Human-induced CD49a+ NK cells promote fetal growth
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PROVIDER: PRJNA765937 | ENA |
REPOSITORIES: ENA
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Project description:CD49a+ natural killer (NK) cells are critical in promoting fetal development and maintaining immune tolerance at the maternal-fetal interface in early pregnancy. However, their tissue residency in human tissue hinder thorough studies and clinical application. How to induce functional human CD49a+ NK cells that could benefit pregnancy outcomes is still unknown. Here, we have established three no feeder cell induction systems to induce human CD49a+ NK cells from umbilical cord blood hematopoietic stem cells (HSCs), bone marrow HSCs or peripheral blood NK cells, respectively. These induced NK cells (iNKs) from three cell induction systems show high expression of CD49a, CD9, CD39, CD151, low expression of CD16, and no obvious cytotoxic capability, phenotypically and functionally similar with decidual NK cells. Furthermore, these iNKs also have high expression of growth-promoting factors and proangiogenic factors. Importantly, these iNKs have shown their capabilities to promote fetal growth and improve uterine artery blood flow in a murine pregnancy model in vivo. This research reveals properties of human-induced CD49a+ NK cells in promoting fetal growth from three cell induction systems, which may improve the feasibility of applying these iNKs to the patients having adverse pregnancy outcomes.
2022-02-23 | GSE184719 | GEO
Project description:Natural killer (NK) cells are present in large populations at the maternal-fetal interface during early pregnancy, but their roles in fetal growth are unclear. Here, we identify a CD49a+Eomes+ subset of NK cells that have the capability to secrete growth-promoting-factors (GPF), including pleiotrophin, osteoglycin and osteopontin in both humans and mice. Decreases in this GPF-secreting NK subset impair fetal development, and leads to fetal growth restriction. The transcriptional factor Nfil3 but not T-bet affects the function and the number of this decidual NK subset. The crosstalk of the HLA-G-ILT2-KIR2DL4 axis promotes the GPF-secreting function of this NK subset. Adoptive transfer of these induced CD49a+Eomes+NK cells can reverse the impaired fetal growth and rebuild an appropriate local microenvironment. These findings reveal new properties of NK cells in promoting fetal growth as well as novel approaches for therapeutically administering NK cells to reverse restricted nourishments within the microenvironment during early pregnancy. To investigate novel molecular signatures of human decidual NK cells, we performed microarray analysis on dNK cells (CD3−CD56+CD49a+CD49b−) and pNK cells (CD3−CD56+CD49a−CD49b+). dNK cells were purified from first-trimester deciduas. pNK cells were purified from adult peripheral blood mononuclear cells. Samples were collected from healthy adult donors after obtaining informed consent according to the Ethics Committee of the University of Science & Technology of China.
2018-01-04 | GSE97217 | GEO
Project description:Perfect fetal development is a solid foundation for successful fertility, in which the abundant natural killer (NK) cells in the decidua tissue at the maternal-fetal interface play an important role during the first trimester. The functional subsets and transcriptional regulation mechanisms of decidual NK (dNK) cells remain poorly understood. Here, we identified CD49a+PBX1+ dNK cells as a unique subset of NK cells that promote fetal development in both human and mice. PBX1 drove the transcription of key functional molecules pleiotrophin and osteoglycin that promote fetal development through direct promoter binding. In patients with unexplained recurrent spontaneous abortion (URSA), decreased expression of PBX1 and PBX1(G21S) mutation correlated with fetal growth restriction and pregnancy failure. Inactivation of Pbx1 in mouse NK cells caused impaired fetal development due to a decrease in growth promoting factors. Our observations reveal the molecular regulation mechanism of CD49a+PBX1+ dNK cells promoting fetal development, and indicate that impaired PBX1 in dNK cells may serve as pathogenesis and biomarker of URSA.
2021-01-01 | GSE110244 | GEO
Project description:Natural killer (NK) cells are lymphocytes that participate in immune responses through their cytotoxic activity and secretion of cytokines and chemokines. They can be activated by interaction with ligands on target cells or by soluble mediators such as cytokines. In addition, soluble HLA-G, a major histocompatibility complex molecule secreted by fetal trophoblast cells during early pregnancy, stimulates resting NK cells to secrete proinflammatory and proangiogenic factors. Human NK cells are abundant in uterus, where they remain after implantation. Soluble HLA-G is endocytosed into early endosomes of NK cells where its receptor, CD158d, initiates a signaling cascade through DNA-PKcs, Akt and NF-kB3. The physiological relevance of this endosomal signaling pathway, and how the fate and function of NK cells during early pregnancy is regulated, is unknown. Here we show that soluble agonists of CD158d trigger DNA damage response signaling and p21 (CIP1/WAF1) expression to promote senescence in primary NK cells. CD158d engagement resulted in morphological alterations in cell size and shape, chromatin remodeling, and survival in the absence of proliferation, all hallmarks of senescence. Microarray analysis revealed a senescence signature of upregulated genes upon sustained activation through CD158d. The proinflammatory and proangiogenic factors secreted by these metabolically active NK cells are part of a senescence associated secretory phenotype (SASP) that promoted tissue remodeling and angiogenesis as assessed by functional readouts of vascular permeability and endothelial cell tube formation. We propose that ligand-induced senescence is a molecular switch for the sustained activation of NK cells in response to soluble HLA-G for the purpose of remodeling the maternal vasculature in early pregnancy. Time series (4 hr, 16 hr, 64 hr) of NK cells treated with agonist (anti-CD158d mAb) or control. NK cells were from 4 donors.
2012-12-03 | E-GEOD-35330 | biostudies-arrayexpress
Project description:Quantification of proteins in the pancreas of fetal growth restriction.
2022-06-07 | PXD026502 | JPOST Repository
Project description:Natural killer (NK) cells are lymphocytes that participate in immune responses through their cytotoxic activity and secretion of cytokines and chemokines. They can be activated by interaction with ligands on target cells or by soluble mediators such as cytokines. In addition, soluble HLA-G, a major histocompatibility complex molecule secreted by fetal trophoblast cells during early pregnancy, stimulates resting NK cells to secrete proinflammatory and proangiogenic factors. Human NK cells are abundant in uterus, where they remain after implantation. Soluble HLA-G is endocytosed into early endosomes of NK cells where its receptor, CD158d, initiates a signaling cascade through DNA-PKcs, Akt and NF-kB3. The physiological relevance of this endosomal signaling pathway, and how the fate and function of NK cells during early pregnancy is regulated, is unknown. Here we show that soluble agonists of CD158d trigger DNA damage response signaling and p21 (CIP1/WAF1) expression to promote senescence in primary NK cells. CD158d engagement resulted in morphological alterations in cell size and shape, chromatin remodeling, and survival in the absence of proliferation, all hallmarks of senescence. Microarray analysis revealed a senescence signature of upregulated genes upon sustained activation through CD158d. The proinflammatory and proangiogenic factors secreted by these metabolically active NK cells are part of a senescence associated secretory phenotype (SASP) that promoted tissue remodeling and angiogenesis as assessed by functional readouts of vascular permeability and endothelial cell tube formation. We propose that ligand-induced senescence is a molecular switch for the sustained activation of NK cells in response to soluble HLA-G for the purpose of remodeling the maternal vasculature in early pregnancy.
2012-12-03 | GSE35330 | GEO
Project description:NK cells may acquire under certain conditions features of adaptive immune cells. As the functional role of memory NK cells in cancer has so far remained elusive, we reasoned whether tumor-priming itself might promote memory NK cell generation. We provide substantial evidence that independent from pro-inflammatory stimulation, tumor-induced memory-like (TIML) NK cells exhibit a heightened, tumor-restricted cytotoxicity which is dependent on a higher/faster perforin but not IFN-γ release. Comparative transcriptome analysis reveals that gene expression patterns differ between TIML- and Cytokine-induced memory-like (CIML)-NK cells.
2016-04-15 | E-MTAB-4606 | biostudies-arrayexpress
Project description:Fetal growth restriction (FGR) affects 5-10% of pregnancies worldwide, and can have serious consequences for both mother and child. Both preventative and treatment strategies are currently largely lacking due to a poor understanding of the pathogenesis of FGR. There is strong genetic evidence for the involvement of KIR and HLA genes in FGR, however, the specific HLA and KIR risk alleles and their functional effects have been difficult to map due to linkage disequilibrium, maternal and paternal influence, and an inability to investigate pathological human pregnancies at critical early gestational stages. Here we demonstrate that the interaction between two defined genes, the maternal KIR2DL1 expressed on uterine natural killer (NK) cells, and the paternally-inherited HLA-C*0501, expressed on fetal trophoblast cells, leads to FGR in a humanised mouse model. We show that the initial KIR2DL1 and C*0501 interaction leads to pathogenic uterine arterial remodeling and a modulation of uterine NK cell function. We delineate how this initial effect cascades to changes in transcriptional expression and intercellular communication in a myriad of cell types and pathways at the maternal-fetal interface. These findings reveal new mechanistic insight into the importance of specific KIR and HLA risk alleles in FGR, and provide new avenues of prevention and treatment to reduce disease burden and improve long-term health outcomes of the child.
2022-05-20 | GSE202983 | GEO
Project description:DYRK2 knockout mice exhibit fetal growth retardation
| PRJNA611501 | ENA
Project description:Cytokine induced NK memory transcriptional profile characterization
| PRJNA504634 | ENA