Human embryonic stem cells as an in vitro model for studying developmental origins of type 2 diabetes

The developmental origins of health and diseases(DOHaD)is a concept stating that adverse intrauterine environments contribute to the health risks of offspring.Since the theory emerged more than 30 years ago,many epidemiological and animal studies have confirmed that in utero exposure to environmental insults,including hyperglycemia and chemicals,increased the risk of developing noncommunicable diseases(NCDs).These NCDs include metabolic syndrome,type 2 diabetes,and complications such as diabetic cardiomyopathy.Studying the effects of different environmental insults on early embryo development would aid in understanding the underlying mechanisms by which these insults promote NCD development.Embryonic stem cells(ESCs)have also been utilized by researchers to study the DOHaD.ESCs have pluripotent characteristics and can be differentiated into almost every cell lineage;therefore,they are excellent in vitro models for studying early developmental events.More importantly,human ESCs(hESCs)are the best alternative to human embryos for research because of ethical concerns.In this review,we will discuss different maternal conditions associated with DOHaD,focusing on the complications of maternal diabetes.Next,we will review the differentiation protocols developed to generate different cell lineages from hESCs.Additionally,we will review how hESCs are utilized as a model for research into the DOHaD.The effects of environmental insults on hESC differentiation and the possible involvement of epigenetic regulation will be discussed.

Maternal low protein diet and fetal programming of lean type 2 diabetes

Maternal nutrition is found to be the key factor that determines fetal health in utero and metabolic health during adulthood.Metabolic diseases have been primarily attributed to impaired maternal nutrition during pregnancy,and impaired nutrition has been an immense issue across the globe.In recent years,type 2 diabetes(T2D)has reached epidemic proportion and is a severe public health problem in many countries.Although plenty of research has already been conducted to tackle T2D which is associated with obesity,little is known regarding the etiology and pathophysiology of lean T2D,a variant of T2D.Recent studies have focused on the effects of epigenetic variation on the contribution of in utero origins of lean T2D,although other mechanisms might also contribute to the pathology.Observational studies in humans and experiments in animals strongly suggest an association between maternal low protein diet and lean T2D phenotype.In addition,clear sex-specific disease prevalence was observed in different studies.Consequently,more research is essential for the understanding of the etiology and pathophysiology of lean T2D,which might help to develop better disease prevention and treatment strategies.This review examines the role of protein insufficiency in the maternal diet as the central driver of the developmental programming of lean T2D.

Maternal high salt-diet increases offspring's blood pressure with dysfunction of NO/PKGI signaling pathway in heart tissue

Background:High salt-diets have become significant threats to human health,resulting in hypertension and cardiovascular diseases.Hypertensive disorders during pregnancy are complicated,since the maternal cardiovascular system undergoes extensive physiological changes during pregnancy.High-salt diets during pregnancy can disturb the intrauterine environment and negatively affect fetal development.Therefore,we explored how high-salt diets during pregnancy could affect the offspring.Methods:Rats were divided into three groups and fed with low,normal,and high salt diets.The offspring were separated into three groups after weaning based on dietary salt concentration.The blood pressure and urine protein content of both dams and offspring were measured.To evaluate cardiac function,we used Masson staining and immunodetection to confirm the fibrosis status.Finally,we extracted protein from cardiac tissue to test the expression levels of the Nitric Oxide(NO)/cGMP-dependent protein kinase I(PKGI)pathway and the angiotensin receptor.Results:High-salt diets increased blood pressure,and offspring previously exposed to high-salt environments were predisposed to hypertension.High-salt diets were also found to induce cardiac fibrosis and exacerbate fibrosis in offspring and alter the epithelial-mesenchymal transition(EMT).Under these conditions,the NO/PKGI pathway was activated in cardiac tissue and the type-1angiotensin II receptor(AT1R)was upregulated,though the type-2 angiotensin II receptor(AT2R)had the opposite effect.Conclusion:High-salt diets induce high blood pressure and increase predisposition to hypertension in offspring.They are accompanied by cardiac fibrosis,which could be caused by the activation of NO/PKGI and upregulation of AT1R.

Postnatal toxicant exposure in 3xTgAD mice promotes gene x environment-related early alterations to neuroimmune epigenetic profiles

Aim:The purpose of this study was to evaluate sex-biased,maladaptive changes to epigenetic regulation critical for development of neuroimmune crosstalk resulting from an early-life toxicant exposure previously associated with increased susceptibility to later-life neurodegeneration.Methods:An evaluation of early-life gene x environment(GxE)interactions was performed in a mouse model of Alzheimer's disease(Tg)orally exposed to lead acetate(Pb)from postnatal day(PND)5-9.Following exposure,immunohistochemical analysis was used to evaluate hippocampal expression of DAP12,a marker for perinatal microglia related to microglial-mediated postnatal synaptic pruning of neurons.Altered profiles of three microRNAs critical to homeostatic microglia:neuron signaling(miR-34a,miR-124,miR-132)were measured by qRT-PCR.Results:Atypical and deleterious expression patterns in Pb-exposed Tg mice were detected with significant female bias by PND 10.Early exposure to Pb resulted in the upregulation of miR-124,a microRNA involved in microglial quiescence,as well as miR-34a,involved in p53-dependent apoptosis and decreased phagocytosis,by PND 21 and during a period of microglial-mediated synaptic pruning specific to females.In addition,we observed a sustained,imbalanced upregulation of miR-132 in Pb-exposed Tg females as well as decreased expression of DAP12.Conclusion:This study demonstrates the exacerbating effects and early manifestation of GxE interactions in this model.Furthermore,these findings underscore a period of female-specific vulnerability to epigenetic maladaptation during postnatal development,with implications on the faulty later-life adaptability of neuroimmune signaling.Further investigation is warranted to evaluate the persistence and relative contribution of these early influences on the etiopathology of Alzheimer's disease.