Biology subjects

Faulkner, S.

Publications and source records attributed to Faulkner, S..

3 recordsLinked to original sources

bioRxiv2026

Placental prostaglandin signaling disrupts barrier integrity and relays an acute inflammatory signal to the fetus.

Maternal inflammation during pregnancy is a major risk factor for adverse neurodevelopmental outcomes, yet the mechanisms linking maternal immune activation (MIA) to placenta-fetal brain axis dysfunction remain unclear. Using a poly-(I:C) mouse model, we show that MIA rapidly disrupts placental-blood barrier (PBB) integrity by disrupting pericyte-endothelium coupling within 48 hours, leading to increased placental permeability detected by in vivo MRI. We identify a prostaglandin E2 (PGE2)-dependent pathway involving cyclooxygenase-2 (COX2) and prostaglandin E-synthase (mPGES1) as a key mediator of this effect. Pharmacological inhibition of COX2 prevented MIA-induced structural and functional changes. In vitro explant studies confirmed that PGE2 acts via the EP3 receptor to disrupt pericyte-endothelium interactions, while ex vivo perfusion demonstrated that in addition to its local effects on PBB structure, placenta-derived PGE2 enters the fetal circulation. Finally, similar vascular alterations were observed in human placentas from pregnancies with severe maternal inflammation. These findings reveal a conserved inflammatory mechanism that compromises PBB integrity and may relay signals to the fetal brain, highlighting potential therapeutic targets for neuroprotection during prenatal inflammation. One Sentence SummaryMaternal immune activation during pregnancy disrupts placental vascular integrity through a COX2-dependent prostaglandin E2 pathway, which compromises the placenta-blood barrier and relays inflammatory signals to the fetus, identifying potential therapeutic targets for neuroprotection.

developmental biology↗

bioRxiv2025

Donor Age Impairs Vasculogenic Potential of hiPSC-Derived Endothelial Progenitors

BackgroundHuman induced pluripotent stem cells (hiPSCs) hold promise for vascular regeneration, but preliminary research often relies on neonatal donors, whereas clinical applications will use cells derived from older adults. Although the impact of donor age on reprogramming efficiency has been studied, its effect on the functionality of hiPSC-derived endothelial progenitors (hiPSC-EPs) remains unclear. This question is the focus of the current study. Methods and ResultsWe derived EPs from iPSCs sourced from three neonatal donors (ND) and three mature donors (MD) matched 1:1 for sex and somatic cell origin. We assessed their functional, epigenetic, and transcriptomic characteristics. Despite higher CD34 yields from MD-iPSCs, MD-hiPSC-EPs formed poorly interconnected and non-lumenized vascular structures in 3D hydrogels, compared to neonatal donor (ND) lines. In 2D culture, MD-hiPSC-EPs exhibited reduced cell density and aberrant VE-Cadherin localization. DNA methylation analysis revealed that somatic cell origin was the dominant driver of variance, but consistent differences in methylation of mesoderm commitment, angiogenesis, ECM remodeling, and cytoskeleton-related genes were observed between age groups. Epigenetic age prediction showed MD-hiPSC-EPs had more developmentally advanced signatures, potentially explaining their shift away from vasculogenic competence. Our RNA-sequencing findings confirm trends seen in the DNA methylation data and show differential expression of pathways linked to mitochondrial regulation and nitric oxide signaling. ConclusionsDonor age significantly alters the vasculogenic function of hiPSC-EPs. These findings underscore the necessity of donor-specific considerations in hiPSC-based vascular engineering and highlight potential barriers to translating hiPSC-derived therapeutics into older patient populations.

bioengineering↗

bioRxiv2020

Intact nucleosomal context enables chromodomain reader MRG15 to distinguish H3K36me3 from -me2

A wealth of in vivo evidence demonstrates the physiological importance of histone H3 trimethylation at lysine 36 (H3K36me3), to which chromodomain-containing proteins, such as MRG15, bind preferentially compared to their dimethyl (H3K36me2) counterparts. However, in vitro studies using isolated H3 peptides have failed to recapitulate a causal interaction. Here, we show that MRG15 can clearly discriminate between synthetic, fully intact model nucleosomes containing H3K36me2 and H3K36me3. MRG15 docking studies, along with experimental observations and nucleosome structure analysis suggest a model where the H3K36 side chain is sequestered in intact nucleosomes via a hydrogen bonding interaction with the DNA backbone, which is abrogated when the third methyl group is added to form H3K36me3. Hence, this mechanism provides a methyl-switch for contextdependent reader selectivity. These results highlight the importance of such intra-chromatin interactions in understanding epigenetic regulation, a feature which is absent in commonly-used peptide or histone-only models.

biochemistry↗