Biology subjects

Young, R. E.

Publications and source records attributed to Young, R. E..

6 recordsLinked to original sources

bioRxiv2025

Investigating the Impact of Hypoxia and Syncytialization on Lipid Nanoparticle-Mediated mRNA Delivery to Placental Cells

Placental dysfunction leads to pregnancy-related disorders that affect up to 15% of pregnancies. Several of these, such as preeclampsia, are symptomatically managed but have no curative treatments other than preterm delivery. Placental dysfunction arises from improper placental development, leading to restricted blood vessel formation and a hypoxic placental microenvironment. The development of placental therapeutics is challenging due to the complex physiology that enables the placenta to have precise control over endocytosis and transport. Here, we use a simple culture system that combines hypoxia and trophoblast syncytialization to model the functional syncytiotrophoblast layer of the placenta under hypoxic stress. Using this model, we evaluate the impact of hypoxia on lipid nanoparticle (LNP)-mediated mRNA delivery. Our data shows that hypoxia hinders syncytiotrophoblast formation in vitro. Despite this, LNP delivery to syncytiotrophoblasts increases protein translation and secretion, particularly under hypoxic conditions. Further, we show delivery of a therapeutic mRNA, placental growth factor (PlGF), to syncytiotrophoblasts in hypoxia, which restored diminished PlGF levels back to normoxic controls. These findings provide an LNP platform for efficient mRNA delivery to hypoxic trophoblasts and demonstrate the importance of considering hypoxia towards the development of drug delivery platforms for placental therapeutics. Translational Impact StatementThis study investigates lipid nanoparticle (LNP)-mediated mRNA delivery to placental cells cultured in a simple hypoxia model, simulating the microenvironment of the placenta during pregnancy complications such as preeclampsia. We provide insights essential for developing LNP drug delivery platforms for treating disorders of the placenta. These findings will guide future design of LNP-based treatments for delivery to the diseased, hypoxic placenta, minimizing systemic exposure and improving outcomes in maternal and fetal health for conditions lacking effective, targeted interventions.

bioengineering↗

bioRxiv2025

Cytokine mRNA Delivery and Local Immunomodulation in the Placenta using Lipid Nanoparticles

During pregnancy, the maternal immune system adapts to balance tolerance of the semi-allogenic fetus while protecting the fetus from pathogens. Dysregulated immune activity at the maternal-fetal interface contributes to pregnancy complications, such as recurrent pregnancy loss and preeclampsia. Compared to healthy placentas, preeclamptic placentas exhibit increased pro-inflammatory signaling, including a predominance of inflammatory macrophages, leading to impaired tissue remodeling and restricted blood flow. However, the precise mechanisms driving this immune imbalance remain poorly understood, in part due to the lack of tools to probe individual pathways. Here, we use lipid nanoparticles (LNPs) to deliver cytokine-encoded mRNA to placental cells, called trophoblasts, enabling local immunomodulation. LNP-mediated delivery of IL-4 and IL-13 mRNA induced cytokine secretion by trophoblasts, leading to polarization of primary human monocytes toward anti-inflammatory phenotypes. Notably, lowering the mRNA dose increased expression of alternatively-activated macrophage markers, revealing an inverse relationship between dose and polarization status. Intravenous injection of LNPs in pregnant mice achieved placental secretion of IL-4 and IL-13 with minimal changes to pro-inflammatory cytokines in the serum. These findings establish LNPs as a tool for local immunomodulation in the placenta, offering a strategy to study and treat immune dysfunction in pregnancy and in other inflammatory conditions.

bioengineering↗

bioRxiv2023

The lung employs an intrinsic surfactant-mediated inflammatory response for viral defense

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) causes an acute respiratory distress syndrome (ARDS) that resembles surfactant deficient RDS. Using a novel multi-cell type, human induced pluripotent stem cell (hiPSC)-derived lung organoid (LO) system, validated against primary lung cells, we found that inflammatory cytokine/chemokine production and interferon (IFN) responses are dynamically regulated autonomously within the lung following SARS-CoV-2 infection, an intrinsic defense mechanism mediated by surfactant proteins (SP). Single cell RNA sequencing revealed broad infectability of most lung cell types through canonical (ACE2) and non-canonical (endocytotic) viral entry routes. SARS-CoV-2 triggers rapid apoptosis, impairing viral dissemination. In the absence of surfactant protein B (SP-B), resistance to infection was impaired and cytokine/chemokine production and IFN responses were modulated. Exogenous surfactant, recombinant SP-B, or genomic correction of the SP-B deletion restored resistance to SARS-CoV-2 and improved viability.

immunology↗

bioRxiv2022

Lipid Nanoparticle Composition Drives Delivery of mRNA to the Placenta

Ionizable lipid nanoparticles (LNPs) have gained attention as mRNA delivery platforms for vaccination against COVID-19 and for protein replacement therapies. LNPs enhance mRNA stability, circulation time, cellular uptake, and preferential delivery to specific tissues compared to mRNA with no carrier platform. However, LNPs have yet to be developed for safe and effective mRNA delivery to the placenta as a method to treat placental dysfunction. Here, we develop LNPs that enable high levels of mRNA delivery to trophoblasts in vitro and to the placenta in vivo with no toxicity. We conducted a Design of Experiments to explore how LNP composition, including the type and molar ratio of each lipid component, drives trophoblast and placental delivery. Our data revealed that a specific combination of ionizable lipid and phospholipid in the LNP design yields high transfection efficiency in vitro. Further, we present one LNP platform that exhibits highest delivery of placental growth factor mRNA to the placenta in pregnant mice, which demonstrates induced protein synthesis and secretion of a therapeutic protein. Lastly, our high-performing LNPs have no toxicity to both the pregnant mice and fetuses. Our results demonstrate the feasibility of LNPs as a platform for mRNA delivery to the placenta. Our top LNPs may provide a therapeutic platform to treat diseases that originate from placental dysfunction during pregnancy.

bioengineering↗

bioRxiv2020

Single Nucleus Multiomic Profiling Reveals Age-Dynamic Regulation of Host Genes Associated with SARS-CoV-2 Infection

Respiratory failure is the leading cause of COVID-19 death and disproportionately impacts adults more than children. Here, we present a large-scale snATAC-seq dataset (90,980 nuclei) of the human lung, generated in parallel with snRNA-seq (46,500 nuclei), from healthy donors of ~30 weeks, ~3 years and ~30 years of age. Focusing on genes implicated in SARS-CoV-2 cell entry, we observed an increase in the proportion of alveolar epithelial cells expressing ACE2 and TMPRSS2 in adult compared to young lungs. Consistent with expression dynamics, 10 chromatin peaks linked to TMPRSS2 exhibited significantly increased activity with age and harbored IRF and STAT binding sites. Furthermore, we identified 14 common sequence variants in age-increasing peaks with predicted regulatory function, including several associated with respiratory traits and TMPRSS2 expression. Our findings reveal a plausible contributor to why children are more resistant to COVID-19 and provide an epigenomic basis for transferring this resistance to older populations.

genomics↗

bioRxiv2018

Extensive recombination suppression and chromosome-wide differentiation of a segregation distorter in Drosophila

Segregation distorters violate Mendelian Inheritance by over-representing themselves in the progeny of carrier individuals and are commonly associated with chromosomal inversions. When distorting alleles are found on sex chromosomes, the progeny of carrier individuals will exhibit skewed sex ratios, as exemplified by the array of Sex-Ratio (SR) distorting chromosomes found in Drosophila. Because of the strong selective pressures such chromosomes are thought to inflict on genomes, segregation distorters and their associated inversions are expected to experience rapid turn-over. However, the SR X-chromosome of Drosophila pseudoobscura is found at high frequencies in natural populations, forms stable latitudinal clines, appears to be unsuppressed, and shows evidence of being quite long-lived. Despite being a historically significant and well-studied segregation distortion system, the mechanisms allowing for the long-term persistence of the D. pseudoobscura SR chromosome remain unclear. Here, we perform a comparative genomic analysis between SR and uninverted standard X-chromosomes in D. pseudoobscura to study its evolutionary history and dynamics. We find a substantial level of differentiation between the SR and standard chromosome and estimate that the associated inversions have likely existed for the entire lifetime of the species (> 2 million generations). Through direct recombination experiments and population genetic analyses, we infer that this high level of differentiation is maintained by a combination of suppressed recombination and epistatic selection. Finally, our data reveal a massive mutational target size for protein and expression level changes specific to SR generated by its three non-overlapping inversions. Together our results imply that the entire SR chromosome in D. pseudoobscura behaves as a single co-adapted gene complex and has been maintained through a combination of suppressed recombination and epistatic selection. This finding highlights the dramatic consequences segregation distorters can have in shaping chromosome-wide patterns of recombination, nucleotide variation, and gene expression.

evolutionary biology↗