Induced Human Decidual NK-Like Cells Improve Utero-Placental Perfusion in Mice

Cavalli, Ricardo de Carvalho; Cerdeira, Ana Sofia; Pernicone, Elizabeth; Korkes, Henri Augusto; Burke, Suzanne D.; Rajakumar, Augustine; Thadhani, Ravi; Roberts, Drucilla J.; Bhasin, Manoj; Karumanchi, S. Ananth; Kopcow, Hernan D.

doi:10.1371/journal.pone.0164353

Cited by 20 publications

(27 citation statements)

References 56 publications

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“…Decidual natural killer (dNK) cells have a key role in spiral artery remodelling 60 . In vivo studies showed that injection of dNK cells into immunocompromised mice with elevated uterine artery resistance reduced this resistance, suggesting improved placentation 61 . Thus, appropriate activation of dNK cells is essential for normal placentation.…”

Section: Abnormal Placentationmentioning

confidence: 99%

Pre-eclampsia: pathogenesis, novel diagnostics and therapies

et al. 2019

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Pre-eclampsia is a complication of pregnancy that is associated with substantial maternal and fetal morbidity and mortality. The disease presents with new-onset hypertension and often proteinuria in the mother, which can progress to multi-organ dysfunction, including hepatic, renal and cerebral disease, if the fetus and placenta are not delivered. Maternal endothelial dysfunction due to circulating factors of fetal origin from the placenta is a hallmark of pre-eclampsia. Risk factors for the disease include maternal comorbidities, such as chronic kidney disease, hypertension and obesity; a family history of pre-eclampsia, nulliparity or multiple pregnancies; and previous preeclampsia or intrauterine fetal growth restriction. In the past decade, the discovery and characterization of novel antiangiogenic pathways have been particularly impactful both in increasing understanding of the disease pathophysiology and in directing predictive and therapeutic efforts. In this Review, we discuss the pathogenic role of antiangiogenic proteins released by the placenta in the development of pre-eclampsia and review novel therapeutic strategies directed at restoring the angiogenic imbalance observed during pre-eclampsia. We also highlight other notable advances in the field, including the identification of long-term maternal and fetal risks conferred by pre-eclampsia.

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Section: Abnormal Placentationmentioning

confidence: 99%

Pre-eclampsia: pathogenesis, novel diagnostics and therapies

et al. 2019

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“…In addition, TGF-β signaling is thought to be critical for the development of SG NK1.1 + CD49a + cells ( 3 ) as well as the conversion of cNK cells into ILC1s in the tumor microenvironment ( 42 ). The Kopcow group previously reported that when cultured in the combined conditions of hypoxia, TGF-β1, and a demethylating agent, NK cells from human peripheral blood obtain decidual NK cell markers and functions ( 43 , 44 ). However, we did not apply TGF-β in our system, and very few CD49a − CD49b + NK cells were detected in culture; these cells were also Eomes − .…”

Section: Discussionmentioning

confidence: 99%

Cytokine-Based Generation of CD49a+Eomes−/+ Natural Killer Cell Subsets

Zhang

et al. 2018

Front. Immunol.

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Recent studies have identified CD49a+Eomes− and CD49a+Eomes+ subsets of tissue-resident NK (trNK) cells in different organs of the mouse. However, the characteristics of CD49a+Eomes−/+ NK cell development and the regulation of Eomes expression in NK cells remain unclear. Here, we established an in vitro cytokine-based feeder-free system in which bone marrow progenitor cells differentiate into CD49a+ NK cells. IL-15 was identified as being the key cytokine in this system that supported the development and maintenance of CD49a+ NK cells. The CD49a+ NK cells generated were Eomes−CD49b− and shared the same phenotype as hepatic trNK cells. IL-4 induced the expression of Eomes in generated NK cells and converted them into CD49a+Eomes+ cells, which were phenotypically and functionally similar to uterine trNK cells. Moreover, the IL-4/STAT6 axis was identified as being important in the generation of CD49a+Eomes+ induced NK cells. Collectively, these studies describe an approach to generate CD49a+Eomes−/+ subsets of NK cells and demonstrate important roles for IL-15 and IL-4 in the differentiation of these cells. These findings have potential for developmental research underlying the generation of different subsets of NK cells and the application of adoptive NK cell transfer therapies.

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“…Following implantation in the uterine endometrium, the early growth of the embryo occurs in hypoxic conditions in the uterus (68). Hypoxia in turn stimulates the secretion of VEGF and other angiogenic factors from uNK cells to support the demands for increased vascularization (69, 70). In addition, TGFβ plays an important role in inducing regulatory uNK cell functions (41, 69–71).…”

Section: If An Nk Cell Cannot Be Defined By How It Looks Could It Bementioning

confidence: 99%

What Defines NK Cell Functional Fate: Phenotype or Metabolism?

Poznanski

Ashkar

2019

Front. Immunol.

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NK cells are capable of an array of functions that range widely from their classic anti-tumor and anti-viral cytotoxic effector functions, to their critical regulatory roles in controlling inflammatory immune responses and promoting tissue growth. However, the mechanisms that polarize NK cells to these distinct and opposing functions are incompletely understood. NK cell functional subsets are primarily identified and studied based on phenotype, which has served as an accessible means for profiling NK cells and does offer information on NK cell activation state. However, inconsistencies have emerged in using classic phenotypes to inform function, which raise the questions: Can phenotype in fact define NK cell functional fate? What factors do profile and drive NK cell fate? In other immune cells, cell metabolism has been shown to critically determine subset polarization. There is a growing body of evidence that cell metabolism is integral to NK cell effector functions. Glucose-driven glycolysis and oxidative metabolism have been shown to drive classic NK cell anti-tumor and anti-viral effector functions. Recent studies have uncovered a critical role for metabolism in NK cell development, education, and memory generation. In this review, we will draw on the evidence to date to investigate the relationship between NK cell phenotype, metabolism, and functional fate. We explore a paradigm in which the differential activity of metabolic pathways within NK cells produce distinct metabolic fingerprints that comprehensively distinguish and drive the range of NK cell functional abilities. We will discuss future areas of study that are needed to develop and test this paradigm and suggest strategies to efficiently profile NK cells based on metabolism. Given the emerging role of metabolism in driving NK cell fates, profiling and modulating NK cell metabolism holds profound therapeutic potential to tune inflammatory and regulatory NK cell responses to treat disease.

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Induced Human Decidual NK-Like Cells Improve Utero-Placental Perfusion in Mice

Cited by 20 publications

References 56 publications

Pre-eclampsia: pathogenesis, novel diagnostics and therapies

Pre-eclampsia: pathogenesis, novel diagnostics and therapies

Cytokine-Based Generation of CD49a+Eomes−/+ Natural Killer Cell Subsets

What Defines NK Cell Functional Fate: Phenotype or Metabolism?

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