Fetal Development Research Articles

Optimizing lipid nanoparticles for fetal gene delivery in vitro, ex vivo, and aided with machine learning

There is a clinical need to develop lipid nanoparticles (LNPs) to deliver congenital therapies to the fetus during pregnancy. The aim of these therapies is to restore normal fetal development and prevent irreversible conditions after birth. As a first step, LNPs need to be optimized for transplacental transport, safety on the placental barrier and fetal organs and transfection efficiency. We developed and characterized a library of LNPs of varying compositions and used machine learning (ML) models to delineate the determinants of LNP size and zeta potential. Utilizing different in vitro placental models with the help of a Random Forest algorithm, we could identify the top features driving percentage LNP transport and kinetics at 24 h, out of a total of 18 input features represented by 41 LNP formulations and 48 different transport experiments. We further evaluated the LNPs for safety, placental cell uptake, transfection efficiency in placental trophoblasts and fetal lung fibroblasts. To ensure the integrity of the LNPs following transplacental transport, we screened LNPs for transport and transfection using a high-throughput integrated transport-transfection in vitro model. Finally, we assessed toxicity of the LNPs in a tracheal occlusion fetal lung explant model. LNPs showed little to no toxicity to fetal and placental cells. Immunoglobin G (IgG) orientation on the surface of LNPs, PEGylated lipids, and ionizable lipids had significant effects on placental transport. The Random Forest algorithm identified the top features driving LNPs placental transport percentage and kinetics. Zeta potential emerged in the top driving features. Building on the ML model results, we developed new LNP formulations to further optimize the transport leading to 622 % increase in transport at 24 h versus control LNP formulation. To induce preferential siRNA transfection of fetal lung, we further optimized cationic lipid percentage and the lipid-to-siRNA ratio. Studying LNPs in an integrated placental and fetal lung fibroblasts model showed a strong correlation between zeta potential and fetal lung transfection. Finally, we assessed the toxicity of LNPs in a tracheal occlusion lung explant model. The optimized formulations appeared to be safe on ex vivo fetal lungs as indicated by insignificant changes in apoptosis (Caspase-3) and proliferation (Ki67) markers. In conclusion, we have optimized an LNP formulation that is safe, with high transplacental transport and preferential transfection in fetal lung cells. Our research findings represent an important step toward establishing the safety and effectiveness of LNPs for gene delivery to the fetal organs.

Embryonic and Fetal Heart Development Before 12 Weeks of Gestation.

To assess embryonic and fetal cardiac growth and development using transvaginal 2-dimensional sonography before 12 weeks of gestation. Transvaginal scans for first-trimester dating were performed for 131 normal fetuses at 8-11 + 6 weeks of gestation. The basal-apical length (BAL), transverse length (TL), cardiac circumference (ECC), embryonic cardiac area (ECA), global sphericity index (GSI), and cardio-thoracic area ratio (CTAR) were able to be obtained in 105 normal embryos and fetuses. Nomograms for several cardiac parameters including BAL, TL, ECC, ECA, GSI, and CTAR were constructed. BAL, TL, ECC, and ECA increased curvilinearly with advancing gestation (R2 = 0.97406, 0.980396, 0.978359, and 0.920705, respectively, P < .001). GSI (mean, 1.14; SD, 0.10) and CTAR (mean, 15.7%; SD, 3.3%) values were constant at 8-11 + 6 weeks of gestation. There were significant curvilinear correlations between BAL, TL, ECC, and ECA, and crown-rump length (CRL) (R2 = 0.975976, 0.983482, 0.980673, and 0.929936, respectively, P < .001). GSI and CTAR values were not changed with the increase of CRL during this period. Our results provide nomograms for several cardiac parameters which may improve the understanding of embryonic and fetal cardiac growth and development prior to 12 weeks of gestation.

Fetal Teratomas: Advances in Diagnosis and Management.

Fetal teratomas, though rare, represent a significant proportion of tumors arising during fetal development. These tumors arise from pluripotent cells and can present in varying degrees of severity, ranging from incidental findings to life-threatening conditions. Prenatal imaging, via ultrasound and MRI, is necessary for diagnosis and risk assessment. The management of fetal teratomas, particularly those associated with complications like hydrops or airway obstruction, often requires a multidisciplinary approach. Interventions such as ex-utero intrapartum treatment (EXIT) procedures and minimally invasive alternatives have emerged as critical tools to improve neonatal outcomes in severe cases. Despite advances in fetal therapies, careful prenatal monitoring and individualized management remain essential, especially for tumors with high vascularity or those that risk compromising cardiac output. This review explores the diagnostic methods, management strategies, and outcomes associated with fetal teratomas, highlighting recent advancements that contribute to improving survival and reducing morbidity in affected neonates.

The Impact of Genetic Research and Discoveries During the Past Century on Behaviour

This article examines the relationship between genetics and behaviour over the past century as part of the series "WHAT THEY DID TO YOU - 100 YEARS AGO." The series delves into various aspects of genetics and its wide-reaching effects on behaviour, environment, and human development. The exploration begins with a thorough understanding of the fundamental principles of genetics, discussing how genes serve as the blueprints of life encoded in DNA, influencing every aspect of our being from physical traits to complex behaviours. By understanding genetic inheritance, mutations, and diversity, we can better appreciate the intricate interplay between our genes and our lives. Future articles will expand to explore how genetic predispositions affect behavioural tendencies and personality traits; the dynamic interaction between our genetic makeup and environmental factors, including epigenetic changes; how our five senses shape our thoughts, decisions, and overall lifestyle; and the genetic and environmental influences on fetal development from conception to birth. This series aims to provide a comprehensive understanding of how genetics has shaped our lives over the past century and how we can use this knowledge to influence future outcomes. By unravelling the complex web of genetic and environmental interactions, this research hopes to offer insights into the profound impact of our genetic legacy and the potential for shaping a better future.

Clinical case of a live-born child with triploidy

Theoretical data on etiopathogenesis, clinical manifestations of triploidy, life expectancy of children in case of live-birth with this chromosomal anomaly are presented. A clinical case of a triploidy in a child is described. The girl was born from the first pregnancy from young healthy parents. Parents are not close relatives. Pregnancy was complicated with anemia, recurrent threats of miscarriage, progressive lack of water, progressive violation of uteroplacental blood flow and delay in fetal development. A congenital heart defect was diagnosed prenatally. The girl was born at 38 weeks of pregnancy with low indicators of physical development by caesarean section. Multiple developmental anomalies and malformations were revealed after birth. Combined congenital heart disease was confirmed by instrumental examination. Karyotyping revealed karyotype 69, ХХХ. Dynamic observation revealed that the child's age-related skills were not formed. Epileptic seizures occurred from the age of 4 months. The seizures had a status course. Surgical correction of congenital heart disease was performed in two stages: at 4.5 months and at 9.5 months in this patient. A fatal outcome occurred with an increase in multiple organ failure at the age of 10 months. The features of the clinical case, the possibilities of prenatal diagnosis of triploidy are analyzed.

Gestational organophosphate pesticide exposure and childhood cardiovascular outcomes

IntroductionThe general population is chronically exposed to organophosphate pesticides through various routes including ingestion, hand-to-mouth contact, inhalation, and dermal contact. Exposure to organophosphate pesticides during pregnancy impairs fetal development, but the potential long-term effects of gestational organophosphate pesticide exposure are less well understood. MethodsWe investigated associations between gestational organophosphate pesticide exposure and cardiovascular outcomes in 643 children in the Generation R Study, a prospective pregnancy cohort based in Rotterdam, The Netherlands. Urinary organophosphate pesticide metabolites (dimethyl [∑DMAP], diethyl [∑DEAP], and total dialkyl phosphate [∑DAP] metabolites) were quantified in three urine samples collected from pregnant participants, and their children were followed until age 10 years at which time cardiac magnetic resonance imaging, ultrasonography, blood pressure, and serum biomarkers assessed cardiovascular health. Linear regression models estimated associations (β and 95 % confidence interval [CI]) between a one-interquartile range (IQR) increase in averaged gestational exposure biomarker concentrations and z-scored pediatric cardiovascular outcomes. We investigated effect modification of associations by PON1 genotype. ResultsCarotid intima-media thickness z-score was lower (β: -0.14 [95 % CI: −0.25, −0.02]) and HDL cholesterol z-score was higher (β: 0.14 [95 % CI: 0.02, 0.25]) for increases in ∑DEAP concentrations. Carotid intima-media distensibility z-score was lower (β: -0.08 [95 % CI: −0.19, 0.03]) for increases in ∑DMAP concentrations, and systolic blood pressure z-score was higher (β: 0.10 [95 % CI: −0.01, 0.21]) for increases in ∑DMAP and ∑DAP. Among those with PON1-161CC and PON1-L55MTT genotypes, higher organophosphate pesticide concentrations conferred an excess risk of adverse vascular and glycemic outcomes, respectively. ConclusionsWe observed heterogenous associations between gestational organophosphate pesticide exposure and pediatric cardiovascular health: an anti-atherogenic profile was observed for increases in ∑DEAP concentrations, and impairments in multiple aspects of cardiovascular health was observed for increases in ∑DMAP concentrations. PON1-161 and PON1-L55M single nucleotide polymorphisms modified associations for vascular and glycemic outcomes, respectively.

Embryo Transfer Surgery via Laparotomy in Gilts.

This protocol aims to demonstrate the surgical technique for transferring cloned pig embryos to the oviduct, a method widely used in the production of genetically modified pigs for biomedical research. Nine gilts underwent hormonal synchronization and laparotomy for the transfer of cloned embryos produced by somatic cell nuclear transfer (SCNT) at stages of up to 4 cells on day 2 to the oviduct. Gestational diagnosis was conducted via ultrasound examination 30 days post-transfer surgery. Six out of the nine operated gilts exhibited signs of pregnancy on ultrasound examination. However, as there was no progression in fetal development as assessed by echography, the gilts underwent necropsy at 60 days for the collection of biological material and assessment of the reproductive system. Adhesions were observed in the uterine horns, ovaries, and oviducts. From the uterine lumen of two of the euthanized gilts, one and four embryonic structures with gestational ages ranging between 12 to 20 days were obtained. Despite the absence of live piglets, likely attributed to the low-efficiency rate of transferring cloned pig embryos, which is influenced by various factors, including the number and quality of transferred embryos, the presented surgical technique proved to be rapid and safe.

Double umbilical artery converging into a single umbilical artery: A case report.

The normal structure and Doppler parameters of the umbilical cord are closely related to many diseases, including fetal infection, chromosomal abnormalities, hypoxia, and growth and development restrictions. We report a case of bilateral umbilical artery confluence resulting in the formation of a single umbilical artery in the free segment of the fetal umbilical cord, diagnosed at 24 weeks and 4 days gestation. The fetus was born prematurely after premature membrane rupture at 31 weeks and 3 days gestation. The Toxoplasma, Others, Rubellavirus, Cytomegalovirus, Herpesvirus test showed positive results for Toxoplasma gondii, rubella virus, and herpes simplex virus IgG antibodies. A 36-year-old woman had vaginal discharge for > 1 hour at 31 weeks + 3 days gestation and came to our obstetrics department for treatment. The pregnant woman sought treatment due to premature membrane rupture and vaginal discharge for > 1 hour. The vaginal discharge was caused by Escherichia coli. After cesarean section, the Toxoplasma, Others, Rubellavirus, Cytomegalovirus, Herpesvirus test revealed positive results for the following: T gondii, rubella virus, and herpes simplex virus IgG antibodies. The patient underwent 2 ultrasound examinations and was diagnosed with umbilical artery malformation (the free segment of the umbilical cord on the fetal side converged into a single umbilical artery), which may have been related to fetal infection. The patient received anti-inflammatory and fetal lung maturation treatment for 2 days before undergoing a cesarean section. The mother and newborn received anti-inflammatory, symptomatic, and supportive treatment and were discharged after 1 week of improvement. After 1 month, 6 months, and 1 year of follow-up after birth, the growth and development of the infant (height and weight) were significantly lower than those of her peers, and her responses to sound and light were slightly delayed. Umbilical artery malformation is extremely rare and may be related to intrauterine parasitic and viral infections. Ultrasound has the advantages of being noninvasive and cost-effective and can be used to dynamically observe umbilical artery structure. An abnormal change in umbilical artery structure found during ultrasound examination can indicate intrauterine infection risk, which provides clinical guidance for further examination of pregnant women, early diagnosis, timely targeted treatment, and fetal prognosis improvement.

Cryodehydration applied to bovine fetal hearts: A model for studying cardiac organogenesis.

The study aimed to standardize the cryodehydration technique for bovine fetal hearts, focusing on optimizing protocols for each developmental stage to preserve morphological characteristics. We analyzed 29 bovine fetal hearts categorized into early, middle, and late developmental stages. These hearts underwent cryodehydration until a 60%-70% reduction in original fluid volume was achieved. Biometric data were recorded and statistically analyzed using Pearson correlation tests for age versus weight and age versus number of cryodehydration sessions. Morphometric comparisons before and after cryodehydration were performed using paired t-tests. In Group I, hearts exhibited well-defined structures, including the atrium cordis, ventriculus cordis, auricula atrii, aorta, truncus pulmonalis, and ramus coronaries arteria, which were preserved in Groups II and III. Additionally, in Group I the heart had a conical or flat apex cordis, whereas those in Groups II and III had a more pronounced apex. The average number of cryodehydration sessions required was 9.38 (±1.2) days for Group I, 12.37 (±1.4) days for Group II, and 15 days for Group III. A positive correlation was found between age and sample weight, indicating that more developed hearts were heavier. Similarly, there was a positive correlation between gestational age and the number of cryodehydration sessions, suggesting that more advanced stages required more cryodehydration sessions. Paired t-tests demonstrated high statistical significance in the morphometric parameters before and after cryodehydration, indicating a loss of mass during dehydration. However, there was no alteration in the macroscopic structure of the hearts, which remained morphologically preserved. In conclusion, cryodehydration shows promise for preserving and analyzing the external morphological characteristics of bovine fetal cardiac development. It also provides lightweight, odorless, and easy-to-handle specimens ideal for detailed morphological studies and offers a unique perspective for investigating cardiac morphology in biological research contexts.

ENZYMES AND METABOLITES OF ENDOGENOUS CARBON MONOXIDE IN THE FETOPLACENTAL SYSTEM DURING PHYSIOLOGICAL GESTATION AND PLACENTAL DYSFUNCTION

Introduction. Prenatal ontogenesis largely depends on the functional and metabolic viability of the placenta and the entire fetoplacental complex. That is why the dysfunction of the placenta due to the changes in cellular regulation processes will lead to pregnancy complications and impaired fetal develop-ment. An important component of the system of intra- and intercellular regulators is the gas transmitter – carbon monoxide. Its role in cellular signaling and communication reactions, and at the same time, insufficient data of its metabolism, justifies the need to conduct research on this gas transmitter during complicated pregnancy. The aim of the work. To study the features of the metabolism of the active cellular mediator - the gas transmitter carbon monoxide in different objects of the fetoplacental system during physiological pregnancy and placental dysfunction. Material and methods. The research materials included placental tissue, amnion and amniotic fluid. The work uses spectrophotometric methods, enzyme immunoassay, and ion exchange chromatography. Results. Multidirectional changes in the activity of the studied enzymes (heme oxygenase and histidine decarboxylase), the content of the substrate of His-tidine reaction and the product of reaction of Histamine are established in case of placental disfunction. There is a certain correlation between the discov-ered studied components. Indicators of carbon monoxide metabolism can be markers for predicting postnatal damage – cerebral disorders in newborns. Conclusions. The identified injuries are obviously important links in the chain of disorders accompanied by the development of placental dysfunction.

Regional differences in autism and intellectual disability risk associated with cesarean section delivery.

Prior epidemiological studies investigating the association between delivery mode (i.e., vaginal birth and cesarean section [C-section]) and autism spectrum disorder (ASD) and intellectual disability (ID) risk have reported mixed findings. This study examined ASD and ID risks associated with primary and repeat C-section within diverse US regions. During even years 2000-2016, 8-years-olds were identified with ASD and/or ID and matched to birth records [ASD only (N = 8566, 83.6% male), ASD + ID (N = 3445, 79.5% male), ID only (N = 6158, 60.8% male)] using the Centers for Disease Control and Prevention's Autism and Developmental Disabilities Monitoring Network methodology. The comparison birth cohort (N = 1,456,914, 51.1% male) comprised all births recorded in the National Center for Health Statistics corresponding to birth years and counties in which surveillance occurred. C-section rates in the birth cohort demonstrated significant regional variation with lowest rates in the West. Overall models demonstrate increased odds of disability associated with primary and repeat C-section. Adjusted models, stratified by region, identified significant variability in disability likelihood associated with repeat C-section: increased odds occurred for all case groups in the Southeast, for ASD only and ID only in the Mid-Atlantic, and no case groups in the West. Regional variability in disability risk associated with repeat C-section coincides with differences in birth cohorts' C-section rates. This suggests increased likelihood of disability is not incurred by the procedure itself, but rather C-section serves as a proxy for exposures with regional variability that influence fetal development and C-section rates.

Revisiting the human umbilical cord epithelium. An atypical epithelial sheath with distinctive features.

The umbilical cord epithelium (UCE) is the surface tissue that covers the umbilical cord (UC). It is widely considered a single-layered epithelium composed of squamous or cuboidal cells, which are in constant contact with amniotic fluid. The objective of this study was to elucidate the distinctive structural characteristics and abundance of specific proteins in this unique epithelium, many of which have not been previously demonstrated. Samples of the UC were obtained from term pregnancies (n = 12) and processed for examination using stereo, light, electron, and 3D high-resolution confocal microscopy. Sections displayed a range of stratification, ranging from a single squamous layer to 4-5 layers of round/cuboid cells, challenging the notion of considering it as a single-layered structure. Cells are located on a well-developed basement membrane (BM), as evidenced by the expression of BM-specific proteins and PAS staining. The cells possess distinctive cytoplasmic domains that are tightly bound to each other by desmosomes and interdigitating anchoring surfaces. Desquamations and limited organelles suggest that the cells have reached the final stages of differentiation and are no longer actively synthesizing proteins, despite maintaining stratification-specific expression levels of cytoskeletal, junctional, receptor, and stem cell proteins. Although definitive keratinization was not observed, the distribution of proteins and the distinctive structural organization of the single/multi-layered cells suggest that they exhibit plasticity, likely due to adaptive mechanisms in response to chemical and/or mechanical stimuli during fetal development. These structural alterations may facilitate the active transportation of soluble ingredients between the amniotic fluid and cord blood through an intercellular route.

Maternal e-cigarette exposure alters DNA methylome, site-specific CpG and CH methylation, and transcriptomic signatures in the neonatal brain

Maternal use of e-cigarette (e-cig) aerosols poses significant risks to fetal brain development, potentially increasing susceptibility to neurodevelopmental disorders in later life. However, the underlying mechanisms remain incompletely understood. This study aimed to understand the effects of fetal e-cig exposure on DNA methylome and transcriptomic changes in the neonatal brain. Pregnant rats were exposed to e-cig aerosols, and neonatal brains (5 males and 5 females/group) from both control and e-cig-exposed groups were used for experimental analysis. Results indicated that prenatal e-cig exposure altered site-specific DNA methylation patterns at both CpG and CH (non-CpG) sites, predominantly in intergenic and intronic regions, with sex dimorphism in methylation and gene expression changes. Gene ontology analysis revealed that e-cig exposure not only affected neuron projection development and axonogenesis but also altered pathways related to neurodegeneration and long-term depression. These findings provide novel insights into the dynamic changes of CpG and CH methylation induced by e-cig exposure, underscoring the susceptibility of the developing brain to maternal e-cig exposure and its potential implications for developmental disorders and neurodegenerative diseases later in life.

Pre-pregnancy and gestational interventions to prevent childhood obesity.

Childhood obesity is a significant global health issue with complex and multifactorial origins, often beginning before conception and influenced by both maternal and paternal health. The increased prevalence of pre-pregnancy obesity and gestational diabetes mellitus in women of reproductive age contributes to a heightened risk of metabolic dysfunction in offspring. Current clinical practices often implement lifestyle interventions after the first trimester, and have limited success, implying that they miss a critical window for effective metabolic adjustments. This review examines the limitations of lifestyle interventions during pregnancy in improving perinatal outcomes and highlights the importance of initiating such interventions before conception to positively impact parental health and fetal development. A re-evaluation of strategies is needed to enhance the metabolic health of prospective parents as a preventive measure against childhood obesity.

Type of delivery lacks the association with dietary patterns followed by pregnant women in their third trimester.

Background: Maternal nutrition plays a crucial role in fetal development, women's health, and reproductive capacity. Dietary pattern (DP) is a measure of overall diet and has become widespread in nutrition research as an alternative method to studying individual components of the diet. Aim: this study aims to determine the adopted DPs by Jordanian pregnant women and evaluate their potential associations with the mode of delivery. Methods: A cross-sectional study included 249 healthy Jordanian pregnant women in their third trimester of pregnancy who attended antenatal clinics at Jordan University. Personal information was gathered using a pre-tested structured questionnaire. To investigate dietary patterns, a valid and reliable food frequency questionnaire was employed, and a pregnant physical activity questionnaire was used to estimate physical activity levels. The mode of delivery data was collected from the medical records after delivery. Results: The majority of pregnant women (82.3%) fell within the age range of 20 to 35 years. Notably, 34.5% of the mothers were classified as overweight or obese. Additionally, around one in five deliveries involved emergency cesarean sections. Four distinct DPs were identified and labelled as "fruit and vegetables", "healthy", "traditional", and 'fat and sugar" dietary patterns. However, no significant association was found between these identified dietary patterns and the occurrence of Caesarean section (CS) across all tertiles. Conclusion: The analysis revealed no substantial protective effect of the DPs against the occurrence of CS across all tertiles of dietary patterns. However, further studies are needed to either confirm or challenge our findings.

The Influence of Birth Weight, Socio-Economic Status, and Adult Health on Brain Volumes during Ageing

Introduction: Greater late-life brain volumes are associated with resilience against dementia. We examined relationships between birth weight, lifelong socio-economic status, and health with late-life brain volumes. We hypothesised that early life factors directly affect late-life brain volumes. Methods: Adults aged 59–67 y underwent MRI and brain volumes were measured. Birth weight and lifelong health, and socio-economic status were quantified and the principal components of each extracted. Relationships were examined using regression and structural equation analysis. Results: Birth weight (β = 0.095, p = 0.017) and childhood socio-economic status (β = 0.091, p = 0.033, n = 280) were directly associated with brain volume. Childhood socio-economic status was further associated with grey matter volume (β = 0.04, p = 0.047). Adult health was linked to increased brain volume (β = 0.15, p = 0.003). Conclusion: Birth weight and childhood socio-economic status are associated with whole and regional brain volume through direct mechanisms. Optimal fetal development, reduced childhood poverty, and good adult health could reduce brain atrophy and delay dementia onset in late-life.

IL-4 promotes chondrogenesis of bone marrow mesenchymal stem cellsand blockade of IL-4Rα retards the endochondral ossification during rat embryonic bone development.

Interleukin-4 (IL-4)/IL-4 receptor alpha (IL-4Rα) signalling pathways play important roles in the complex process of bone formation and bone remodelling. However, whether IL-4/IL-4Rα participates in skeletogenesis during embryonic development is not completely understood. We used the anti-IL-4Rα monoclonal antibody (anti-IL-4Rα mAb) as a powerful investigational tool to evaluate the potential roles of IL-4/IL-4Rα in the chondrogenic differentiation of rat bone marrow mesenchymal stem cells (BMSCs) in vitro. Simultaneously, we explored the effect of IL-4/IL-4Rα on bone ossification during rat embryo-fetal development. In this study, we found that, compared to the control group, IL-4 can significantly promote the chondrogenic differentiation of BMSCs. Furthermore, following exposure to anti-IL-4Rα mAb in pregnant rats, unexpected phenomena were observed in fetal bone development, including non-ossification of the fetal sternum, an incomplete ossification centre in long bones and a reduced number of ossification points in digit (toe) bones. To further investigate the underlying mechanism of the phenotype, we studied the rat sternum as the target organ, starting from different time points of sternum development in the embryonic stage. The results indicated that the retardation mainly occurred in the middle and late stages of embryonic development. This retardation was characterized by the inhibition of the differentiation process of mesenchymal stem cells into chondrocytes, resulting in reduced angiogenesis near the ossification centre, failure of osteoblasts to invade the centre of the cartilage body with the blood vessels and delayed formation of the primary ossification centre (POC). Overall, our study demonstrated the significant function of IL-4/IL-4Rα in chondrogenic differentiation of BMSCs and bone ossification during embryo-fetal development.

Fetal Liver-like Organoids Recapitulate Blood-Liver Niche Development and Multipotent Hematopoiesis from Human Pluripotent Stem Cells.

The fetal liver is a hematopoietic organ, hosting a diverse and evolving progenitor population. While human liver organoids derived from pluripotent stem cells (PSCs) mimic aspects of embryonic and fetal development, they typically lack the complex hematopoietic niche and the interaction between hepatic and hematopoietic development. We describe the generation of human Fetal Liver-like Organoids (FLOs), that model human hepato-hematopoietic interactions previously characterized in mouse models. Developing FLOs first integrate a yolk sac-like hemogenic endothelium into hepatic endoderm and mesoderm specification. As the hepatic and hematopoietic lineages differentiate, the FLO culture model establishes an autonomous niche capable of driving subsequent progenitor differentiation without exogenous factors. Consistent with yolk sac-derived waves, hematopoietic progenitor cells (HPCs) within FLOs exhibit multipotency with a preference for myeloid lineage commitment, while retaining fetal B and T cell differentiation potential. We reconstruct in FLOs the embryonic monocyte-to-macrophage and granulocyte immune trajectories within the FLO microenvironment and assess their functional responses in the liver niche. In vivo, FLOs demonstrate a liver engraftment bias of hematopoietic cells, recapitulating a key phenomenon of human hematopoietic ontogeny. Our findings highlight the intrinsic capacity of liver organoids to support hematopoietic development, establishing FLOs as a platform for modeling and manipulating human blood-liver niche interactions during critical stages of development and disease.

Light and scanning electron microscope characterization of mandibular symphysis tissue as a functional adaptation in the mandible development of human fetuses.

When developing, the mandible presents great plasticity and contains condensed mesenchymal cells that develops into Meckel's cartilage, of which the anterior part forms the mandibular symphysis. Mandible human development studies focus on investigating whether the beginning of mandibular fusion in fetal period is related to symphysis ossification and the tensions imposed on it, considering that tongue movements, mouth opening, and closing can be seen in fetuses. This research analyses tissue modifications during human mandibular symphysis growth using light and scanning electron microscopy to relate them to its functional structure. The study sample consisted of 12 human fetuses distributed into two groups: Group I (GI) of 10-14 weeks old and Group II (GII) of 20-24 weeks old. Fragments of mandibular symphysis were removed en bloc together with the surrounding tissues to preserve the relation with adjacent structures. Decalcified specimens were prepared in semi-serial coronal sections 5-μm-thick and stained with hematoxylin and eosin, Masson՚s trichrome, Verhoeff, and Sirius red for histological analysis with light microscopy. Collagen fibers Type I or III and elastic fibers were quantified by volume fraction (Vv). Coronal sections of the GI and GII symphyseal region were submitted to scanning electron microscopy. Comparison between groups used independent t-test. Our study presents the different endochondral ossification stages in the anterior part of Meckel's cartilage in GI. Both groups showed abundantly vascularized mesenchymal tissue with intense cellular activity forming the mandibular symphysis, such as a source of new osteoblasts adjacent to the newly deposited bone matrix. Scanning electron microscopy analysis revealed an invasion of the bony trabecula in the transverse direction from the hemimandible, rectilinear in GI and sinuous in GII due to interdigitating bone process, promoting its ossification. In collagen Vv analysis was verified a prevalence of type I in GII and type III in GI, indicating a proportional relation between maturation and tissue arrangement. Functionally, the collagen and elastic fibers in the mandibular symphysis were arranged in a pantographic network, and the fibrillar interconnectivity clearly contributes to resilience capacity and efficiency of the force transfer. This study inferred the functional significance of the knowledge about the tissue composition of mandibular symphysis, and the importance of this tissue for surrounding structures. The mesenchymal tissue of mandibular symphysis participates in bone growth process, revealing an adaptation mechanism of mandibular symphysis in the fetal period investigated.

Placental Transcriptomic Signatures of Prenatal Phthalate Exposure and Identification of Placenta-Brain Genes Associated with the Effects of Phthalate Exposure on Neurodevelopment in Children.

Prenatal exposure to phthalates may affect placental function and fetal development, but the underlying mechanisms are unclear. The aim of our study was to explore the alterations in the placental transcriptome associated with prenatal phthalate exposure and to further analyze whether the placental-brain axis (PBA) genes play a mediating role in the association between prenatal phthalate exposure and children's neurodevelopment. We included 172 participants from the Ma'anshan Birth Cohort and collected data on seven phthalate metabolites in urine during pregnancy, placental tissue RNA-seq, and neurodevelopment of offspring. Bioinformatics analysis revealed that aberrant regulation of the placental transcriptome was associated with prenatal phthalate exposure. Exposure to phthalates during pregnancy was found to be associated with neurodevelopmental delay in children aged 6, 18, and 48 months using the multiple linear regression model. Meanwhile, employing mediation analysis, nine PBA genes were identified that mediate the association between exposure to phthalates during pregnancy and the neurodevelopment of children. Our study will provide a basis for potential mechanisms by which prenatal exposure to phthalates affects placental function and children's neurodevelopment.