Biology subjects

Myatt, L.

Publications and source records attributed to Myatt, L..

5 recordsLinked to original sources

bioRxiv2025

Dysregulation of placental mitochondrial structure dynamics and clearance in maternal obesity and gestational diabetes

IntroductionThe placenta is exposed to an altered metabolic environment in obesity and gestational diabetes (GDM) leading to disruption in placental function. Mitochondria are critical for energy production and cellular adaptation to stress. We previously reported reduced trophoblast mitochondrial respiration in GDM. Here we examine changes in mitochondrial structure dynamics, quality and protein homeostasis as well as clearance in both obese and GDM placentas of male and female fetuses. As obesity significantly increases the risk for GDM, our goal is to determine the distinct effects of each on placental mitochondria. MethodsWe collected placental villous tissue following elective cesarean section at term from lean (LN, pre-pregnancy BMI 18.5-24.9), obese (OB, BMI>30) or obese with type A2 GDM women. Expression of proteins involved in mitochondrial biogenesis, structure dynamics, quality control and clearance were assessed by Western blotting. Significant changes between groups were determined in fetal sex-dependent and independent manner. ResultsOnly placentas from obese women showed increase in proteins regulating mitochondrial biogenesis (PGC-1 and SIRT1). We report fetal sex-specific changes in mitochondrial fusion but an overall decline in fission in OB and GDM placentas. Both maternal obesity and GDM affected proteins involved in maintaining mitochondrial protein quality and genome stability. This was accompanied by a reduction in mitochondrial complexes, suggesting impaired mitochondrial function. Obesity led to partial activation of mitophagy pathways (e.g., increased PINK1 without PARKIN activation), GDM placentas failed to mount this response. DiscussionObesity and GDM affect placental mitochondria through distinct complex sex-specific mechanisms that may contribute to altered mitochondrial function.

molecular biology↗

bioRxiv2025

Differential activation of p53-Lamin A/C and p16-RB mediated senescence pathways in trophoblast from pregnancies complicated by type A2 Gestational Diabetes Mellitus

Gestational diabetes mellitus (GDM) increases maternal risks such as hypertension and future type 2 diabetes while also contributing to fetal complications such as large-for-gestational-age infants and stillbirth. The placenta which is crucial for fetal development, exhibits structural and functional changes in GDM, but the impact of these alterations on placental trophoblast function remains unclear. During their differentiation villous cytotrophoblast display several characteristics of senescent cells however the role of senescence pathways in placental function remains unexplored in GDM. Here we investigate whether placental senescence pathways are altered in GDM, utilizing term villous tissue and primary trophoblasts to assess molecular changes, and determined fetal sex-based differences. Our data suggest that both p21 and p16 mediated senescence pathways are activated during trophoblast differentiation and are dysregulated in GDM placenta in a sexually dimorphic manner. We also provide evidence for increased activation of p53-Lamin A/C and p16-RB pathways in trophoblast from GDM placentas. Reduced expression of p21 and its downstream effects on GCM1 expression and {beta}hCG secretion outline how altered physiological senescence can affect trophoblast differentiation and function. This is a seminal study highlighting how placental senescence pathways are altered in pregnancies complicated by GDM.

cell biology↗

bioRxiv2024

Changes in maternal blood and placental lipidomic profile in obesity and gestational diabetes: Evidence for sexual dimorphism

IntroductionObesity and gestational diabetes (GDM) are associated with adverse pregnancy outcomes and program the offspring for cardiometabolic disease in a sexually dimorphic manner. The placenta transfers lipids to the fetus and uses these substrates to support its own metabolism impacting the amount of substrate available to the growing fetus. MethodsWe collected maternal plasma and placental villous tissue following elective cesarean section at term from women who were lean (pre-pregnancy BMI 18.5-24.9), obese (BMI>30) and type A2 GDM (matched to obese BMI) with male or female fetus (n=4 each group). Lipids were extracted and fatty acid composition of different lipid classes were analyzed by LC-MS/MS analysis. Significant changes in GDM vs obese, GDM vs lean, and obese vs lean were determined using t-test with a Tukey correction set at p<0.05. ResultsIn placental samples 436 lipids were identified, among which 85 showed significant changes. Of note only in male placentas significant decreases in C22:6 - docosahexaenoic acid (DHA) in phosphatidylcholine (PC) and triglyceride lipid species were seen when comparing tissue from GDM women to lean. In maternal plasma we observed no effect of obesity. GDM or fetal sex. ConclusionThis is the first study assessing fatty acid composition of lipids in matched maternal plasma and placental tissue from lean, obese, and GDM women stratified by fetal sex. It highlights how GDM affects distribution of fatty acids in lipid classes changes in a sexually dimorphic manner in the placenta.

molecular biology↗

bioRxiv2024

Transcriptomic comparison of in vitro models of the human placenta

Studying the human placenta through in vitro cell culture methods is necessary due to limited access and amenability of human placental tissue to certain experimental methods as well as distinct anatomical and physiological differences between animal and human placentas. Selecting an in vitro culture model of the human placenta is challenging due to representation of different trophoblast cell types with distinct biological roles and limited comparative studies that define key characteristics of these models. Therefore, the aim of this research was to create a comprehensive transcriptomic comparison of common in vitro models of the human placenta compared to bulk placental tissue from the CANDLE and GAPPS cohorts (N=1083). We performed differential gene expression analysis on publicly available RNA sequencing data from 6 common in vitro models of the human placenta (HTR-8/SVneo, BeWo, JEG-3, JAR, Primary Trophoblasts, and Villous Explants) and compared to CANDLE and GAPPS bulk placental tissue or cytotrophoblast, syncytiotrophoblast, and extravillous trophoblast cell types derived from bulk placental tissue. All in vitro placental models had a substantial number of differentially expressed genes (DEGs, FDR<0.01) compared to the CANDLE and GAPPS placentas (Average DEGs=10,873), and the individual trophoblast cell types (Average DEGs=5,346), indicating that there are vast differences in gene expression compared to bulk and cell-type specific human placental tissue. Hierarchical clustering identified 53 gene clusters with distinct expression profiles across placental models, with 22 clusters enriched for specific KEGG pathways, 7 clusters enriched for high-expression placental genes, and 7 clusters enriched for absorption, distribution, metabolism, and excretion genes. In vitro placental models were classified by fetal sex based on expression of Y-chromosome genes that identified HTR-8/SVneo cells as being of female origin, while JEG-3, JAR, and BeWo cells are of male origin. Overall, none of the models were a close approximation of the transcriptome of bulk human placental tissue, highlighting the challenges with model selection. To enable researchers to select appropriate models, we have compiled data on differential gene expression, clustering, and fetal sex into an accessible web application: "Comparative Transcriptomic Placental Model Atlas (CTPMA)" which can be utilized by researchers to make informed decisions about their selection of in vitro placental models.

developmental biology↗

bioRxiv2022

A Genome Scale Transcriptional Regulatory Model of the Human Placenta

Gene regulation is essential to placental function and fetal development. We report a genome-scale transcriptional regulatory network (TRN) of the human placenta built using digital genomic footprinting and transcriptomic data. We integrated 475 transcriptomes and 12 DNase hypersensitivity datasets from placental samples to globally and quantitatively map transcription factor (TF)-target gene interactions. In an independent dataset, the TRN model predicted target gene expression with an out of sample R2 value greater than 0.25 for 74% of target genes. We performed siRNA knockdowns of 4 TFs and achieved concordance between the predicted gene targets in our TRN and differences in expression of knockdowns with an accuracy of >0.7 for 3 of the 4 TFs. Our final model contained 113,158 interactions across 391 TFs and 7,712 target genes and is publicly available. We identified six TFs which were significantly enriched as regulators for genes previously associated with preterm birth.

systems biology↗