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Notch2 controls prolactin and insulin-like growth factor binding protein-1 expression in decidualizing human stromal cells of early pregnancy.

ABSTRACT: Decidualization, the transformation of the human uterine mucosa into the endometrium of pregnancy, is critical for successful implantation and embryonic development. However, key regulatory factors controlling differentiation of uterine stromal cells into hormone-secreting decidual cells have not been fully elucidated. Hence, we herein investigated the role of the Notch signaling pathway in human decidual stromal cells (HDSC) isolated from early pregnancy samples. Immunofluorescence of first trimester decidual tissues revealed expression of Notch2 receptor and its putative, membrane-anchored interaction partners Jagged1, Delta-like (DLL) 1 and DLL4 in stromal cells whereas other Notch receptors and ligands were absent from these cells. During in vitro differentiation with estrogen/progesterone (E2P4) and/or cyclic adenosine monophosphate (cAMP) HDSC constitutively expressed Notch2 and weakly downregulated Jagged1 mRNA and protein, measured by quantitative PCR (qPCR) and Western blotting, respectively. However, increased levels of DLL1 and DLL4 were observed in the decidualizing cultures. Transfection of a Notch luciferase reporter and qPCR of the Notch target gene hairy and enhancer of split 1 (HES1) revealed an induction of canonical Notch activity during in vitro differentiation. In contrast, treatment of HDSC with a chemical Notch/?-secretase inhibitor decreased cAMP/E2P4-stimulated Notch luciferase activity, HES1 transcript levels and mRNA expression of the decidual marker genes prolactin (PRL) and insulin-like growth factor binding protein 1 (IGFBP1). Similarly, siRNA-mediated gene silencing or antibody-mediated blocking of Notch2 diminished HES1, PRL and IGFBP1 mRNA levels as well as secreted PRL protein. In summary, the data suggest that canonical, Notch2-dependent signaling plays a role in human decidualization.

SUBMITTER: Otti GR

PROVIDER: S-EPMC4232464 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Notch2 controls prolactin and insulin-like growth factor binding protein-1 expression in decidualizing human stromal cells of early pregnancy.

Otti Gerlinde R GR Saleh Leila L Velicky Philipp P Fiala Christian C Pollheimer Jürgen J Knöfler Martin M

PloS one 20141114 11

Decidualization, the transformation of the human uterine mucosa into the endometrium of pregnancy, is critical for successful implantation and embryonic development. However, key regulatory factors controlling differentiation of uterine stromal cells into hormone-secreting decidual cells have not been fully elucidated. Hence, we herein investigated the role of the Notch signaling pathway in human decidual stromal cells (HDSC) isolated from early pregnancy samples. Immunofluorescence of first tri ...[more]

PMID: 25397403

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Project description:AIMS/HYPOTHESIS:This study aimed to examine changes in the insulin secretory response in early pregnancy, while accounting for changes in insulin sensitivity. METHODS:This is a secondary analysis of a previously conducted longitudinal physiological study. In 34 women, insulin secretory response (by IVGTT) and insulin sensitivity (by euglycaemic clamp) were assessed prior to pregnancy, in early pregnancy (12-14 weeks gestation) and in late pregnancy (34-36 weeks gestation). Using mixed-effects models, we compared insulin secretory response and sensitivity in early pregnancy to the same variables prior to pregnancy and in late pregnancy, with adjustment for age, obesity status and gestational diabetes mellitus (GDM). We examined changes in insulin secretory response after adjustment for insulin sensitivity using both multivariate modelling and the disposition index (DI). We explored the relationship between insulin secretory response and circulating hormones. RESULTS:The insulin secretory response increased from prior to pregnancy to early pregnancy (unadjusted mean [SD] first-phase insulin response 465.1 [268.5] to 720 [358.2], p?<?0.0001) and from early pregnancy to late pregnancy (to 924 [494.6], p?=?0.01). Insulin sensitivity increased from prior to pregnancy to early pregnancy (insulin sensitivity index 0.10 [0.04] to 0.12 [0.05], p?=?0.001) and decreased in late pregnancy (to 0.06 [0.03], p?<?0.0001). Accounting for changes in insulin sensitivity, using either multivariate modelling or the DI, did not attenuate the early-pregnancy augmentation of insulin secretory response. Leptin was positively associated with insulin secretory response, independent of insulin sensitivity and adiposity (p?=?0.004). Adjustment for leptin attenuated the observed augmentation of insulin secretory response in early pregnancy (adjusted mean change 121.5, p?=?0.13). CONCLUSIONS/INTERPRETATION:The insulin secretory response increases markedly in early pregnancy, prior to and independent of changes in insulin sensitivity. Circulating hormones may mediate this metabolic adaptation. Identifying mediators of this physiological effect could have therapeutic implications for treating hyperglycaemia during and outside of pregnancy.

Dataset Information

Notch2 controls prolactin and insulin-like growth factor binding protein-1 expression in decidualizing human stromal cells of early pregnancy.

Publications

Notch2 controls prolactin and insulin-like growth factor binding protein-1 expression in decidualizing human stromal cells of early pregnancy.

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