Fetal Programming Research Articles

The Uptake of Partner Participation in Sequential Preconception Carrier Screening

Introduction: Carrier screening that is performed in the preconception period allows for couples at risk for having children affected with certain single gene (Mendelian) conditions to be identified. This is the most optimal timeframe to perform such screening. Most obstetric providers utilize a sequential process in which the patient first undergoes screening and their partner is only offered testing if the initial results reveal that the first is a carrier for one or more autosomal recessive (AR) deleterious variants. If the partner fails to undergo screening, the couple cannot obtain meaningful and actionable risk information for future or current pregnancies. In this study, we sought to assess the frequency of completed carrier screening risk assessment among individuals and couples who were undergoing preconception screening at two prenatal screening programs staffed by genetic counselors and geneticists. Materials and Methods: We reviewed the screening outcomes for individuals and couples who presented for preconception carrier screening from January 1, 2020 through December 30, 2021 at Insight Medical Genetics and the clinical genetics program at Northwestern Medicine. All individuals received pretest genetic counseling prior to screening and posttest counseling after results were available. We evaluated individuals who were found to be a carrier of at least one deleterious variant and whether the partner of that person underwent carrier screening, and, if so, which type of screening. Results: 548 patients who identified as women underwent preconception carrier screening during the study period, along with 3 men presenting for initial screening. These screens consisted of a panel containing primarily autosomal recessive conditions with a few X-linked conditions. 247 individuals (45.1%) were positive for at least one pathogenic variant; of these, 244 (98.8%) were variants in genes associated with autosomal recessive conditions. A total of 219 partners (88.7%) underwent carrier screening, including the 3 female partners of the men who initiated carrier screening. Of note, 4 of the patients who underwent carrier screening reported not having a partner at the time of screening; accordingly, the partners who underwent screening represent 89.8% of individuals eligible for partner screening following an initial positive result. Of the 219 partners who underwent carrier screening, 201 (91.8%) chose a carrier screening panel of 150+ conditions, while 18 chose a more limited panel that included the gene(s) of relevance based on their partner’s results, with or without additional genes relevant to their learned/self-identified ethnicity or race. Conclusions: Approximately 10% of couples presenting for preconception genetic counseling and carrier screening found to be at potential risk for a child with an autosomal recessive condition did not obtain the requisite information to fully assess their risk of having an affected child. It is possible that the frequency of couples who do not obtain complete and actionable screening information is even higher when carrier screening is provided without the assistance of certified genetic counselors or geneticists. Recently, cell free DNA-based maternal screening has been introduced that assesses the risk for a limited number of genetic conditions in the fetus that may not require assessment of the partner. Nonetheless, providers must communicate to their patients that meaningful risk information can only be obtained when the partner undergoes screening in cases where the initial member of the couple is found to be a carrier of at least one autosomal recessive condition. Laboratories and professional societies need to develop effective educational outreach to patients and providers alike to improve the screening process for couples who want to determine if they are at risk to have a child with an inherited condition.

Pemberdayaan Ibu Hamil dan Kader Kesehatan dalam Penerapan Program Stimulasi Pralahir

Delays in a child's growth and development can be caused by a lack of stimulation. Some pregnant women do not know, do not realize and have a bad attitude in providing prenatal stimulation. Not all health service facilities provide classes for pregnant women that are equipped with prenatal stimulation programs. Even though parents play an important role in providing stimulation since the fetus is in the womb. Providing prenatal stimulation supports the child's growth and development after birth. Based on this urgency, there is a need for training for pregnant women and health cadres. The aim of this community service is to increase knowledge, awareness and ability of pregnant women in providing prenatal stimulation, as well as increasing community participation in supporting the implementation of prenatal stimulation programs. The results showed an increase in the knowledge aspect of 27.28 points, with an average pre-test score of 64.54 (fair category), post- test 91.82 (good category). The average ability to perform prenatal stimulation was in the good category (94.55). These results show that this training can increase participants' knowledge and abilities in carrying out prenatal stimulation programs.

One Size Does Not Fit All: A Multifaceted Approach to Educate Families about Newborn Screening.

All families deserve access to readily available, accurate, and relevant information to help them navigate the newborn screening system. Current practices, limited resources, and a siloed newborn screening system create numerous challenges for both providers and families to implement educational opportunities to engage families in ways that meet their needs with relevant and meaningful approaches. Engaging families in newborn screening, especially those from historically underserved communities, is necessary to increase knowledge and confidence which leads to overall improved outcomes for families. This article describes three strategies that the Navigate Newborn Screening Program developed, tested, and implemented in the United States, including online learning modules, a prenatal education pilot program, and social media awareness campaign, as well as the extent to which they were successful in reaching and educating families about newborn screening. Using quality improvement methods and evidence-driven approaches, each of these three strategies demonstrate promising practices for advancing awareness, knowledge, and self-efficacy for families navigating the newborn screening system-particularly families in medically underserved and underrepresented communities. A model for bidirectional engagement of families is outlined to support scaling and implementing promising educational efforts for both providers and families in the newborn screening system.

Maternal SARS-CoV-2 impacts fetal placental macrophage programs and placenta-derived microglial models of neurodevelopment

BackgroundThe SARS-CoV-2 virus activates maternal and placental immune responses. Such activation in the setting of other infections during pregnancy is known to impact fetal brain development. The effects of maternal immune activation on neurodevelopment are mediated at least in part by fetal brain microglia. However, microglia are inaccessible for direct analysis, and there are no validated non-invasive surrogate models to evaluate in utero microglial priming and function. We have previously demonstrated shared transcriptional programs between microglia and Hofbauer cells (HBCs, or fetal placental macrophages) in mouse models.Methods and resultsWe assessed the impact of maternal SARS-CoV-2 on HBCs isolated from 24 term placentas (N = 10 SARS-CoV-2 positive cases, 14 negative controls). Using single-cell RNA-sequencing, we demonstrated that HBC subpopulations exhibit distinct cellular programs, with specific subpopulations differentially impacted by SARS-CoV-2. Assessment of differentially expressed genes implied impaired phagocytosis, a key function of both HBCs and microglia, in some subclusters. Leveraging previously validated models of microglial synaptic pruning, we showed that HBCs isolated from placentas of SARS-CoV-2 positive pregnancies can be transdifferentiated into microglia-like cells (HBC-iMGs), with impaired synaptic pruning behavior compared to HBC models from negative controls.ConclusionThese findings suggest that HBCs isolated at birth can be used to create personalized cellular models of offspring microglial programming.

A Review of Fetal Development in Pregnancies with Maternal Type 2 Diabetes Mellitus (T2DM)-Associated Hypothalamic-Pituitary-Adrenal (HPA) Axis Dysregulation: Possible Links to Pregestational Prediabetes.

Research has identified fetal risk factors for adult diseases, forming the basis for the Developmental Origins of Health and Disease (DOHaD) hypothesis. DOHaD suggests that maternal insults during pregnancy cause structural and functional changes in fetal organs, increasing the risk of chronic diseases like type 2 diabetes mellitus (T2DM) in adulthood. It is proposed that altered maternal physiology, such as increased glucocorticoid (GC) levels associated with a dysregulated hypothalamic-pituitary-adrenal (HPA) axis in maternal stress and T2DM during pregnancy, exposes the fetus to excess GC. Prenatal glucocorticoid exposure reduces fetal growth and programs the fetal HPA axis, permanently altering its activity into adulthood. This programmed HPA axis is linked to increased risks of hypertension, cardiovascular diseases, and mental disorders in adulthood. With the global rise in T2DM, particularly among young adults of reproductive age, it is crucial to prevent its onset. T2DM is often preceded by a prediabetic state, a condition that does not show any symptoms, causing many to unknowingly progress to T2DM. Studying prediabetes is essential, as it is a reversible stage that may help prevent T2DM-related pregnancy complications. The existing literature focuses on HPA axis dysregulation in T2DM pregnancies and its link to fetal programming. However, the effects of prediabetes on HPA axis function, specifically glucocorticoid in pregnancy and fetal outcomes, are not well understood. This review consolidates research on T2DM during pregnancy, its impact on fetal programming via the HPA axis, and possible links with pregestational prediabetes.

Stress response to social isolation followed by exposure to a novel object in aged ewes born to undernourished mothers

Fetal programming by subnutrition affects offspring’s behaviour, metabolism, and sensitivity to stressors in sheep. The objective was to determine the stress response of ewes born to mothers nutritionally restricted during gestation to social isolation followed by exposure to a novel object. Twenty-six-year-old Corriedale ewes born to mothers who grazed high or low pasture allowances (HPA and LPA groups) from 23 days before conception until 122 days of gestation were used. Ewes were individually isolated in a novel place for 10 min, and 5 min after its beginning, an orange ball was dropped into the test pen. The ewes’ behaviours were recorded during the test. Blood proteins, glucose and cortisol concentrations, heart and respiratory rates and rectal and surface temperatures were determined. The number of times looking at the ball tended to be greater in HPA ewes than LPA (6.7 ± 1.0 vs 4.7 ± 0.8, P = 0.08). The LPA ewes had greater serum albumin concentration than HPA ewes (3.2 ± 0.1 g/dL vs 3.0 ± 0.1 g/dL, P = 0.02), regardless of the applied stressors. Overall, the nutritional treatments applied to ewes during their intrauterine development did not modify the stress responses to social isolation followed by exposure to a novel object.

Fetal programming and lactation: modulating gene expression in response to undernutrition during intrauterine life.

Adverse environmental conditions during intrauterine life, known as fetal programming, significantly contribute to the development of diseases in adulthood. Fetal programming induced by factors like maternal undernutrition leads to low birth weight and increases the risk of cardiometabolic diseases. We studied a rat model of maternal undernutrition during gestation (MUN) to investigate gene expression changes in cardiac tissue using RNA-sequencing of day 0-1 litters. Moreover, we analyzed the impact of lactation at day 21, in MUN model and cross-fostering experiments, on cardiac structure and function assessed by transthoracic echocardiography, and gene expression changes though qPCR. Our analysis identified specific genes with altered expression in MUN rats at birth. Two of them, Agt and Pparg, stand out for being associated with cardiac hypertrophy and fibrosis. At the end of the lactation period, MUN males showed increased expression of Agt and decreased expression of Pparg, correlating with cardiac hypertrophy. Cross-fostering experiments revealed that lactation with control breastmilk mitigated these expression changes reducing cardiac hypertrophy in MUN males. Our findings highlight the interplay between fetal programming, gene expression, and cardiac hypertrophy suggesting that lactation period is a potential intervention window to mitigate the effects of fetal programming. Heart remodeling involves the alteration of several groups of genes and lactation period plays a key role in establishing gene expression modification caused by fetal programming. We could identify expression changes of relevant genes in cardiac tissue induced by undernutrition during fetal life. We expose the contribution of the lactation period in modulating the expression of Agt and Pparg, relevant genes associated with cardiac hypertrophy. This evidence reveal lactation as a crucial intervention window for preventing or countering fetal programming.

Impact of no publicly accessible prenatal education programming on patients and their care providers: a descriptive qualitative study in Nova Scotia, Canada

ObjectivePatients in Nova Scotia do not have access to public prenatal education programming. This study aimed to explore whether care providers find patients are uninformed or misinformed, and the impact...

Stage specific effects of insulin and Wnt on cell fate decisions in human induced pluripotent stem cell-derived cardiomyocytes

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Dutch Heart Foundation Background Reactivation of the so-called fetal gene programs and pathways have been reported in failing hearts, however, it remains unclear whether this phenomenon is beneficial or detrimental to the remaining functional myocardium. During cardiac development, the orchestration of these embryonic growth pathways, facilitate temporal and stage-specific cell fate decisions such as required for specification and growth of the various myocardial compartments. Previously, we demonstrated that molecular activation of the Wnt pathway resulted in massive expansion of immature human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Yet, it is unknown what exact cues guide the cell fate decisions of immature hiPSC-CMs to either proliferate or terminally differentiate into more mature cardiomyocytes. Purpose This work uncovers the embryonic growth pathways that control the cues for proliferation versus terminal differentiation in functional immature hiPSC-CMs. Methods We utilised spontaneously beating hiPSC-CMs at day 11 of differentiation and performed a combinatory screen for various dosages of CHIR99021/Wnt and Insulin/Akt pathway. Proliferation was determined by quantification of cell number and the proportion of Ki67 positive hiPSC-CMs. Terminal differentiation was evaluated by presence of more mature sarcomere markers and cell cycle exit. Results Our combinatory screen for Insulin/Akt and CHIR99021/Wnt demonstrates synergistic effects on proliferation of immature hiPSC-CMs, whereas the absence of these pathway activators leads to rapid cell cycle exit and terminal differentiation of hiPSC-CMs. Detailed characterization reveals that CHIR99021/Wnt also importantly regulates sarcomere homeostasis and architecture in hiPSC-CMs. Moreover, we identify a novel temporal interplay between CHIR99021/Wnt via TCF and Insulin/Akt via FOXO as regulators of cell-fate decision in immature hiPSC-CMs. Conclusions Molecular targeting of the embryonic growth pathways in acute and chronic forms of heart failure requires a detailed understanding of the specific effects on cardiomyocyte function and sarcomere architecture. This work provides a starting point to develop future strategies to target acute and chronic forms of heart failure via modulation of embryonic growth pathways.Graphical Summary

Effects of Low and High Maternal Protein Intake on Fetal Skeletal Muscle miRNAome in Sheep.

Prenatal maternal feeding plays an important role in fetal development and has the potential to induce long-lasting epigenetic modifications. MicroRNAs (miRNAs) are non-coding, single-stranded RNAs that serve as one epigenetic mechanism. Though miRNAs have crucial roles in fetal programming, growth, and development, there is limited data regarding the maternal diet and miRNA expression in sheep. Therefore, we analyzed high and low maternal dietary protein for miRNA expression in fetal longissimus dorsi. Pregnant ewes were fed an isoenergetic high-protein (HP, 160-270 g/day), low-protein (LP, 73-112 g/day), or standard-protein diet (SP, 119-198 g/day) during pregnancy. miRNA expression profiles were evaluated using the Affymetrix GeneChip miRNA 4.0 Array. Twelve up-regulated, differentially expressed miRNAs (DE miRNAs) were identified which are targeting 65 genes. The oar-3957-5p miRNA was highly up-regulated in the LP and SP compared to the HP. Previous transcriptome analysis identified that integrin and non-receptor protein tyrosine phosphatase genes targeted by miRNAs were detected in the current experiment. A total of 28 GO terms and 10 pathway-based gene sets were significantly (padj < 0.05) enriched in the target genes. Most genes targeted by the identified miRNAs are involved in immune and muscle disease pathways. Our study demonstrated that dietary protein intake during pregnancy affected fetal skeletal muscle epigenetics via miRNA expression.

New ideas about the maternal gut microbiome as a source of fetal programming

New genetic technologies that have emerged and been introduced into practice over the past 20 years, including 16s rRNA sequencing, have significantly expanded our understanding of the microbial composition of the human body. The gut is one of the most densely populated microbial niches in the human body. Numerous studies have shown the relationship of the gut microbiome with various non-communicable diseases, including diabetes mellitus, obesity, allergies and even mental disorders. The perinatal period, as one of the most hormonally dependent ones in human ontogenesis, has a direct impact on the composition of the intestinal microbiota, just as the microbiota itself can be a precursor and etiological cause of pregnancy complications. In this regard, the aim of this review article was to systematize data on the gut microbiota of the maternal body in normal and pathological pregnancy, as well as to analyze data on the interaction of the maternal gut microbiome with the fetal immune system. The review presents data on changes in the maternal intestinal microbiome in normal pregnancy, during infertility, as well as in pregnancy complicated with obesity, gestational diabetes mellitus and preeclampsia. The review also shows how the maternal microbiome is able to “educate” the fetal immune system in utero, thereby preparing the child, who develops in a sterile womb, for extrauterine life surrounded by a large number of various microorganisms. These mechanisms include the direct effect of not only the microorganisms themselves, but also, even largely, their metabolites — primarily short-chain fatty acids. All these presented data allow for concluding that the maternal microbiome is essentially a separate regulatory homeostatic system, along with the immune, endocrine and cardiovascular systems, which may determine the development of certain complications of pregnancy and shape the health of the unborn child. Interventions in the composition of the maternal gut microbiota may be a way to modulate the course of pregnancy and prevent major obstetric syndromes.

#2605 Evaluation of cardiac fetal gene program in experimental uremia

Abstract Background and Aims Heart failure (HF) and uremia share several potent cardiac hypertrophic stimuli such as wall stress, sympathetic activation, renin angiotensin system activation and oxidative stress. In heart failure, induction of fetal gene program is one of the major processes through which such stimuli lead to progressive pathological hypertrophy and myocardial dysfunction. The fetal genes are activated by the transcription factor, myocyte enhance factor 2 (MEF2) which is a downstream target of the Ca++- Calmodulin Dependent Kinase II (CAMKII) pathway. The CAMKII pathway has been shown to be the major transduction pathway of the hypertrophic stimuli in HF [1, 2]. We hosphorzed that such mechanisms are also at play in uremic cardiomyopathy and tested the hypothesis in a rodent model of experimental uremia. Method Wistar rats (n = 18) had subtotal nephrectomy (STNx) or sham surgery (sham) and were followed up for 10 weeks. In vivo and in vitro cardiac assessments were performed. Cardiac tissue was extracted, and protein expression of CAMKII and hosphor-CAMKII were quantified using immunoblotting. Protein expression of MEF2 and its target fetal genes were also studied. Histological analyses were performed to quantify myocardial fibrosis. Data was analysed using an independent sample t-test with Welch's correction and expressed as mean± SEM. Results STNx resulted in higher echocardiographic left ventricular mass, heart weight to tibia length ratio and myocardial fibrosis in the STNx group (Fig. 1) demonstrating cardiac pathological hypertrophy. CaMKII signalling was activated and the expression of MEF2 was also increased following STNx (Fig. 1). There was trend towards increased expression of fetal genes (Fig. 1). However, the difference did not reach statistical significance. Conclusion The study shows that experimental uremia induces cardiac pathological hypertrophy along with activation of intracellular pathways involved in fetal gene induction. Further studies evaluating fetal genes at an earlier time course in the evolution of pathological hypertrophy will be worthwhile.

Integrative analysis of transcriptome, DNA methylome, and chromatin accessibility reveals candidate therapeutic targets in hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is the most common inherited heart disease and is characterized by primary left ventricular hypertrophy usually caused by mutations in sarcomere genes. The mechanism underlying cardiac remodeling in HCM remains incompletely understood. An investigation of HCM through integrative analysis at multi-omics levels will be helpful for treating HCM. DNA methylation and chromatin accessibility, as well as gene expression, were assessed by nucleosome occupancy and methylome sequencing (NOMe-seq) and RNA-seq, respectively, using the cardiac tissues of HCM patients. Compared with those of the controls, the transcriptome, DNA methylome, and chromatin accessibility of the HCM myocardium showed multifaceted differences. At the transcriptome level, HCM hearts returned to the fetal gene program through decreased sarcomeric and metabolic gene expression and increased extracellular matrix gene expression. In the DNA methylome, hypermethylated and hypomethylated differentially methylated regions were identified in HCM. At the chromatin accessibility level, HCM hearts showed changes in different genome elements. Several transcription factors, including SP1 and EGR1, exhibited a fetal-like pattern of binding motifs in nucleosome-depleted regions in HCM. In particular, the inhibition of SP1 or EGR1 in an HCM mouse model harboring sarcomere mutations markedly alleviated the HCM phenotype of the mutant mice and reversed fetal gene reprogramming. Overall, this study not only provides a high-precision multi-omics map of HCM heart tissue but also sheds light on the therapeutic strategy by intervening in the fetal gene reprogramming in HCM.

Impact of Gut–Brain Axis on Hepatobiliary Diseases in Fetal Programming

The hepatobiliary system is vital for the biotransformation and disposition of endogenous molecules. Any impairment in the normal functioning of the hepatobiliary system leads to a spectrum of hepatobiliary diseases (HBDs), such as liver cirrhosis, fatty liver, biliary dyskinesia, gallbladder cancer, etc. Especially in pregnancy, HBD may result in increased maternal and fetal morbidity and mortality. Maternal HBD is a burden to the fetus’s growth, complicates fetal development, and risks the mother’s life. In fetal programming, the maternal mechanism is significantly disturbed by multiple factors (especially diet) that influence the development of the fetus and increase the frequency of metabolic diseases later in life. Additionally, maternal under-nutrition or over-nutrition (especially in high-fat, high-carbohydrate, or protein-rich diets) lead to dysregulation in gut hormones (CCK, GLP-1, etc.), microbiota metabolite production (SCFA, LPS, TMA, etc.), neurotransmitters (POMC, NPY, etc.), and hepatobiliary signaling (insulin resistance, TNF-a, SREBPs, etc.), which significantly impact fetal programming. Recently, biotherapeutics have provided a new horizon for treating HBD during fetal programming to save the lives of the mother and fetus. This review focuses on how maternal impaired hepatobiliary metabolic signaling leads to disease transmission to the fetus mediated through the gut–brain axis.

Pregestational Prediabetes Induces Maternal Hypothalamic-Pituitary-Adrenal (HPA) Axis Dysregulation and Results in Adverse Foetal Outcomes.

Maternal type 2 diabetes mellitus (T2DM) has been shown to result in foetal programming of the hypothalamic-pituitary-adrenal (HPA) axis, leading to adverse foetal outcomes. T2DM is preceded by prediabetes and shares similar pathophysiological complications. However, no studies have investigated the effects of maternal prediabetes on foetal HPA axis function and postnatal offspring development. Hence, this study investigated the effects of pregestational prediabetes on maternal HPA axis function and postnatal offspring development. Pre-diabetic (PD) and non-pre-diabetic (NPD) female Sprague Dawley rats were mated with non-prediabetic males. After gestation, male pups born from the PD and NPD groups were collected. Markers of HPA axis function, adrenocorticotropin hormone (ACTH) and corticosterone, were measured in all dams and pups. Glucose tolerance, insulin and gene expressions of mineralocorticoid (MR) and glucocorticoid (GR) receptors were further measured in all pups at birth and their developmental milestones. The results demonstrated increased basal concentrations of ACTH and corticosterone in the dams from the PD group by comparison to NPD. Furthermore, the results show an increase basal ACTH and corticosterone concentrations, disturbed MR and GR gene expression, glucose intolerance and insulin resistance assessed via the Homeostasis Model Assessment (HOMA) indices in the pups born from the PD group compared to NPD group at all developmental milestones. These observations reveal that pregestational prediabetes is associated with maternal dysregulation of the HPA axis, impacting offspring HPA axis development along with impaired glucose handling.

A randomized comparative-effectiveness study of two enhanced prenatal care models for low-income pregnant people: Engaging Mothers & Babies; Reimagining Antenatal Care for Everyone (EMBRACE)

BackgroundImproving perinatal mental health and care experiences and preventing adverse maternal and infant outcomes are essential prenatal care components, yet existing services often miss the mark, particularly for low-income populations. An enhanced group prenatal care program, “Glow! Group Prenatal Care and Support,” was developed in California's Central Valley in response to poor perinatal mental health, disrespectful care experiences, and high rates of adverse birth outcomes among families with low incomes. MethodsEngaging Mothers & Babies; Reimagining Antenatal Care for Everyone (EMBRACE) is a pragmatic, two-arm, randomized, comparative-effectiveness study designed to assess depression (primary outcome), the experience of care (secondary outcome), and preterm birth (exploratory outcome) among Medi-Cal (California's Medicaid program)-eligible pregnant and birthing people, comparing those assigned to Glow! Group Prenatal Care and Support (Glow/GC) with those assigned to enhanced, individual prenatal care through the California Department of Public Health's Comprehensive Perinatal Services Program (CPSP/IC). Participating clinical practices offer the two comparators, alternating between comparators every 6 weeks, with the starting comparator randomized at the practice level. Participant-reported outcomes are assessed through interviewer-administered surveys at study entry, during the participant's third trimester, and at 3 months postpartum; preterm birth and other clinical outcomes are abstracted from labor and delivery records. Patient care experiences are further assessed in qualitative interviews. The protocol complies with the Standard Protocol Items for Randomized Trials. ConclusionsThis comparative-effectiveness study will be used to determine which of two forms of enhanced prenatal care is more effective, informing future decisions regarding their use.Trial Registration: ClinicalTrials.gov: NCT04154423.

Foetal programming in sheep: Reproductive and productive implications

The aim of this study was to evaluate the effects of pregnant ewe nutrition on the performance of offspring in terms of meat, wool production, and reproduction. Foetal programming in sheep has focused on several aspects related to foetal growth, postnatal production, behaviour, and immunological performance. Currently, significant efforts are being made to understand the endocrine, metabolic, and epigenetic mechanisms involved in offspring development. Current studies have not only evaluated the foetal period, despite the pre-conception parental nutrition has demonstrated an effect on the foetal, embryonic, and pre-implantation periods and can generate permanent effects in the foetal and postnatal phases. The performance of offspring is the result of interactions between the genome, epigenome, and environmental interventions during conception. Several factors influence the expression of phenotypic characteristics in progenies; however, this study focused on presenting data on the effect of pregnant ewe nutrition alone on foetal growth and the productive aspects of their offspring.

Primitive macrophages induce sarcomeric maturation and functional enhancement of developing human cardiac microtissues via efferocytic pathways.

Yolk sac macrophages are the first to seed the developing heart, however we have no understanding of their roles in human heart development and function due to a lack of accessible tissue. Here, we bridge this gap by differentiating human embryonic stem cells (hESCs) into primitive LYVE1+ macrophages (hESC-macrophages) that stably engraft within contractile cardiac microtissues composed of hESC-cardiomyocytes and fibroblasts. Engraftment induces a human fetal cardiac macrophage gene program enriched in efferocytic pathways. Functionally, hESC-macrophages trigger cardiomyocyte sarcomeric protein maturation, enhance contractile force and improve relaxation kinetics. Mechanistically, hESC-macrophages engage in phosphatidylserine dependent ingestion of apoptotic cardiomyocyte cargo, which reduces microtissue stress, leading hESC-cardiomyocytes to more closely resemble early human fetal ventricular cardiomyocytes, both transcriptionally and metabolically. Inhibiting hESC-macrophage efferocytosis impairs sarcomeric protein maturation and reduces cardiac microtissue function. Taken together, macrophage-engineered human cardiac microtissues represent a considerably improved model for human heart development, and reveal a major beneficial role for human primitive macrophages in enhancing early cardiac tissue function.

Childhood atopic disorders in relation to placental changes-A systematic review and meta-analysis.

Fetal programming may arise from prenatal exposure and increase the risk of diseases later in life, potentially mediated by the placenta. The objective of this systematic review was to summarize and critically evaluate publications describing associations between human placental changes and risk of atopic disorders during childhood. The review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines. The inclusion criteria were original research articles or case reports written in English describing a human placental change in relation to disease occurring in offspring during childhood. The MEDLINE and EMBASE databases were searched for eligible studies. Risk of bias (RoB) was assessed using the ROBINS-I tool. The results were pooled both in a narrative way and by a meta-analysis. Nineteen studies were included (n = 12,997 participants). All studies had an overall serious RoB, and publication bias could not be completely ruled out. However, five studies showed that histological chorioamnionitis in preterm-born children was associated with asthma-related problems (pooled odds ratio = 3.25 (95% confidence interval = 2.22-4.75)). In term-born children, a large placenta (≥750 g) increased the risk of being prescribed anti-asthma medications during the first year of life. Placental histone acetylation, DNA methylation, and gene expression differences were found to be associated with different atopic disorders in term-born children. There is some evidence supporting the idea that the placenta can mediate an increased risk of atopic disorders in children. However, further studies are needed to validate the findings, properly control for confounders, and examine potential mechanisms.

AJAP1 Regulates Human Epithelial Cell Behaviors Required for Epicardium and EPDC Formation During Cardiac Development

Introduction: The epicardium forms the outermost layer of the heart. It is composed of a single layer of specialized epithelial cells that make important cellular contributions to cardiovascular development. During embryonic development, the epicardium is a source of multipotent progenitor cells, growth factors and extracellular matrix (ECM) components. The epicardium gives rise to multipotent epicardial-derived cells (EPDCs) which undergo epithelial-to-mesenchymal transition and differentiate into non-myocyte cardiac lineages. It is also a source of paracrine signals essential for myocardial growth and coronary vessel formation that become dormant after gestation. Adult epicardial cells can be reactivated in response to myocardial injury or ischemia to express a fetal gene program for regenerative cardiac repair. The drive to harness epicardial cells for cardiac regeneration is tethered to its roles in cardiovascular development. Thus, it is necessary to identify molecules that regulate epicardial cell behaviors required for epicardium formation and EPDC differentiation. Using our Tbx5-deficient mouse model of defective epicardium formation ( Tbx5epi−/−), we identified a transcript that is novel to the heart. Adherens junction associated protein 1 is a cell adhesion molecule that is encoded by the AJAP1 transcript which was downregulated in Tbx5epi−/− mice with impaired epicardium formation. Our preliminary studies revealed that AJAP is expressed in epithelial cells of the epicardium during heart development. Silencing of AJAP1 in primary cultured human epithelial cells reduces their ability to migrate. A role for AJAP1 in the epicardium during cardiac development remains to be identified. Study Objective: This study was designed to investigate the impact of AJAP1 on epithelial cell functions that are required for formation of the epicardium and differentiation of EPDCs. Methods: Studies were conducted in a primary human epithelial cell line, HMEpiC, which served as an in vitro model system to examine the contributions of AJAP1 to epithelial cell behaviors. HMEpiCs were transfected with small interfering RNAs (siRNAs) targeting either human AJAP1 to knock down its endogenous expression or a non-targeting negative control siRNA. AJAP1 knockdown was confirmed by quantitative PCR and immunofluorescence. We conducted assays on control and AJAP1 knockdown (KD) cells to examine the effects on epithelial cell behaviors contributing to epicardium formation and EPDC differentiation. This included analysis of cell proliferation, apoptosis, and adhesion to extracellular matrices. Results: Endogenous AJAP1 mRNA expression was reduced significantly by siRNA-mediated knockdown in human epithelial cells. We observed changes in cell morphology that correlated with a significant increase in apoptosis in AJAP1 KD cells compared to negative control cells. Proliferation of HMEpiCs was unchanged by AJAP1 knockdown. Also, we observed a significant increase in the adhesion of AJAP1 KD cells to certain extracellular matrices versus control cells. Conclusion: These findings provide evidence for the AJAP1 cell adhesion molecule to regulate epithelial cell behaviors that are crucial to formation of the epicardium and differentiation of EPDCs during cardiac development. PCOM Center for Chronic Disorders of Aging; PCOM Division of Research. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.