Natural killer cells direct hemochorial placentation by regulating hypoxia-inducible factor dependent trophoblast lineage decisions

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 108; no. 39; pp. 16295 - 16300
• Main Authors: Chakraborty, Damayanti, Rumi, M. A. Karim, Konno, Toshihiro, Soares, Michael J
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 27.09.2011; National Acad Sciences
• Subjects: Animals; Arteries; Biological Sciences; Cell Lineage; Cells; Differentiation; Endothelium; Female; Genotype & phenotype; Hypoxia; Hypoxia-inducible factor 1 alpha; Hypoxia-Inducible Factor 1, alpha Subunit - physiology; Hypoxia-inducible factors; Killer Cells, Natural - physiology; Natural killer cells; Oxygen; Oxygen - metabolism; Oxygen tension; phenotype; Placenta; Placenta - blood supply; Placenta - cytology; Placenta - metabolism; Placentation; Pregnancy; Proteins; Rats; Rats, Sprague-Dawley; Reflexes; Renovations; Signal Transduction; Stem cells; Stroma; trophoblast; Trophoblasts; Trophoblasts - cytology; Uterus
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1109478108

Natural killer (NK) cells are recruited into the uterine stroma during establishment of the hemochorial placenta and are proposed regulators of uterine spiral artery remodeling. Failures in uterine spiral artery remodeling are linked to diseases of pregnancy. This prompted an investigation of the involvement of NK cells in placentation. NK cell depletion decreased the delivery of proangiogenic factors and delayed uterine spiral artery development, leading to decreased oxygen tension at the placentation site, stabilized hypoxia-inducible factor 1A protein, and redirected trophoblast differentiation to an invasive phenotype. Trophoblast cells replaced the endothelium of uterine spiral arteries extending the depth of the placental vascular bed and accelerating vessel remodeling. Hypoxia-regulated trophoblast lineage decisions, including expansion of invasive trophoblast, could be reproduced in vitro by using rat trophoblast stem cells and were dependent on hypoxia-inducible factor signaling. We conclude that NK cells guide hemochorial placentation through controlling a hypoxia-sensitive adaptive reflex regulating trophoblast lineage decisions.