental expression of MARK/Par-l/MELK-related protein kinase xMAK-V in Xenopus laevis. Dev Genes Evol. 214(3): 139-43.

210. Robertson E, Bradley A, Kuehn M, Evans M. Germ-line transmission of genes introduced into cultured pluripotential cells by retroviral vector .Nature. 1986 Oct 2-8;323(6087):445-8.

211. Saez JC, Berthoud VM, Branes MC, Martinez AD, Beyer EC Plasma membrane channels formed by connexins: their regulation and functions. Physiol Rev. 2003 Oct;83(4): 1359-400

212. Sambrook, J., Fritsch E. F. and Maniatis T. 1989.: Molecular Cloning: A Laboratory Manual, 2nd. ed. New York. Cold Spring Harbor Laboratory Press. 1.21-1.53.

213. Samokhvalov IM, Samokhvalova N1, Nishikawa S. Cell tracing shows the contribution of the yolk sac to adult haematopoiesis. Nature. 2007 Apr 26;446(7139):1056-61.

214. Santos, F., Hendrich, B., Reik, W., Dean, W. Dynamic reprogramming of DNA methylation in the early mouse embryo.Dev Biol. 2002, 241: 172-182.

215. Santos, F., Peters, A.H., Otte, A.P., Reik, W., Dean, W. Dynamic chromatin modifications characterise the first cell cycle in mouse embryos. Dev Biol. 2005, 280: 225-236.

216. Santos, F., Zakhartchenko, V., Stojkovic, M., Peters, A., Jenuwein, T., Wolf, E., Reik, W., Dean, W. Epigenetic marking correlates with developmental potential in cloned bovine preimplantation embryos. Curr Biol. 2003, 13: 1116-1121.

217. Sarraf, S.A., Stancheva, I. Methyl-CpG binding protein MBD1 couples histone H3 methylation at lysine 9 by SETDB1 to DNA replication and chromatin assembly. Mol Cell. 2004, 15:595-605.

218. Schoonjans L, Albright GM, Li JL, Collen D, and Moreadith RW. Pluripotential rabbit embryonic stem (ES) cells are capable of forming overt coat color chimeras following injection into blastocysts. MolReprodDev 45: 439-443, 1996.

219. Schuldiner M, Yanuka O, Itskovitz-Eldor J, Melton DA, and Benvenisty N. From the cover: effects of eight growth factors on the differentiation of cells derived from human embryonic stem cells. Proc Natl Acad Sci USA 97: 11307-11312, 2000

220. Schoonjans L, Albright GM, Li JL, Collen D, and Moreadith RW. Pluripotential rabbit embryonic stem (ES) cells are capable of forming overt coat color chimeras following injection into blastocysts. Mol Reprod Dev 45: 439-443, 1996.

221. Seifinejad A, Tabebordbar M, Baharvand H, Boyer LA, Hosseini Salekdeh G.Progress and Promise Towards Safe Induced Pluripotent Stem Cells for Therapy. Stem Cell Rev. 2010 Feb 24.

222. Shen, Y., Chow, J., Wang, Z., and Fan, G. (2006). Abnormal CpG island methylation occurs during in vitro differentiation of human embryonic stem cells.Hum. Mol. Genet. 15,2623-2635.

223. Shim, J.H., Kim, S.E., Woo, D.H., Kim, S.K., Oh, C.H., McKay, R., and Kim, J.H. (2007). Directed differentiation of human embryonic stem cells towards a pancreatic cell fate. Diabetologia 50, 1228-1238.

224. Shimizu, R., Yamamoto, M. Gene expression regulation and domain function of hematopoietic GATA factors. Semin Cell Dev Biol. 2005, 16: 129-136.

225. Shimozaki K, Namihira M, Nakashima K, Taga T. Stage- and site-specific DNA demethylation during neural cell development from embryonic stem cells. J Neurochem. 2005 Apr;93(2):432-9.

226. Siegfried, Z., Eden, S., Mendelsohn, M., Feng, X., Tsuberi, B.Z., Cedar, H. DNA methylation represses transcription in vivo. Nat Genet. 1999, 22: 203-206.

227. Singal, R., vanWert, J.M., Ferdinand, L. Jr. Methylation of alpha-type embryonic globin gene alpha pi represses transcription in primary erythroid cells. Blood. 2002, 100: 42174222.

228. Sohl G., Willecke K. An update on connexin genes and their nomenclature in mouse and man. Cell Commun. Adhes. 2003. V. 10. P. 173-180.

229. Solt.er D, Skreb N, Damjanov I. Extrauterine growth of mouse egg-cylinders results in malignant teratoma. Nature. 1970 Aug l;227(5257):503-4.

230. Spence, J.R., and Wells, J.M. (2007). Translational embryology: Using embryonic principles to generate pancreatic endocrine cells from embryonic stem cells. Dev. Dyn. 236, 3218-3227.

231. Stadtfeld M, Brennand K, Hochedlinger K Reprogramming of pancreatic beta cells into induced pluripotent stem cells.Curr Biol. 2008 Jun 24;18(12):890-4

232. Stadtfeld M, Nagaya M, Utikal J, Weir G, Hochedlinger K.Induced pluripotent stem cells generated without viral integration. Science. 2008 Nov 7;322(5903):945-949.

233. Stalker H.J., Ayme S., Delneste D., Scarpelli H., Vekemans M., Der Kaloustian V.M. Duplication of 9ql2-q33: a case report and implications for the dup(9q) syndrome. Am J Med Genet. 1993 Feb 15;45(4):456-9.

234. Stevens LC, Hummel KP. A description of spontaneous congenital testicular teratomas in strain 129 mice.J Natl Cancer Inst. 1957 May; 18(5):719-47.

235. Sukoyan MA, Vatolin SY, Golubitsa AN, Zhelezova AI, Semenova LA, Serov OL. Embryonic stem cells derived from morulae, inner cell mass, and blastocysts of mink: comparisons of their pluripotencies. Mol Reprod Dev. 1993 Oct;36(2): 148-58.

236. Sutton J, Costa R, Klug M, et al. Genesis, a winged helix transcriptional repressor with expression restricted to embryonic stem cells. J Biol Chem 1996;271:23126-23123.

237. Swigut,T.,andWysocka,J. (2007).H3K27demethylases,at long last.Cell 131,29-32.

238. Soria B, Roche E, Berna G, Leon-Quinto T, Reig JA, and Martin F. Insulin-secreting cells derived from embryonic stem cells normalize glycemia in streptozotocin-induced diabetic mice. Diabetes 49: 157-162, 2000.

239. Takahashi, K., and Yamanaka, S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663-676.

240. Tamiolakis D, Papadopoulos N, Lambropoulou M, Venizelos J, Verettas D, Tsikouras P, Koutsougeras G, Papadopoulos H, Karpouzis A, Kouskoukis C. Ber-H2 (CD30) immunohistochemical staining of human fetal tissues. Int J Biol Sci. 2005b; 1(4): 135-40.

241. Tanaka K. and Nigg E. A. 1999. Cloning and characterization of the murine Nek3 protein kinase, a novel member of the NIMA family of putative cell cycle regulators. J. Biol. Chem. 274: 13491-13497.

242. Taylor, C.J., Bolton, E.M., Pocock, S., Sharpies, L.D., Pedersen, R.A., and Bradley, J.A. (2005). Lancet 366, 2019-2025)

243. Thomson JA, Itskovitzeldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshall VS, Jones JM: Embryonic stem cell lines derived from human blastocysts Science 282:1145-1147 (1998).

244. Thomson JA, Kalishman J, Golos TG, Durning M, Harris CP, Becker RA, and Hearn JP. Isolation of a primate embryonic stem cell line. Proc Natl Acad Sci USA 92: 78447848, 1995

245. Tsai, F.Y., Orkin, S.H. Transcription factor GATA-2 is required for proliferation/survival of early hematopoietic cells and mast cell formation, but not for erythroid and myeloid terminal differentiation. Blood. 1997, 89: 3636-3643.

246. Turksen K, Troy TC. Human embryonic stem cells: isolation, maintenance, and differentiation. Methods Mol Biol. 2006;331:1-12.

247. Valiunas V, Polosina YY, Miller H, Potapova IA, Valiuniene L, Doronin S, Mathias RT, Robinson RB, Rosen MR, Cohen IS, Brink PR Connexin-specific cell-to-cell transfer of short interfering RNA by gap junctions. J Physiol. 2005 Oct 15;568(Pt 2):459-68

248. Villar, I.C., Francis, S., Webb, A., Hobbs, A.J., Ahluwalia, A. Novel aspects of endothelium-dependent regulation of vascular tone. Kidney Int. 2006, 70: 840-853.

249. Vodyanik, M.A., Bork, J.A., Thomson, J.A., and Slukvin, I.I. (2005). Human embryonic stem cell-derived CD34+ cells: efficient production in the coculture with OP9 stromal cells and analysis of lymphohematopoietic potential. Blood 105, 617-626.

250. Waddington, C.H. (1942). The epigenotype. Endeavour 1, 18-20.

251. Wade, P.A., Gegonne, A., Jones, P.L., Ballestar, E„ Aubry, F., Wolffe, A.P. Mi-2 complex, couples DNA methylation to chromatin remodelling and histone deacetylation. Nat Genet. 1999, 23: 62-66.

252. Wang Y., Wang F., Sun T., Barisic D,. Trostinskaia A., Wygle D., Puscheck E and Rappolee D.A. 2004. Entire mutagen activated protein kinase (MAPK) pathway is present in preimplantation mouse embryos. Developmental Dynamics. 231: 72-87.

253. Wang, H., Cao, R., Xia, L., Erdjument-Bromage, H., Borchers, C., Tempst, P., Zhang, Y. Purification and functional characterization of a histone H3-lysine 4-specific methyltransferase. Mol Cell. 2001, 8: 1207-1217.

254. Wang, Y., Medvid, R., Melton, C., Jaenisch, R„ and Blelloch, R. (2007). DGCR8 is essential for microRNA biogenesis and silencing of embryonic stem cell selfrenewal.Nat. Genet. 39, 380-385.

255. Wang, Y., Yates, F., Naveiras, O., Ernst, P., and Daley, G.Q. (2005b). Embryonic stem cell-derived hematopoietic stem cells. Proc. Natl. Acad. Sci. USA 102, 19081-19086.

256. Warner A. Gap junctions in development—a perspective. Semin. Cell Biol. 1992. V. 3. № 1. P. 81-91.

257. Watanabe, D., Suetake, I., Tada, T., Tajima, S. Stage- and cell-specific expression of Dnmt3a and Dnmt3b during embryogenesis. Mech Dev. 2002, 118: 187-190.

258. Weaver BA, Cleveland DW: Aneuploidy: Instigator arid inhibitor of tumorigenesis. Cancer Res 67:10103-10105 (2007).

259. Weiss, M.J., Orkin, S.H. GATA transcription factors: key regulators of hematopoiesis. Exp Hematol. 1995, 23: 99-107.

260. Wernig, M., Meissner, A., Foreman, R., Brambrink, T., Ku, M., Hochedlinger,K., Bernstein, B.E., and Jaenisch, R. (2007). In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state. Nature 448, 318-324.

261. Wilks A.F. 1989. Two putative protein-tyrosine kinases identified by application of the polymerase chain reaction. Proc Natl Acad Sci USA. 86: 1603-1607.

262. Woll, P.S., Morris, J.K., Painschab, M.S., Marcus, R.K., Kohn, A.D., Biechele, T.L., Moon, R.T., and Kaufman, D.S. (2007). Wnt signaling promotes hematoendothelial cell development from human embryonic stem cells. Blood 111, 122-131.

263. Worsdorfer P., Maxeiner S., Markopoulos C. et al. // Stem. Cells. 2008. V. 26. № 2. P. 431-429.

264. Wu, Q., Chen, X., Zhang, J., Loh, Y. H„ Low, T. Y., Zhang, W., Sze, S. K., Lim, B. and Ng, H. H. (2006). Sall4 interacts with Nanog and co-occupies Nanog genomic sites in embryonic stem cells. J. Biol. Chem. 281, 24090-24094.

265. Xu, C., Police, S., Rao, N., and Carpenter, M.K. (2002). Characterization and enrichment of cardiomyocytes derived from human embryonic stem cells.Circ. Res. 91, 501— 508.

266. Xu, D., Wilson, T.J., Chan, D., De Luca, E., Zhou, J., Hertzog, P.J., Kola, I. Etsl is required for p53 transcriptional activity in UV-induced apoptosis in embryonic stem cells. EMBO J. 2002, 21: 4081-4093.

267. Xu, R.H., Peck, R.M., Li, D.S., Feng, X., Ludwig, T., and Thomson, J.A. (2005). Basic FGF and suppression of BMP signaling sustain undifferentiated proliferation of human ES cells. Nat. Methods 2,185-190.

268. Yamaguchi, T.P. (2001). Heads or tails: Wnts and anterior-posterior patterning. Curr. Biol. 11,713-724.

269. Yan, Y., Yang, D., Zarnowska, E.D., Du, Z., Werbel, B„ Valliere, C., Pearce, R.A., Thomson, J.A., and Zhang, S.C. (2005). Directed differentiation of dopaminergic neuronal subtypes from human embryonic stem cells. Stem Cells 23, 781-790.

270. Ying, Q. L., Nichols, J., Chambers, I. & Smith, A. BMP induction of Id proteins suppresses differentiation and sustains embryonic stem cell self-renewal in collaboration with STAT3. Cell 115, 281-292 (2003).

271. Ying, Q.L., Stavridis, M., Griffiths, D., Li, M„ and Smith, A. (2003). Conversion of embiyonic stem cells into neuroectodermal precursors in adherent monoculture. Nat. Biotechnol. 21, 183-186.

272. Yuan, H., Corbi, N., Basilico, C. and Dailey, L. (1995). Developmental-specific activity of the FGF-4 enhancer requires the synergistic action of Sox2 and Oct-3. Genes Dev. 9, 2635-2645.

273. Zeng X, Cai J, Chen J, Luo Y, You ZB, Fotter E, Wang Y, Harvey B, Miura T, Backman C, Chen GJ, Rao MS, Freed WJ: Dopaminergic differentiation of human embryonic stem cells. Stem Cells 22:925-940 (2004).

274. Zhang, P., Li, J., Tan, Z., Wang, C., Liu, T., Chen, L., Yong, J., Jiang, W., Sun, X., Du, L., et al. (2008). Short-term BMP-4 treatment initiates mesoderm induction in human embryonic stem cells. Blood 111, 1933-1941.

275. Zhang, R., Min, W., Sessa, W.C. Functional analysis of the human endothelial nitric oxide synthase promoter. Spl and GATA factors are necessary for basal transcription in endothelial cells. J Biol Chem. 1995, 270: 15320-15326.

276. Zhang, S.C., Wernig, M., Duncan, I.D., Brustle, O., and Thomson, J.A. (2001). In vitro differentiation of transplantable neural precursors from human embryonic stem cells. Nat. Biotechnol. 19, 1129-1133.

277. Zhao, C., Meng, A. Spl-like transcription factors are regulators of embryonic development in vertebrates. Dev Growth Differ. 2005, 47: 201-211.

278. Zhou, Y., Lim, K.C., Onodera, K. Rescue of the embryonic lethal hematopoietic defect reveals a critical role for GATA-2 in urogenital development. EMBO J. 1998, 17: 66896700.

279. Zhou, Y., Yamamoto, M., Engel, J.D. GATA2 is required for the generation of V2 interneurons. Development. 2000, 127: 3829-3838

280. Zindy, F., Eischen, C.M., Randle, D.H., Kamijo, T., Cleveland, J.L., Sherr, C.J., and Roussel, M.F. (1998). Myc signaling via the ARF tumor suppressor regulates p53-dependent apoptosis and immortalization. Genes Dev. 12, 2424-2433.

281. Zvetkova, I., Apedaile, A., Ramsahoye, B., Mermoud, J.E., Crompton, L.A., John, R., Feil, R., Brockdorff, N. Global hypomethylation of the genome in XX embryonic stem cells. Nat Genet. 2005, 37: 1274-1279.