Poorly controlled diabetes mellitus alters placental structure, efficiency, and plasticity

Nteeba, Jackson; Varberg, Kaela M.; Scott, Regan L.; Simon, Mikaela E; Iqbal, Khursheed; Soares, Michael J.

doi:10.1136/bmjdrc-2020-001243

Cited by 27 publications

(29 citation statements)

References 51 publications

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“…Animal Care and Treatment Specifications. Holtzman Sprague-Dawley rats were obtained from Envigo and maintained in an environmentally controlled facility with lights on from 0600 to 2000 h with free access to food and water as described previously (53). Virgin female rats (age 8 to 10 wk) were mated with adult male rats (age >3 mo).…”

Section: Methodsmentioning

confidence: 99%

“…Rat TS Cell Culture. Blastocyst-derived rat TS cells (54) were cultured in rat TS cell medium (RPMI 1640, 20% [vol/vol] fetal bovine serum [FBS]; Thermo Fisher Scientific), 100 μm 2-mercaptoethanol (M7522; Sigma-Aldrich), 1 mM sodium pyruvate (11360-070, Thermo Fisher Scientific), 50 μM penicillin (15140122, Thermo Fisher Scientific), and 50 U/mL streptomycin (15140122, Thermo Fisher Scientific) supplemented with 70% rat embryonic fibroblast conditioned medium prepared as described previously (53,54), fibroblast growth factor 4 (FGF4; 25 ng/mL, 100-31; Peprotech), and heparin (1 μg/mL, H3149; Sigma-Aldrich). For induction of differentiation, rat TS cells were cultured for 8 d in rat TS cell medium containing 1% (vol/vol) FBS and without FGF4 and heparin.…”

Section: Methodsmentioning

confidence: 99%

“…RNA Isolation, cDNA Synthesis, and qRT-PCR. Total RNA was isolated from cells and tissues with TRIzol reagent (15596018, Thermo Fisher Scientific) as described previously (53). cDNA was synthesized from 1 μg of total RNA using a High-Capacity cDNA Reverse Transcription Kit (4368813; Thermo Fisher Scientific) and diluted 10 times with water.…”

Section: Methodsmentioning

confidence: 99%

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ASCL2 reciprocally controls key trophoblast lineage decisions during hemochorial placenta development

Varberg

Iqbal

Muto

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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Invasive trophoblast cells are critical to spiral artery remodeling in hemochorial placentation. Insufficient trophoblast cell invasion and vascular remodeling can lead to pregnancy disorders including preeclampsia, preterm birth, and intrauterine growth restriction. Previous studies in mice identified achaete-scute homolog 2 (ASCL2) as essential to extraembryonic development. We hypothesized that ASCL2 is a critical and conserved regulator of invasive trophoblast cell lineage development. In contrast to the mouse, the rat possesses deep intrauterine trophoblast cell invasion and spiral artery remodeling similar to human placentation. In this study, we investigated invasive/extravillous trophoblast (EVT) cell differentiation using human trophoblast stem (TS) cells and a loss-of-function mutant Ascl2 rat model. ASCL2 transcripts are expressed in the EVT column and junctional zone, which represent tissue sources of invasive trophoblast progenitor cells within human and rat placentation sites, respectively. Differentiation of human TS cells into EVT cells resulted in significant up-regulation of ASCL2 and several other transcripts indicative of EVT cell differentiation. Disruption of ASCL2 impaired EVT cell differentiation, as indicated by cell morphology and transcript profiles. RNA sequencing analysis of ASCL2-deficient trophoblast cells identified both down-regulation of EVT cell-associated transcripts and up-regulation of syncytiotrophoblast-associated transcripts, indicative of dual activating and repressing functions. ASCL2 deficiency in the rat impacted placental morphogenesis, resulting in junctional zone dysgenesis and failed intrauterine trophoblast cell invasion. ASCL2 acts as a critical and conserved regulator of invasive trophoblast cell lineage development and a modulator of the syncytiotrophoblast lineage.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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ASCL2 reciprocally controls key trophoblast lineage decisions during hemochorial placenta development

Varberg

Iqbal

Muto

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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“…32 Consequently and in consistent to various other research studies, 25 mM glucose was used in our study to simulate hyperglycemia observed in patients with diabetes. 33,34 It is also evident that type 2 diabetes type 2 diabetes is characterized by a chronic state of low-grade inflammation 35 and metabolic endotoxemia, where increased levels of LPS have commonly observed in patients with type 2 diabetes. 36,37 To replicate the chronic inflammation in ex vivo conditions, we used LPS concentration which has previously been shown to induce acute inflammatory response.…”

Section: Discussionmentioning

confidence: 99%

Potential role of epicardial adipose tissue in coronary artery endothelial cell dysfunction in type 2 diabetes

et al. 2021

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Cardiovascular disease is the most prevalent cause of morbidity and mortality in diabetes. Epicardial adipose tissue (EAT) lies in direct contact with the myocardium and coronary arteries and can influence cardiac (patho) physiology through paracrine signaling pathways. This study hypothesized that the proteins released from EAT represent a critical molecular link between the diabetic state and coronary artery endothelial cell dysfunction. To simulate type 2 diabetes-associated metabolic and inflammatory status in an ex vivo tissue culture model, human EAT samples were treated with a cocktail composed of high glucose, high palmitate, and lipopolysaccharide (gplEAT) and were compared with control EAT (conEAT).Compared to conEAT, gplEAT showed a markedly increased gene expression profile of proinflammatory cytokines, corroborating EAT inflammation, a hallmark feature observed in patients with type 2 diabetes. Luminex assay of EAT-secretome identified increased release of various proinflammatory cytokines, including tumor necrosis factor-alpha (TNF-alpha), interferon-alpha 2 (IFNA2), interleukin 1 beta (IL1B), interleukin 5 (IL5), interleukin 13 (IL13), and CCL5, among others, in response to high glucose, high palmitate, and lipopolysaccharide. Conditioned culture media was used to collect the concentrated proteins (CPs). In response to gplEAT-CPs, human coronary artery endothelial cells (HCAECs) exhibited an inflammatory endothelial cell phenotype, featuring a significantly increased gene expression of proinflammatory cytokines and cell surface expression of VCAM-1.Moreover, gplEAT-CPs severely decreased Akt-eNOS signaling, nitric oxide production, and angiogenic potential of HCAECs, when compared with conEAT-CPs.

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“…Maternal glucose can cross the placenta ( 1 – 5 ) which, in turn, can send signals into the maternal and fetal circulations. The precise nature of these signals and their regulation in response to glucose changes are still unknown ( 6 ). In particular, the mechanisms underlying the regulator effects of hyperglycemia on placental development and growth have not been fully investigated yet.…”

Section: Introductionmentioning

confidence: 99%

Maternal Diabetes Impairs Insulin and IGF-1 Receptor Expression and Signaling in Human Placenta

et al. 2021

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BackgroundMaternal high blood glucose during pregnancy increases the risk for both maternal and fetal adverse outcomes. The mechanisms underlying the regulator effects of hyperglycemia on placental development and growth have not been fully illustrated yet. The placenta expresses high amounts of both insulin receptor (IR) and insulin-like growth factor receptor (IGF-1R). It has been reported that the placenta of diabetic women has structural and functional alterations and the insulin/IGF system is likely to play a role in these changes. The aim of the present study was to measure the content of IR and IGF-1R and their phosphorylation in the placenta of women with type 1 diabetes mellitus (T1D) or with gestational diabetes mellitus (GDM) compared to women with normal glucose tolerance (NGT) during pregnancy.MethodsPlacental tissues were obtained from 80 Caucasian women with a singleton pregnancy. In particular, we collected placenta samples from 20 T1D patients, 20 GDM patients and 40 NGT women during pregnancy. Clinical characteristics and anthropometric measures of all women as well as delivery and newborn characteristics were recorded. Patients were also subdivided on the basis of peripartum glycemia either ≥90 mg/dl or <90 mg/dl, regardless of the diagnosis.ResultsIn T1D patients, a higher rate of adverse outcomes was observed. Compared to the GDM women, the T1D group showed significantly higher average capillary blood glucose levels at the third trimester of pregnancy and at peripartum, and higher third-trimester HbA1c values. In both T1D and GDM women, HbA1c values during pregnancy correlated with glucose values in the peripartum period (R-squared 0.14, p=0.02). A positive correlation was observed between phosphorylation of placental IR and the glucose levels during the third trimester of GDM and T1D pregnancy (R-squared 0.21, p=0.003). In the placenta of T1D patients, IGF-1R phosphorylation and IR isoform A (IR-A) expression were significantly increased (p=0.006 and p=0.040, respectively), compared to the NGT women. Moreover, IGF-1R phosphorylation was significantly increased (p<0.0001) in the placenta of patients with peripartum glucose >90 mg/dl, while IR-A expression was increased in those with peripartum blood glucose higher than 120 mg/dl (p=0.046).ConclusionsTo the best of our knowledge, our study represents the first one in which an increased maternal blood glucose level during pregnancy is associated with an increased IGF-1R phosphorylation and IR-A expression in the placenta. Both these mechanisms can promote an excessive fetal growth.

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Poorly controlled diabetes mellitus alters placental structure, efficiency, and plasticity

Cited by 27 publications

References 51 publications

ASCL2 reciprocally controls key trophoblast lineage decisions during hemochorial placenta development

ASCL2 reciprocally controls key trophoblast lineage decisions during hemochorial placenta development

Potential role of epicardial adipose tissue in coronary artery endothelial cell dysfunction in type 2 diabetes

Maternal Diabetes Impairs Insulin and IGF-1 Receptor Expression and Signaling in Human Placenta

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