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Natural killer cell-triggered vascular transformation: maternal care before birth?

Cellular & Molecular Immunology volume 8, pages 1–11 (2011)Cite this article

Abstract

Natural killer (NK) cells are found in lymphoid and non-lymphoid organs. In addition to important roles in immune surveillance, some NK cells contribute to angiogenesis and circulatory regulation. The uterus of early pregnancy is a non-lymphoid organ enriched in NK cells that are specifically recruited to placental attachment sites. In species with invasive hemochorial placentation, these uterine natural killer (uNK) cells, via secretion of cytokines, chemokines, mucins, enzymes and angiogenic growth factors, contribute to the physiological change of mesometrial endometrium into the unique stromal environment called decidua basalis. In humans, uNK cells have the phenotype CD56brightCD16dim and they appear in great abundance in the late secretory phase of the menstrual cycle and early pregnancy. Gene expression studies indicate that CD56brightCD16dim uterine and circulating cells are functionally distinct. In humans but not mice or other species with post-implantation decidualization, uNK cells may contribute to blastocyst implantation and are of interest as therapeutic targets in female infertility. Histological and genetic studies in mice first identified triggering of the process of gestation spiral arterial modification as a major uNK cell function, achieved via interferon (IFN)-γ secretion. During spiral arterial modification, branches from the uterine artery that traverse the endometrium/decidua transiently lose their muscular coat and ability to vasoconstrict. The expression of vascular markers changes from arterial to venous as these vessels dilate and become low-resistance, high-volume channels. Full understanding of the vascular interactions of human uNK cells is difficult to obtain because endometrial time-course studies are not possible in pregnant women. Here we briefly review key information concerning uNK cell functions from studies in rodents, summarize highlights concerning human uNK cells and describe our preliminary studies on development of a humanized, pregnant mouse model for in vivo investigations of human uNK cell functions.

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References

  1. Reeves RK, Gillis J, Wong FE, Yu Y, Connole M, Johnson RP . CD16− natural killer cells: enrichment in mucosal and secondary lymphoid tissues and altered function during chronic SIV infection. Blood 2010; 115: 4439–4446.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Sun JC, Beilke JN, Lanier LL . Adaptive immune features of natural killer cells. Nature 2009; 457: 557–561.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Peel S . Granulated metrial gland cells. Adv Anat Embryol Cell Biol 1989; 115: 1–112.

    Article  CAS  PubMed  Google Scholar 

  4. Manaster I, Mizrahi S, Goldman-Wohl D, Sela HY, Stern-Ginossar N, Lankry D et al. Endometrial NK cells are special immature cells that await pregnancy. J Immunol 2008; 181: 1869–1876.

    Article  CAS  PubMed  Google Scholar 

  5. Lash GE, Robson SC, Bulmer JN . Review: functional role of uterine natural killer (uNK) cells in human early pregnancy decidua. Placenta 2010; 31: S87–S92.

    Article  PubMed  CAS  Google Scholar 

  6. Kiso Y, Yamashiro S, McBey BA, Croy BA . Tissue-specific differentiation of a natural killer cell subset in ectopically grafted murine uterine tissue. Transplantation 1992; 54: 185–187.

    Article  CAS  PubMed  Google Scholar 

  7. Kiso Y, McBey BA, Mason L, Croy BA . Histological assessment of the mouse uterus from birth to puberty for the appearance of LGL-1+ natural killer cells. Biol Reprod 1992; 47: 227–232.

    Article  CAS  PubMed  Google Scholar 

  8. Bany BM, Cross JC . Post-implantation mouse conceptuses produce paracrine signals that regulate the uterine endometrium undergoing decidualization. Dev Biol 2006; 294: 445–456.

    Article  CAS  PubMed  Google Scholar 

  9. Oh MJ, Croy BA . A map of relationships between uterine natural killer cells and progesterone receptor expressing cells during mouse pregnancy. Placenta 2008; 29: 317–323.

    Article  CAS  PubMed  Google Scholar 

  10. Herington JL, Underwood T, McConaha M, Bany BM . Paracrine signals from the mouse conceptus are not required for the normal progression of decidualization. Endocrinology 2009; 150: 4404–4413.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kruse A, Martens N, Fernekorn U, Hallmann R, Butcher EC . Alterations in the expression of homing-associated molecules at the maternal/fetal interface during the course of pregnancy. Biol Reprod 2002; 66: 333–345.

    Article  CAS  PubMed  Google Scholar 

  12. Ye W, Zheng LM, Young J, Liu CC . The involvement of interleukin (IL)-15 in regulating the differentiation of granulated metrial gland cells in mouse pregnant uterus. J Exp Med 1996; 184: 2405–2410.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Chantakru S, Miller C, Roach LE, Kuziel WA, Maeda N, Wang WC et al. Contributions from self-renewal and trafficking to the uterine NK cell population of early pregnancy. J Immunol 2002; 168: 22–28.

    Article  CAS  PubMed  Google Scholar 

  14. Croy BA, Zhang J, Tayade C, Colucci F, Yadi H, Yamada AT . Analysis of uterine natural killer cells in mice. In: Campbell KS Natural Killer Cell Protocols, 2nd edn. Totowa NJ: Humana Press 2010: 465–503.

    Chapter  Google Scholar 

  15. Bianco J, Stephenson K, Yamada AT, Croy BA . Time-course analyses addressing the acquisition of DBA lectin reactivity in mouse lymphoid organs and uterus during the first week of pregnancy. Placenta 2008; 29: 1009–1015.

    Article  CAS  PubMed  Google Scholar 

  16. Tayade C, Fang Y, Black GP, V A Jr, Erlebacher A, Croy BA . Differential transcription of Eomes and T-bet during maturation of mouse uterine natural killer cells. J Leukoc Biol 2005; 78: 1347–1355.

    Article  CAS  PubMed  Google Scholar 

  17. Zhang JH, Yamada AT, Croy BA . DBA-lectin reactivity defines natural killer cells that have homed to mouse decidua. Placenta 2009; 30: 968–973.

    Article  PubMed  CAS  Google Scholar 

  18. Yadi H, Burke S, Madeja Z, Hemberger M, Moffett A, Colucci F . Unique receptor repertoire in mouse uterine NK cells. J Immunol 2008; 181: 6140–6147.

    Article  CAS  PubMed  Google Scholar 

  19. Luross JA, Yamashiro S, Croy BA . A study on the relationship between parity and differentiation of granulated metrial gland cells. Placenta 1996; 17: 521–525.

    Article  CAS  PubMed  Google Scholar 

  20. Stewart I, Peel S . Granulated metrial gland cells at implantation sites of the pregnant mouse uterus. Anat Embryol (Berl) 1980; 160: 227–238.

    Article  CAS  Google Scholar 

  21. Stewart IJ . Granulated metrial gland cells in ‘minor’ species. J Reprod Immunol 1998; 40: 129–146.

    Article  CAS  PubMed  Google Scholar 

  22. Ashkar AA, Di Santo JP, Croy BA . Interferon gamma contributes to initiation of uterine vascular modification, decidual integrity, and uterine natural killer cell maturation during normal murine pregnancy. J Exp Med 2000; 192: 259–270.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Ashkar AA, Black GP, Wei Q, He H, Liang L, Head JR et al. Assessment of requirements for IL-15 and IFN regulatory factors in uterine NK cell differentiation and function during pregnancy. J Immunol 2003; 171: 2937–2944.

    Article  CAS  PubMed  Google Scholar 

  24. Zhang J, Dong H, Wang B, Zhu S, Croy BA . Dynamic changes occur in patterns of endometrial EFNB2/EPHB4 expression during the period of spiral arterial modification in mice. Biol Reprod 2008; 79: 450–458.

    Article  CAS  PubMed  Google Scholar 

  25. Wang C, Tanaka T, Nakamura H, Umesaki N, Hirai K, Ishiko O et al. Granulated metrial gland cells in the murine uterus: localization, kinetics, and the functional role in angiogenesis during pregnancy. Microsc Res Tech 2003; 60: 420–429.

    Article  CAS  PubMed  Google Scholar 

  26. Wang C, Umesaki N, Nakamura H, Tanaka T, Nakatani K, Sakaguchi I et al. Expression of vascular endothelial growth factor by granulated metrial gland cells in pregnant murine uteri. Cell Tissue Res 2000; 300: 285–293.

    Article  CAS  PubMed  Google Scholar 

  27. Carmeliet P, Jain RK . Angiogenesis in cancer and other diseases. Nature 2000; 407: 249–257.

    Article  CAS  PubMed  Google Scholar 

  28. Tayade C, Fang Y, Hilchie D, Croy BA . Lymphocyte contributions to altered endometrial angiogenesis during early and midgestation fetal loss. J Leukoc Biol 2007: 82: 877–886.

    Article  CAS  PubMed  Google Scholar 

  29. Parker LH, Schmidt M, Jin SW, Gray AM, Beis D, Pham T et al. The endothelial-cell-derived secreted factor Egfl7 regulates vascular tube formation. Nature 2004; 428: 754–758.

    Article  CAS  PubMed  Google Scholar 

  30. Kuhnert F, Mancuso MR, Hampton J, Stankunas K, Asano T, Chen CZ et al. Attribution of vascular phenotypes of the murine Egfl7 locus to the microRNA miR-126. Development 2008; 135: 3989–3993.

    Article  CAS  PubMed  Google Scholar 

  31. Hunt JS, Miller L, Vassmer D, Croy BA . Expression of the inducible nitric oxide synthase gene in mouse uterine leukocytes and potential relationships with uterine function during pregnancy. Biol Reprod 1997; 57: 827–836.

    Article  CAS  PubMed  Google Scholar 

  32. Burke SD, Barrette VF, Bianco J, Thorne JG, Yamada AT, Pang SC et al. Spiral arterial remodeling is not essential for normal blood pressure regulation in pregnant mice. Hypertension 2010; 55: 729–737.

    Article  CAS  PubMed  Google Scholar 

  33. Kamizono S, Duncan GS, Seidel MG, Morimoto A, Hamada K, Grosveld G et al. Nfil3/E4bp4 is required for the development and maturation of NK cells in vivo. J Exp Med 2009; 206: 2977–2986.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Gascoyne DM, Long E, Veiga-Fernandes H, de Boer J, Williams O, Seddon B et al. The basic leucine zipper transcription factor E4BP4 is essential for natural killer cell development. Nat Immunol 2009; 10: 1118–1124.

    Article  CAS  PubMed  Google Scholar 

  35. Guzik TJ, Hoch NE, Brown KA, McCann LA, Rahman A, Dikalov S et al. Role of the T cell in the genesis of angiotensin II induced hypertension and vascular dysfunction. J Exp Med 2007; 204: 2449–2460.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Kammerer U, Eggert AO, Kapp M, McLellan AD, Geijtenbeek TB, Dietl J et al. Unique appearance of proliferating antigen-presenting cells expressing DC-SIGN (CD209) in the decidua of early human pregnancy. Am J Pathol 2003; 162: 887–896.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Moffett-King A . Natural killer cells and pregnancy. Nat Rev Immunol 2002; 2: 656–663.

    Article  CAS  PubMed  Google Scholar 

  38. Moffett A, Regan L, Braude P . Natural killer cells, miscarriage, and infertility. BMJ 2004; 329: 1283–1285.

    Article  PubMed  PubMed Central  Google Scholar 

  39. King A, Wooding P, Gardner L, Loke YW . Expression of perforin, granzyme A and TIA-1 by human uterine CD56+ NK cells implies they are activated and capable of effector functions. Hum Reprod 1993; 8: 2061–2067.

    Article  CAS  PubMed  Google Scholar 

  40. Arruvito L, Giulianelli S, Flores AC, Paladino N, Barboza M, Lanari C et al. NK cells expressing a progesterone receptor are susceptible to progesterone-induced apoptosis. J Immunol 2008; 180: 5746–5753.

    Article  CAS  PubMed  Google Scholar 

  41. King A . Uterine leukocytes and decidualization. Hum Reprod Update 2000; 6: 28–36.

    Article  CAS  PubMed  Google Scholar 

  42. Colonna M . Interleukin-22-producing natural killer cells and lymphoid tissue inducer-like cells in mucosal immunity. Immunity 2009; 31: 15–23.

    Article  CAS  PubMed  Google Scholar 

  43. Cella M, Fuchs A, Vermi W, Facchetti F, Otero K, Lennerz JK et al. A human natural killer cell subset provides an innate source of IL-22 for mucosal immunity. Nature 2009; 457: 722–725.

    Article  CAS  PubMed  Google Scholar 

  44. Pang G, Buret A, Batey RT, Chen QY, Couch L, Cripps A et al. Morphological, phenotypic and functional characteristics of a pure population of CD56+CD16−CD3− large granular lymphocytes generated from human duodenal mucosa. Immunology 1993; 79: 498–505.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Bulmer JN, Lash GE . Human uterine natural killer cells: a reappraisal. Mol Immunol 2005; 42: 511–521.

    Article  CAS  PubMed  Google Scholar 

  46. Hanna J, Goldman-Wohl D, Hamani Y, Avraham I, Greenfield C, Natanson-Yaron S et al. Decidual NK cells regulate key developmental processes at the human fetal-maternal interface. Nat Med 2006; 12: 1065–1074.

    Article  CAS  PubMed  Google Scholar 

  47. Strominger JL . Human decidual lymphocytes and the immunobiology of pregnancy. J Reprod Immunol 2004; 62: 17–18.

    Article  PubMed  Google Scholar 

  48. Koopman LA, Kopcow HD, Rybalov B, Boyson JE, Orange JS, Schatz F et al. Human decidual natural killer cells are a unique NK cell subset with immunomodulatory potential. J Exp Med 2003; 198: 1201–1212.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Gargett CE, Schwab KE, Zillwood RM, Nguyen HP, Wu D . Isolation and culture of epithelial progenitors and mesenchymal stem cells from human endometrium. Biol Reprod 2009; 80: 1136–1145.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Vosshenrich CA, Garcia-Ojeda ME, Samson-Villeger SI, Pasqualetto V, Enault L, Goff OR et al. A thymic pathway of mouse natural killer cell development characterized by expression of GATA-3 and CD127. Nat Immunol 2006; 7: 1217–1224.

    Article  CAS  PubMed  Google Scholar 

  51. Freud AG, Becknell B, Roychowdhury S, Mao HC, Ferketich AK, Nuovo GJ et al. A human CD34+ subset resides in lymph nodes and differentiates into CD56bright natural killer cells. Immunity 2005; 22: 295–304.

    Article  CAS  PubMed  Google Scholar 

  52. van den Heuvel M, Peralta C, Bashar S, Taylor S, Horrocks J, Croy BA . Trafficking of peripheral blood CD56bright cells to the decidualizing uterus—new tricks for old dogmas? J Reprod Immunol 2005; 67: 21–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Kendall MD, Clarke AG . The thymus in the mouse changes its activity during pregnancy: a study of the microenvironment. J Anat 2000; 197: 393–411.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Tibbetts TA, DeMayo F, Rich S, Conneely OM, O'Malley BW . Progesterone receptors in the thymus are required for thymic involution during pregnancy and for normal fertility. Proc Natl Acad Sci USA 1999; 96: 12021–12026.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Collins MK, Tay CS, Erlebacher A . Dendritic cell entrapment within the pregnant uterus inhibits immune surveillance of the maternal/fetal interface in mice. J Clin Invest 2009; 119: 2062–2073.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Kitaya K . Accumulation of uterine CD16− natural killer (NK) cells: friends, foes, or Jekyll-and-Hyde relationship for the conceptus? Immunol Invest 2008; 37: 467–481.

    Article  CAS  PubMed  Google Scholar 

  57. Kalkunte SS, Mselle TF, Norris WE, Wira CR, Sentman CL, Sharma S . Vascular endothelial growth factor C facilitates immune tolerance and endovascular activity of human uterine NK cells at the maternal-fetal interface. J Immunol 2009; 182: 4085–4092.

    Article  CAS  PubMed  Google Scholar 

  58. Lash GE, Schiessl B, Kirkley M, Innes BA, Cooper A, Searle RF et al. Expression of angiogenic growth factors by uterine natural killer cells during early pregnancy. J Leukoc Biol 2006; 80: 572–580.

    Article  CAS  PubMed  Google Scholar 

  59. Hu Y, Dutz JP, MacCalman CD, Yong P, Tan R, von Dadelszen P . Decidual NK cells alter in vitro first trimester extravillous cytotrophoblast migration: a role for IFN-gamma. J Immunol 2006; 177: 8522–8530.

    Article  CAS  PubMed  Google Scholar 

  60. Hu Y, Eastabrook G, Tan R, MacCalman CD, Dutz JP, von Dadelszen P . Decidual NK cell-derived conditioned medium enhances capillary tube and network organization in an extravillous cytotrophoblast cell line. Placenta 2010; 31: 213–221.

    Article  CAS  PubMed  Google Scholar 

  61. Smith SD, Dunk CE, Aplin JD, Harris LK, Jones RL . Evidence for immune cell involvement in decidual spiral arteriole remodeling in early human pregnancy. Am J Pathol 2009; 174: 1959–1971.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Saito S, Nishikawa K, Morii T, Enomoto M, Narita N, Motoyoshi K et al. Cytokine production by CD16−CD56bright natural killer cells in the human early pregnancy decidua. Int Immunol 1993; 5: 559–563.

    Article  CAS  PubMed  Google Scholar 

  63. Kitaya K, Yasuo T, Yamaguchi T, Fushiki S, Honjo H . Genes regulated by interferon-gamma in human uterine microvascular endothelial cells. Int J Mol Med 2007; 20: 689–697.

    CAS  PubMed  Google Scholar 

  64. Wang A, Rana S, Karumanchi SA . Preeclampsia: the role of angiogenic factors in its pathogenesis. Physiology 2009; 24: 147–158.

    Article  PubMed  CAS  Google Scholar 

  65. Hiby SE, Walker JJ, O'Shaughnessy KM, Redman CW, Carrington M, Trowsdale J et al. Combinations of maternal KIR and fetal HLA-C genes influence the risk of preeclampsia and reproductive success. J Exp Med 2004; 200: 957–965.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Vivier E, Tomasello E, Baratin M, Walzer T, Ugolini S . Functions of natural killer cells. Nat Immunol 2008; 9: 503–510.

    Article  CAS  PubMed  Google Scholar 

  67. Quenby S, Nik H, Innes B, Lash G, Turner M, Drury J et al. Uterine natural killer cells and angiogenesis in recurrent reproductive failure. Hum Reprod 2009; 24: 45–54.

    Article  CAS  PubMed  Google Scholar 

  68. Barash A, Dekel N, Fieldust S, Segal I, Schechtman E, Granot I . Local injury to the endometrium doubles the incidence of successful pregnancies in patients undergoing in vitro fertilization. Fertil Steril 2003; 79: 1317–1322.

    Article  PubMed  Google Scholar 

  69. Lothar H, Martin S, Thomas H . CD3−CD56+CD16+ natural killer cells and improvement of pregnancy outcome in IVF/ICSI failure after additional IVIG-treatment. Am J Reprod Immunol 2010; 63: 263–265.

    Article  CAS  Google Scholar 

  70. Almog B, Shalom-Paz E, Dufort D, Tulandi T . Promoting implantation by local injury to the endometrium. Fertil Steril. 2010; in press.

  71. Kitaya K, Yasuo T . Leukocyte density and composition in human cycling endometrium with uterine fibroids. Hum Immunol 2010; 71: 158–163.

    Article  CAS  PubMed  Google Scholar 

  72. Kerbel RS . Human tumor xenografts as predictive preclinical models for anticancer drug activity in humans: better than commonly perceived-but they can be improved. Cancer Biol Ther 2003; 2: S134–S139.

    CAS  PubMed  Google Scholar 

  73. Brehm MA, Cuthbert A, Yang C, Miller DM, DiIorio P, Laning J et al. Parameters for establishing humanized mouse models to study human immunity: analysis of human hematopoietic stem cell engraftment in three immunodeficient strains of mice bearing the IL2rgamma(null) mutation. Clin Immunol 2010; 135: 84–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Namikawa R, Weilbaecher KN, Kaneshima H, Yee EJ, McCune JM . Long-term human hematopoiesis in the SCID-hu mouse. J Exp Med 1990; 172: 1055–1063.

    Article  CAS  PubMed  Google Scholar 

  75. Manz MG, Di Santo JP . Renaissance for mouse models of human hematopoiesis and immunobiology. Nat Immunol 2009; 10: 1039–1042.

    Article  CAS  PubMed  Google Scholar 

  76. Brehm MA, Shultz LD, Greiner DL . Humanized mouse models to study human diseases. Curr Opin Endocrinol Diabetes Obes 2010; 17: 120–125.

    Article  PubMed  PubMed Central  Google Scholar 

  77. Huntington ND, Legrand N, Alves NL, Jaron B, Weijer K, Plet A et al. IL-15 trans-presentation promotes human NK cell development and differentiation in vivo. J Exp Med 2009; 206: 25-34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Denton P, Garcia J . Novel humanized murine models for HIV research. Curr HIV/AIDS Rep 2009; 6: 13–19.

    Article  PubMed  PubMed Central  Google Scholar 

  79. Chen Q, Khoury M, Chen J . Expression of human cytokines dramatically improves reconstitution of specific human-blood lineage cells in humanized mice. Proc Natl Acad Sci USA 2009; 106: 21783–21788.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Wang B, Hollander GA, Nichoglannopoulou A, Simpson SJ, Orange JS, Gutierrez-Ramos JC et al. Natural killer cell development is blocked in the context of aberrant T lymphocyte oxtogeny. Int Immunol 1996; 8: 939–951.

    Article  CAS  PubMed  Google Scholar 

  81. Burke SD, Dong H, Hazan AD, Croy A . Aberrant endometrial features of pregnancy in diabetic NOD mice. Diabetes 2007; 56: 2919–2926.

    Article  CAS  PubMed  Google Scholar 

  82. Chantakru S, Kuziel WA, Maeda N, Croy BA . A study on the density and distribution of uterine natural killer cells at mid pregnancy in mice genetically-ablated for CCR2, CCR5 and the CCR5 receptor ligand, MIP-1 alpha. J Reprod Immunol 2001; 49: 33–47.

    Article  CAS  PubMed  Google Scholar 

  83. Xie X, He H, Colonna M, Seya T, Takai T, Croy BA . Pathways participating in activation of mouse uterine natural killer cells during pregnancy. Biol Reprod 2005; 73: 510–518.

    Article  CAS  PubMed  Google Scholar 

  84. Lewis ID, Almeida-Porada G, Du J, Lemischka IR, Moore KA, Zanjani ED et al. Umbilical cord blood cells capable of engrafting in primary, secondary, and tertiary xenogeneic hosts are preserved after ex vivo culture in a noncontact system. Blood 2001; 97: 3441–3449.

    Article  CAS  PubMed  Google Scholar 

  85. Putnam AL, Brusko TM, Lee MR, Liu W, Szot GL, Ghosh T et al. Expansion of human regulatory T-cells from patients with type 1 diabetes. Diabetes 2009; 58: 652–662.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Pearson T, Greiner DL, Shultz LD . Humanized SCID mouse models for biomedical research. Curr Top Microbiol Immunol 2008; 324: 25–51.

    CAS  PubMed  Google Scholar 

  87. Awong G, Herer E, Surh CD, Dick JE, La Motte-Mohs RN, Zuniga-Pflucker JC . Characterization in vitro and engraftment potential in vivo of human progenitor T cells generated from hematopoietic stem cells. Blood 2009; 114: 972–982.

    Article  CAS  PubMed  Google Scholar 

  88. Barker DJP . Nutrition in the Womb: How to Reduce Chronic Disease in the Next Generation. Vols. 1–174. Portland: The Barker Foundation, 2008.

    Google Scholar 

  89. Croy BA, Zhang J, Tayade C, Colucci F, Yadi H, Yamada AT . Analysis of uterine natural killer cells in mice. Methods Mol Biol 2010; 61: 465–503.

    Article  CAS  Google Scholar 

  90. Peel S . Granulated Metrial Gland Cells. New York: Springer-Verlag, 1989; 1–112.

    Google Scholar 

  91. Croy BA, Xie X . In vivo models for studying homing and function of murine uterine natural killer cells. Methods Mol Med 2006; 122: 77–92.

    PubMed  Google Scholar 

  92. Leonard S, Murrant C, Tayade C, van den Heuvel M, Watering R, Croy BA . Mechanisms regulating immune cell contributions to spiral artery modification—facts and hypotheses—a review. Placenta 2006; 122 (Suppl A): S40–S46.

    Article  CAS  Google Scholar 

  93. Mukhtar DD, Stewart I . Migration of granulated metrial gland cells from cultured explants of mouse metrial gland tissue. Cell Tissue Res 1988; 253: 413–417.

    Article  CAS  PubMed  Google Scholar 

  94. Hatta K, Chen Z, Carter AL, Leno-Duran E, Zhang J, Ruiz-Ruiz C et al. Orphan receptor kinase ROR2 is expressed in the mouse uterus. Placenta 2010; 31: 327–333.

    Article  CAS  PubMed  Google Scholar 

  95. Zhang J, Sun R, Wei H, Wu D, Tian Z . Toll-like receptor 3 agonist enhances IFN-gamma and TNF-alpha production by murine uterine NK cells. Int Immunopharmacol 2007; 7: 588–596.

    Article  CAS  PubMed  Google Scholar 

  96. Tayade C, Hilchie D, He H, Fang Y, Moons L, Carmeliet P et al. Genetic deletion of placenta growth factor in mice alters uterine NK cells. J Immunol 2007; 178: 4267–4275.

    Article  CAS  PubMed  Google Scholar 

  97. Guimond MJ, Wang B, Croy BA . Engraftment of bone marrow from severe combined immunodeficient (SCID) mice reverses the reproductive deficits in natural killer cell-deficient tg epsilon 26 mice. J Exp Med 1998; 187: 217–223.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Williams PJ, Searle RF, Robson SC, Innes BA, Bulmer JN . Decidual leucocyte populations in early to late gestation normal human pregnancy. J Reprod Immunol 2009; 82: 24–31.

    Article  CAS  PubMed  Google Scholar 

  99. Trundley A, Moffett A . Human uterine leukocytes and pregnancy. Tissue Antigens 2004; 63: 1–12.

    Article  CAS  PubMed  Google Scholar 

  100. Kumar A, Kumar S, Dinda AK, Luthra K . Differential expression of CXCR4 receptor in early and term human placenta. Placenta 2004; 25: 347–351.

    Article  CAS  PubMed  Google Scholar 

  101. Schneider Henning, Miller RK . Receptor-mediated uptake and transport of macromolecules in the human placenta. Int J Dev Biol 2010; 54: 367–375.

    Article  CAS  PubMed  Google Scholar 

  102. von Versen-Höynck F, Rajakumar A, Bainbridge SA, Gallaher MJ, Roberts JM, Powers RW . Human placental adenosine receptor expression is elevated in preeclampsia and hypoxia increases expression of the A2A receptor. Placenta 2009; 30: 434–442.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  103. Rajaraman G, Murthi P, Pathirage N, Brennecke SP, Kalionis B . Downstream targets of homeobox gene HLX show altered expression in human idiopathic fetal growth restriction. Am J Pathol 2010; 176: 278–287.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Miller RK, Genbacev O, Turner MA, Aplin JD, Caniggia I, Huppertz B . Human placental explants in culture: approaches and assessments. Placenta 2005; 26: 439–448.

    Article  CAS  PubMed  Google Scholar 

  105. Manaster I, Mandelboim O . The unique properties of human NK cells in the uterine mucosa. Placenta 2008; 29: 60–66.

    Article  CAS  Google Scholar 

  106. Kaneko S, Mastaglio S, Bondanza A, Ponzoni M, Sanvito F, Aldrighetti L et al. IL-7 and IL-15 allow the generation of suicide gene-modified alloreactive self-renewing central memory human T lymphocytes. Blood 2009; 113: 1006–1015.

    Article  CAS  PubMed  Google Scholar 

  107. Red-Horse K, Rivera J, Schanz A, Zhou Y, Winn V, Kapidzic M et al. Cytotrophoblast induction of arterial apoptosis and lymphangiogenesis in an in vivo model of human placentation. J Clin Invest 2006; 116: 2643–2652.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Red-Horse K, Zhou Y, Genbacev O, Prakobphol A, Foulk R, McMaster M et al. Trophoblast differentiation during embryo implantation and formation of the maternal–fetal interface. J Clin Invest 2004; 114: 744–754.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank Ms Valérie Barrette and Mr Michael Bilinski (Queen's University) for technical assistance and helpful discussions, Dr Huilian Ye (Genentech Inc., South San Francisco, CA, USA) for providing anti-EGFL7 antibody, Dr Aureo T. Yamada (UNICAMP, Campinas, Brazil) for histological consultations and Mr Richard C. Casselman and Ms Heather Ramshaw (Kingston General Hospital) for human sample collection. These studies were supported by awards from the Natural Sciences and Engineering Research Council, Canada, the Canadian Institutes of Health Research and the Canada Research Chairs Program to BAC and a Province of Ontario/Queen's Postdoctoral Fellowship award to JHZ.

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  1. Department of Anatomy and Cell Biology, Queen's University, Kingston, ON, Canada

    Jianhong Zhang, Zhilin Chen, Graeme N Smith & B. Anne Croy

  2. Department of Obstetrics and Gynecology, Queen's University, Kingston, ON, Canada

    Graeme N Smith

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  2. Zhilin Chen
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  3. Graeme N Smith
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  4. B. Anne Croy
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Correspondence to B. Anne Croy.

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Zhang, J., Chen, Z., Smith, G. et al. Natural killer cell-triggered vascular transformation: maternal care before birth?. Cell Mol Immunol 8, 1–11 (2011). https://doi.org/10.1038/cmi.2010.38

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  • DOI: https://doi.org/10.1038/cmi.2010.38

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