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

Chakraborty, Damayanti; Rumi, M.A. Karim; Konno, Toshihiro; Soares, Michael J.

doi:10.1073/pnas.1109478108

Cited by 150 publications

(217 citation statements)

References 38 publications

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“…These have included genetic mouse models possessing NK cell deficiencies 13 and systemic immunodepletion of NK cells using administration of antibodies to asialo GM1 during rat gestation. 14 The success of the immunodepletion approach is gestation stage-dependent and most effective when administered immediately prior to or concurrent with embryo implantation. From the mouse genetic models, we learned that NK cells promote uterine spiral artery remodeling, including decreasing arterial smooth muscle wall thickness and increasing vessel lumen diameter.…”

Section: Nk Cells Modulate the Timing Of Critical Events During Hemocmentioning

confidence: 99%

“…The absence of NK cells at the maternal-fetal interface results in a transient hypoxia. 14 The effects of NK cell depletion on invasive trophoblast-directed uterine spiral artery remodeling can be mimicked by appropriately timed in vivo hypoxia exposure. 22 A critical developmental window of sensitivity to in vivo hypoxia exposure exists between E8.5 and E9.5 of rat pregnancy.…”

Section: Nk Cells Modulate the Timing Of Critical Events During Hemocmentioning

confidence: 99%

“…Two observations support an involvement characterized initially by a delay in uterine spiral artery development and progression toward the placenta and, subsequently, by an acceleration of endovascular invasive trophoblast cell movement deep into the uterine spiral arteries and extensive uterine spiral artery structural remodeling. 14 These physical changes include replacement of the endothelium with endovascular trophoblast cells, their acquisition of a pseudo-endothelial phenotype, the disappearance of smooth muscle cells in the tunica media of the modified uterine spiral artery, distention of the uterine spiral artery lumen and an increased capacity for blood delivery to the placenta. Thus, NK cells possess two apparently contradictory actions in establishing the hemochorial placenta: (1) they promote uterine spiral artery development and remodeling, and (2) they restrain trophoblast-directed uterine spiral artery remodeling.…”

Section: Oxygen Tension Is a Key Mediator Of Nk Cell Actions At The Pmentioning

confidence: 99%

“…In addition to the robust extension of endovascular trophoblast invasion deep into the uterine spiral arteries in both NK cell-depleted and maternal hypoxia in vivo models, the junctional zone also undergoes an expansion relative to the labyrinth zone. 14,22 TS cell populations are an excellent in vitro model system for elucidating mechanisms regulating differentiation. 23,24 TS cell exposure to a range of oxygen tensions can differentially influence cell proliferation and differentiation.…”

Section: Nk Cells Modulate the Timing Of Critical Events During Hemocmentioning

confidence: 99%

“…15 NK cell immunodepletion in the rat results in striking changes in the uterine spiral arteries, these hypoxia-stimulated actions are mediated by the transcription factor complex, hypoxia-inducible factor (HIF). 14,25 HIFs are basic helix loop helix Per-Arnt/AhRSim (bHLH-PAS) transcription factors. 28 Disruption of HIF signaling impairs TS cell responses to low oxygen and acquisition of an invasive phenotype.…”

Section: Nk Cells Modulate the Timing Of Critical Events During Hemocmentioning

confidence: 99%

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NK cells, hypoxia and trophoblast cell differentiation

2012

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Section: Nk Cells Modulate the Timing Of Critical Events During Hemocmentioning

confidence: 99%

Section: Nk Cells Modulate the Timing Of Critical Events During Hemocmentioning

confidence: 99%

Section: Oxygen Tension Is a Key Mediator Of Nk Cell Actions At The Pmentioning

confidence: 99%

Section: Nk Cells Modulate the Timing Of Critical Events During Hemocmentioning

confidence: 99%

Section: Nk Cells Modulate the Timing Of Critical Events During Hemocmentioning

confidence: 99%

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NK cells, hypoxia and trophoblast cell differentiation

2012

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Hypoxia and Placental Development

Soares

Iqbal

Kozai

2017

Birth Defects Research

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113

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Hemochorial placentation is orchestrated through highly regulated temporal and spatial decisions governing the fate of trophoblast stem/progenitor cells. Trophoblast cell acquisition of specializations facilitating invasion and uterine spiral artery remodeling is a labile process, sensitive to the environment, and represents a process that is vulnerable to dysmorphogenesis in pathologic states. Hypoxia is a signal guiding placental development, and molecular mechanisms directing cellular adaptations to low oxygen tension are integral to trophoblast cell differentiation and placentation. Hypoxia can also be used as an experimental tool to investigate regulatory processes controlling hemochorial placentation. These developmental processes are conserved in mouse, rat, and human placentation. Consequently, elements of these developmental events can be modeled and hypotheses tested in trophoblast stem cells and in genetically-manipulated rodents. Hypoxia is also a consequence of a failed placenta, yielding pathologies that can adversely affect maternal adjustments to pregnancy, fetal health, and susceptibility to adult disease. The capacity of the placenta for adaptation to environmental challenges highlights the importance of its plasticity in safeguarding a healthy pregnancy.

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Hypoxic Stress Forces Adaptive and Maladaptive Placental Stress Responses in Early Pregnancy

Abdulhasan

Awonuga

et al. 2017

Birth Defects Research

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This review focuses on hypoxic stress and its effects on the placental lineage and the earliest differentiation events in mouse and human placental trophoblast stem cells (TSCs). Although the placenta is a decidual organ at the end of pregnancy, its earliest rapid growth and function at the start of pregnancy precedes and supports growth and function of the embryo. Earliest function requires that TSCs differentiate, however, "hypoxia" supports rapid growth, but not differentiation of TSCs. Most of the literature on earliest placental "hypoxia" studies used 2% oxygen which is normoxic for TSCs. Hypoxic stress happens when oxygen level drops below 2%. It decreases anabolism, proliferation, potency/stemness and increases differentiation, despite culture conditions that would sustain proliferation and potency. Thus, to study the pathogenesis due to TSC dysfunction, it is important to study hypoxic stress below 2%. Many studies have been performed using 0.5 to 1% oxygen in cultured mouse TSCs. From all these studies, a small number has examined human trophoblast lines and primary first trimester placental hypoxic stress responses in culture. Some other stress stimuli, aside from hypoxic stress, are used to elucidate common and unique aspects of hypoxic stress. The key outcomes produced by hypoxic stress are mitochondrial, anabolic, and proliferation arrest, and this is coupled with stemness loss and differentiation. Hypoxic stress can lead to depletion of stem cells and miscarriage, or can lead to later dysfunctions in placentation and fetal development. Birth Defects Research 109:1330-1344, 2017. © 2017 Wiley Periodicals, Inc.

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

Cited by 150 publications

References 38 publications

NK cells, hypoxia and trophoblast cell differentiation

NK cells, hypoxia and trophoblast cell differentiation

Hypoxia and Placental Development

Hypoxic Stress Forces Adaptive and Maladaptive Placental Stress Responses in Early Pregnancy

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