Maternal iron deficiency perturbs embryonic cardiovascular development in mice.
Ontology highlight
ABSTRACT:
SUBMITTER: Kalisch-Smith JI
PROVIDER: S-EPMC8187484 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Iron deficiency, which occurs when iron demands chronically exceed intake, is prevalent in pregnant women. Iron deficiency during pregnancy poses major risks for the baby, including fetal growth restriction and long-term health complications. The placenta serves as the interface between a pregnant mother and her baby, and it ensures adequate nutrient provisions for the fetus. Thus, maternal iron deficiency may impact fetal growth and development by altering placental function. We used a rat model of diet-induced iron deficiency to investigate changes in placental growth and development. Pregnant Sprague-Dawley rats were fed either a low-iron or iron-replete diet starting 2 weeks before mating. Compared with controls, both maternal and fetal hemoglobin were reduced in dams fed low-iron diets. Iron deficiency decreased fetal liver and body weight, but not brain, heart, or kidney weight. Placental weight was increased in iron deficiency, due primarily to expansion of the placental junctional zone. The stimulatory effect of iron deficiency on junctional zone development was recapitulated in vitro, as exposure of rat trophoblast stem cells to the iron chelator deferoxamine increased differentiation toward junctional zone trophoblast subtypes. Gene expression analysis revealed 464 transcripts changed at least 1.5-fold (P < 0.05) in placentas from iron-deficient dams, including altered expression of genes associated with oxygen transport and lipoprotein metabolism. Expression of genes associated with iron homeostasis was unchanged despite differences in levels of their encoded proteins. Our findings reveal robust changes in placentation during maternal iron deficiency, which could contribute to the increased risk of fetal distress in these pregnancies.
| S-EPMC8559528 | biostudies-literature
Project description:Iron deficiency (ID) is common in patients with cardiovascular disease. Up to 60% of patients with coronary artery disease, and an even higher proportion of those with heart failure (HF) or pulmonary hypertension have ID; the evidence for cerebrovascular disease, aortic stenosis and atrial fibrillation is less robust. The prevalence of ID increases with the severity of cardiac and renal dysfunction and is probably more common amongst women. Insufficient dietary iron, reduced iron absorption due to increases in hepcidin secondary to the low-grade inflammation associated with atherosclerosis and congestion or reduced gastric acidity, and increased blood loss due to anti-thrombotic therapy or gastro-intestinal or renal disease may all cause ID. For older people in the general population and patients with HF with reduced ejection fraction (HFrEF), both anaemia and ID are associated with a poor prognosis; each may confer independent risk. There is growing evidence that ID is an important therapeutic target for patients with HFrEF, even if they do not have anaemia. Whether this is also true for other HF phenotypes or patients with cardiovascular disease in general is currently unknown. Randomized trials showed that intravenous ferric carboxymaltose improved symptoms, health-related quality of life and exercise capacity and reduced hospitalizations for worsening HF in patients with HFrEF and mildly reduced ejection fraction (<50%). Since ID is easy to treat and is effective for patients with HFrEF, such patients should be investigated for possible ID. This recommendation may extend to other populations in the light of evidence from future trials.
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Project description:The formation of clathrin-coated vesicles is essential for intracellular membrane trafficking between subcellular compartments and is triggered by the ARF family of small GTPases. We previously identified SMAP1 as an ARF6 GTPase-activating protein that functions in clathrin-dependent endocytosis. Because abnormalities in clathrin-dependent trafficking are often associated with oncogenesis, we targeted Smap1 in mice to examine its physiological and pathological significance. Smap1-deficent mice exhibited healthy growth, but their erythroblasts showed enhanced transferrin endocytosis. In mast cells cultured in SCF, Smap1 deficiency did not affect the internalization of c-KIT but impaired the sorting of internalized c-KIT from multivesicular bodies to lysosomes, resulting in intracellular accumulation of undegraded c-KIT that was accompanied by enhanced activation of ERK and increased cell growth. Interestingly, approximately 50% of aged Smap1-deficient mice developed anemia associated with morphologically dysplastic cells of erythroid-myeloid lineage, which are hematological abnormalities similar to myelodysplastic syndrome (MDS) in humans. Furthermore, some Smap1-deficient mice developed acute myeloid leukemia (AML) of various subtypes. Collectively, to our knowledge these results provide the first evidence in a mouse model that the deregulation of clathrin-dependent membrane trafficking may be involved in the development of MDS and subsequent AML.
| S-EPMC3582118 | biostudies-other
Project description:Poor iron status is a global health issue, affecting two thirds of the world population to some degree. It is a particular problem among pregnant women, in both developed and developing countries. Feeding pregnant rats a diet deficient in iron is associated with both hypertension and reduced nephron endowment in adult male offspring. However, the mechanistic pathway leading from iron deficiency to fetal kidney development remains elusive. This study aimed to establish the underlying processes associated with iron deficiency by assessing gene and protein expression changes in the rat embryo, focussing on the responses occurring at the time of the nutritional insult. Analysis of microarray data showed that iron deficiency in utero resulted in the significant up-regulation of 979 genes and down-regulation of 1545 genes in male rat embryos (d13). Affected processes associated with these genes included the initiation of mitosis, BAD-mediated apoptosis, the assembly of RNA polymerase II preinitiation complexes and WNT signalling. Proteomic analyses highlighted 7 proteins demonstrating significant up-regulation with iron deficiency and the down-regulation of 11 proteins. The main functions of these key proteins included cell proliferation, protein transport and folding, cytoskeletal remodelling and the proteasome complex. In line with our recent work, which identified the perturbation of the proteasome complex as a generalised response to in utero malnutrition, we propose that iron deficiency alone leads to a more specific failure in correct protein folding and transport. Such an imbalance in this delicate quality-control system can lead to cellular dysfunction and apoptosis. Therefore these findings offer an insight into the underlying mechanisms associated with the development of the embryo during conditions of poor iron status, and its health in adult life.
| S-EPMC3482177 | biostudies-literature
Project description:Rab25, a member of the Rab11 small GTPase family, is central to achieving cellular polarity in epithelial tissues. Rab25 is highly expressed in epithelial cells of various tissues including breast, vagina, cervix, the gastrointestinal tract, and skin. Rab25 plays key roles in tumorigenesis, mainly by regulating epithelial differentiation and proliferation. However, its role in skin physiology is relatively unknown. In this study, we demonstrated that Rab25 knock-out (KO) mice show a skin barrier dysfunction with high trans-epidermal water loss and low cutaneous hydration. To examine this observation, we investigated the histology and epidermal differentiation markers of the skin in Rab25 KO mice. Rab25 KO increased cell proliferation at the basal layer of epidermis, whereas the supra-basal layer remained unaffected. Ceramide, which is a critical lipid component for skin barrier function, was not altered by Rab25 KO in its distribution or amount, as determined by immunohistochemistry. Notably, levels of epidermal differentiation markers, including loricrin, involucrin, and keratins (5, 14, 1, and 10) increased prominently in Rab25 KO mice. In line with this, depletion of Rab25 with single hairpin RNA increased the expression of differentiation markers in a human keratinocyte cell line, HaCaT. Transcriptomic analysis of the skin revealed increased expression of genes associated with skin development, epidermal development, and keratinocyte differentiation in Rab25 KO mice. Collectively, these results suggested that Rab25 is involved in the regulation of epidermal differentiation and proliferation.
| S-EPMC6824620 | biostudies-literature
Project description:Nogo-B receptor (NgBR) was identified as a receptor specific for Nogo-B. Our previous work has shown that Nogo-B and its receptor (NgBR) are essential for chemotaxis and morphogenesis of endothelial cells in vitro and intersomitic vessel formation via Akt pathway in zebrafish. Here, we further demonstrated the roles of NgBR in regulating vasculature development in mouse embryo and primitive blood vessel formation in embryoid body culture systems, respectively. Our results showed that NgBR homozygous knockout mice are embryonically lethal at E7.5 or earlier, and Tie2Cre-mediated endothelial cell-specific NgBR knockout (NgBR ecKO) mice die at E11.5 and have severe blood vessel assembly defects in embryo. In addition, mutant embryos exhibit dilation of cerebral blood vessel, resulting in thin-walled endothelial caverns. The similar vascular defects also were detected in Cdh5(PAC)-CreERT2 NgBR inducible ecKO mice. Murine NgBR gene-targeting embryonic stem cells (ESC) were generated by homologous recombination approaches. Homozygous knockout of NgBR in ESC results in cell apoptosis. Heterozygous knockout of NgBR does not affect ESC cell survival, but reduces the formation and branching of primitive blood vessels in embryoid body culture systems. Mechanistically, NgBR knockdown not only decreases both Nogo-B and VEGF-stimulated endothelial cell migration by abolishing Akt phosphorylation, but also decreases the expression of CCM1 and CCM2 proteins. Furthermore, we performed immunofluorescence (IF) staining of NgBR in human cerebral cavernous malformation patient tissue sections. The quantitative analysis results showed that NgBR expression levels in CD31 positive endothelial cells is significantly decreased in patient tissue sections. These results suggest that NgBR may be one of important genes coordinating the cerebral vasculature development.
| S-EPMC4767500 | biostudies-literature
Project description:BackgroundIron deficiency (ID) in pregnancy is a common problem that can compromise both maternal and fetal health. Although daily iron supplementation is a simple and effective means of treating ID in pregnancy, ID and ID anemia (IDA) often go unrecognized and untreated due to lack of knowledge of their implications and competing clinical priorities.Methods and findingsIn order to enhance screening and management of ID and IDA in pregnancy, we developed a novel quality-improvement toolkit: ID in pregnancy with maternal iron optimization (IRON MOM), implemented at St. Michael's Hospital in Toronto, Canada. It included clinical pathways for diagnosis and management, educational resources for clinicians and patients, templated laboratory requisitions, and standardized oral iron prescriptions. To assess the impact of IRON MOM, we retrospectively extracted laboratory data of all women seen in both the obstetrics clinic and the inpatient delivery ward settings from the electronic patient record (EPR) to compare measures pre- and post-implementation of the toolkit: a process measure of the rates of ferritin testing, and outcome measures of the proportion of women with an antenatal (predelivery) hemoglobin value below 100 g/L (anemia), the proportion of women who received a red blood cell (RBC) transfusion during pregnancy, and the proportion of women who received an RBC transfusion immediately following delivery or in the 8-week postpartum period. The pre-intervention period was from January 2012 to December 2016, and the post-intervention period was from January 2017 to December 2017. From the EPR, 1,292 and 2,400 ferritin tests and 16,603 and 3,282 antenatal hemoglobin results were extracted pre- and post-intervention, respectively. One year after implementation of IRON MOM, we found a 10-fold increase in the rate of ferritin testing in the obstetric clinics at our hospital and a lower risk of antenatal hemoglobin values below 100 g/L (pre-intervention 13.5% [95% confidence interval (CI) 13.0%-14.11%]; post-intervention 10.6% [95% CI 9.6%-11.7%], p < 0.0001). In addition, a significantly lower proportion of women received an RBC transfusion during their pregnancy (1.2% pre-intervention versus 0.8% post-intervention, p = 0.0499) or immediately following delivery and in the 8 weeks following (2.3% pre-intervention versus 1.6% post-intervention, p = 0.0214). Limitations of this study include the use of aggregate data extracted from the EPR, and lack of a control group.ConclusionsThe introduction of a standardized toolkit including diagnostic and management pathways as well as other aids increased ferritin testing and decreased the incidence of anemia among women presenting for delivery at our site. This strategy also resulted in reduced proportions of women receiving RBC transfusion during pregnancy and in the first 8 weeks postpartum. The IRON MOM toolkit is a low-tech strategy that could be easily scaled to other settings.
| S-EPMC6701755 | biostudies-literature
Project description:BackgroundStudies have shown that sperm-borne microRNAs (miRNAs) are involved in mammalian preimplantation embryonic development. In humans, spermatozoan miR-34c levels are correlated with in vitro fertilization outcomes, such as embryo quality and the clinical pregnancy and live birth rates. In rabbits and cows, miR-34c improves the developmental competence of embryos generated by somatic cell nuclear transfer. However, the mechanisms underlying the regulation of embryonic development by miR-34c remain unknown.MethodsFemale C57BL/6 mice (6-8 weeks old) were superovulated, and pronucleated zygotes were collected and microinjected with an miR-34c inhibitor or a negative-control RNA. The embryonic development of the microinjected zygotes was evaluated, and the messenger RNA (mRNA) expression profiles of the embryos at the two-cell, four-cell and blastocyst stages (five embryos per group) were determined by RNA sequencing analysis. Gene expression levels were verified by reverse transcription-quantitative polymerase chain reaction. Cluster analysis and heat map visualization were performed to detect differentially expressed mRNAs. Pathway and process enrichment analyses were performed using ontology resources. Differentially expressed mRNAs were systematically analyzed using the Search Tool for the Retrieval of Interacting Genes/Proteins database to determine their biological functions.ResultsEmbryonic developmental potential was significantly reduced in zygotes microinjected with the miR-34c inhibitor compared with those microinjected with a negative-control RNA. Two-cell stage embryos microinjected with an miR-34c inhibitor presented altered transcriptomic profiles, with upregulated expression of maternal miR-34c target mRNAs and classical maternal mRNAs. Differentially expressed transcripts were mainly of genes associated with lipid metabolism and cellular membrane function at the two-cell stage, with cell-cycle phase transition and energy metabolism at the four-cell stage; and with vesicle organization, lipid biosynthetic process and endomembrane system organization at the blastocyst stage. We also showed that genes related to preimplantation embryonic development, including Alkbh4, Sp1, Mapk14, Sin3a, Sdc1 and Laptm4b, were significantly downregulated after microinjection of an miR-34c inhibitor.ConclusionsSperm-borne miR-34c may regulate preimplantation embryonic development by affecting multiple biological processes, such as maternal mRNA degradation, cellular metabolism, cell proliferation and blastocyst implantation. Our data demonstrate the importance of sperm-derived miRNAs in the development of preimplantation embryos.
| S-EPMC10131327 | biostudies-literature
Project description:Embigin (Gp70), a receptor for fibronectin and an ancillary protein for monocarboxylate transporters, is known to regulate stem cell niches in sebaceous gland and bone marrow. Here, we show that embigin expression is at high level during early mouse embryogenesis and that embigin is essential for lung development. Markedly increased neonatal mortality of Emb-/- mice can be explained by the compromised lung maturation: in Emb-/- mice (E17.5) the number and the size of the small airways and distal airspace are significantly smaller, there are fewer ATI and ATII cells, and the alkaline phosphatase activity in amniotic fluid is lower. Emb-/- lungs show less peripheral branching already at E12.5, and embigin is highly expressed in lung primordium. Thus, embigin function is essential at early pseudoglandular stage or even earlier. Furthermore, our RNA-seq analysis and Ki67 staining results support the idea that the development of Emb-/- lungs is rather delayed than defected.
| S-EPMC10839689 | biostudies-literature
Project description:Iron is important for many cellular functions, including ATP synthesis and cell proliferation. Insufficient of iron in the diet causes iron deficiency anemia (IDA), which often occurs in people living in the world. Since 50% of women with IDA show amenorrhea, the relationship of between iron deficiency and reproductive function was assessed using mice fed a low Fe diet (LFD). The estrous cycle in the LFD mice was blocked at diestrus, which impair follicle development, and fertility. Further, even LFD mice were injected with exogenous pregnant mare serum gonadotropin (PMSG), follicular development was ceased at the secondary follicle stage, and preovulatory follicles were not observed. Amount of ATP decreased in the ovary of the LFD mice, and expression of follicle development markers (Fshr, Cyp19a1, Ccnd2) and estradiol-17β (E2) was low level compared to levels mice fed a normal diet. Feeding a normal diet with sufficient iron to the LFD mice for an additional 3 weeks completely reversed absence the effects of iron insufficient on the estrous cycle and infertility. Thus, iron restriction depresses ovary functions, especially follicular development from secondary follicle to antral follicles and infertility. These effects are fully reversible by supplementation of a normal diet containing iron.
| S-EPMC7593635 | biostudies-literature