NK cells, hypoxia and trophoblast cell differentiation

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

doi:10.4161/cc.20542

Cited by 36 publications

(31 citation statements)

References 29 publications

(45 reference statements)

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“…Importantly, Soares and colleagues have demonstrated that NK cell depletion in the rat leads to hypoxia and initial delays in spiral artery remodeling; however, invasive trophoblast cells are activated and able to successfully modify the uterine spiral arteries. The authors further demonstrate that increased trophoblast invasion/uterine spiral artery remodeling is an adaptive response regulated by NK cells, and this process might be somewhat delayed in the absence of NK cells but resumes in a delayed manner (Chakraborty et al , 2011, 2012). However, these results do not rule out an independent role of cytokines such as IFN-γ in spiral artery remodeling.…”

Section: Uterine Nk Cells and Tregs In Pregnancy: Why Are They There mentioning

confidence: 84%

“…Multiple maternal immune adaptations are potentially involved and have recently been reviewed elsewhere (Moffett and Loke 2006; Quenby et al , 2009; Thaxton and Sharma 2010; Munoz-Suano et al , 2011; Chakraborty et al , 2012; Hofmann et al , 2014). Here we focus on uterine NK (uNK) cells and Tregs because they are the predominant cell types present at the maternal-fetal interface which may pose as foes to pregnancy.…”

Section: Uterine Nk Cells and Tregs In Pregnancy: Why Are They There mentioning

confidence: 99%

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Natural killer cells and regulatory T cells in early pregnancy loss

Sharma¹

2014

Int. J. Dev. Biol.

124

107

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Survival of the allogeneic embryo in the uterus depends on the maintenance of immune tolerance at the maternal-fetal interface. The pregnant uterus is replete with activated maternal immune cells. How this immune tolerance is acquired and maintained has been a topic of intense investigation. The key immune cells that predominantly populate the pregnant uterus are natural killer (NK) cells. In normal pregnancy, these cells are not killers, but rather provide a microenvironment that is pregnancy compatible and supports healthy placentation. In placental mammals, an array of highly orchestrated immune elements to support successful pregnancy outcome has been incorporated. This includes active cooperation between maternal immune cells, particularly NK cells, and trophoblast cells. This intricate process is required for placentation, immune regulation and to remodel the blood supply to the fetus. During the past decade, various types of maternal immune cells have been thought to be involved in cross-talk with trophoblasts and in programming immune tolerance. RegulatoryT cells (Tregs) have attracted a great deal of attention in promoting implantation and immune tolerance beyond implantation. However, what has not been fully addressed is how this immune-trophoblast axis breaks down during adverse pregnancy outcomes, particularly early pregnancy loss, and in response to unscheduled inflammation. Intense research efforts have begun to shed light on the roles of NK cells and Tregs in early pregnancy loss, although much remains to be unraveled in order to fully characterize the mechanisms underlying their detrimental activity. An increased understanding of host-environment interactions that lead to the cytotoxic phenotype of these otherwise pregnancy compatible maternal immune cells is important for prediction, prevention and treatment of pregnancy maladies, particularly recurrent pregnancy loss. In this review, we discuss relevant information from experimental and human models that may explain the pregnancy disrupting roles of these pivotal sentinel cells at the maternal-fetal interface.

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Section: Uterine Nk Cells and Tregs In Pregnancy: Why Are They There mentioning

confidence: 84%

Section: Uterine Nk Cells and Tregs In Pregnancy: Why Are They There mentioning

confidence: 99%

Natural killer cells and regulatory T cells in early pregnancy loss

Sharma¹

2014

Int. J. Dev. Biol.

124

107

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“…There are limitations to in vitro studies, the reductionist approach of focusing on a single stem cell type precludes the adaptation to gestational hypoxia that has been shown to occur over longer periods of time and in interaction with many fetal and maternal cell types 79–82 . However an advantage of the reductionist approach it to understand substantial periods of hypoxic stress that could occur from E2.5-E6.5 before experimental hypoxia was first applied at E6.5 in the rodent gestational model.…”

Section: Discussionmentioning

confidence: 99%

Hypoxic stress induces, but cannot sustain trophoblast stem cell differentiation to labyrinthine placenta due to mitochondrial insufficiency

et al. 2014

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Dysfunctional stem cell differentiation into placental lineages is associated with gestational diseases. Of the differentiated lineages available to trophoblast stem cells (TSC), elevated O2 and mitochondrial function are necessary to placental lineages at the maternal-placental surface and important in the etiology of preeclampsia. TSC lineage imbalance leads to embryonic failure during uterine implantation. Stress at implantation exacerbates stem cell depletion by decreasing proliferation and increasing differentiation. Implantation site O2 is normally ~2%. In culture, exposure to 2% O2 and fibroblast growth factor (FGF)4 enabled highest mouse TSC multipotency and proliferation. In contrast, hypoxic stress (0.5% O2) initiated the most TSC differentiation after 24 hr despite FGF4. However, hypoxic stress supported differentiation poorly after 4–7 days, despite FGF4 removal. At all tested O2 levels, FGF4 maintained Warburg metabolism; mitochondrial inactivity and aerobic glycolysis. However, hypoxic stress suppressed mitochondrial membrane potential, maintained low mitochondrial cytochrome c oxidase (oxidative phosphorylation/OxPhos), and high pyruvate kinase M2 (glycolysis) despite FGF4 removal. Inhibiting OxPhos inhibited differentiation at the differentiation optimum at 20% O2. Moreover, adding differentiation-inducing hyperosmolar stress failed to induce differentiation during hypoxia. Thus, differentiation depended on OxPhos at 20% O2; hypoxic and hyperosmolar stresses did not induce differentiation at 0.5% O2. Hypoxia-limited differentiation and mitochondrial inhibition and activation suggest that differentiation into two lineages of the labyrinthine placenta requires O2>0.5–2% and mitochondrial function. Stress-activated protein kinase increases an early lineage and suppresses later lineages in proportion to the deviation from optimal O2 for multipotency, thus it is the first enzyme reported to prioritize differentiation.

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“…6,7 The basis of the poor placental development and dysfunction is thus an area of core relevance in the pathophysiology of pre-eclampsia, with a major focus of attention turning to the role of a maladaptive immune response. 8,9 The importance, in healthy pregnancies, of regulating immune responses towards a tolerogenic environment, 10 and the role of immune cells in both regulating foeto-maternal tolerance 11,12 and trophoblast invasion, 13,14 has been propounded with the conjecture that a breakdown of 'immunological tolerance' towards foetal cells may play a role in the pathogenesis of pre-eclampsia. 15 Women with preeclampsia display increased levels of tumour necrosis factor-alpha (TNF-a) in both serum and placental tissue 16,17 and have reduced serum and placental expression of interleukin-10 (IL-10), 18 indicating an alteration in the cytokine balance towards an inflammatory T helper cell (Th1) response.…”

Section: Introductionmentioning

confidence: 99%