Biology subjects

Stoddard, A. E.

Publications and source records attributed to Stoddard, A. E..

3 recordsLinked to original sources

bioRxiv2026

Sphingosine-1-phosphate cross-talks to Notch via a S1PR1-Dll4-MPDZ complex to regulate endothelial barrier function

Sphingosine-1-phosphate (S1P) - a key bioactive component of high-density lipoproteins (HDL) - is instrumental in mediating HDLs cardiovascular benefits, largely by enhancing endothelial barrier integrity1, 2. Here, we discovered that S1P induces Notch1 activation, and this Notch activation is required to enhance Rac1 activity and adherens junction assembly, which in turn stimulates endothelial barrier integrity. S1P rapidly activates Notch1 by stimulating the G-coupled protein receptor, S1P Receptor 1 (S1PR1) to drive internalization of the Notch ligand Delta-like protein 4 (Dll4). Notably, this internalization of Dll4 and subsequent activation of Notch does not involve traditional G-protein signaling; instead, S1P-bound S1PR1 forms a complex with Dll4 via the scaffolding protein MPDZ, and the undergoes co-endocytosis. Importantly, the loss or inhibition of Notch, Dll4, S1PR1, or MPDZ results in barrier defects. These findings elucidate a novel S1PR1-Dll4-MPDZ-Notch1 signaling axis that coordinates S1P and Notch signaling to regulate of endothelial cell signaling and barrier function.

cell biology↗

bioRxiv2025

Synthetic Control of Implanted Engineered Liver Tissue Growth

Despite the promise of engineered tissue implants for the treatment of organ failure, scaling of these constructs to sizes of therapeutic relevance remains a barrier to clinical translation. Here, we propose a strategy to circumvent this limitation: to instead implant a small-scale construct and then induce it to grow in situ after its engraftment into a host. Using engineered liver tissue as a proof-of-concept application, we integrated synthetic biology and tissue engineering tools to build liver tissues that can be expanded on-demand after implantation in vivo. To achieve this goal, we first identified the combination of YAP and growth factor signaling as sufficient to drive human hepatocyte proliferation in dense, 3D engineered tissues. We then engineered control of these signaling axes using synthetic biology tools to drive human liver tissue expansion both in vitro and in vivo. As such, this work establishes a genetic strategy for generating large organ implants through bioengineered, on-demand outgrowth using synthetic triggers (BOOST). TeaserPresenting bioengineered on-demand outgrowth via synthetic biology triggering (BOOST) for in situ solid cell therapy scale up.

bioengineering↗

bioRxiv2020

Differentiation of human intestinal organoids with endogenous vascular endothelial cells

Human pluripotent stem cell (hPSC)-derived intestinal organoids (HIOs) generated using directed differentiation lack some cellular populations found in the native organ, including vasculature. Using single cell RNA sequencing (scRNAseq), we have identified a transient population of endothelial cells (ECs) present early in HIO differentiation that are lost over time in culture. Here, we have developed a method to enhance co-differentiation and maintenance of ECs within HIOs (vHIOs). Given that ECs are known to possess organ specific gene expression, morphology and function, we used bulk RNAseq and scRNAseq to interrogate the developing human intestine, lung, and kidney in order to identify organ-enriched EC-gene signatures in these organ systems. By comparing organ-specific gene signatures along with markers validated by fluorescent in situ hybridization to HIO ECs, we find that HIO ECs grown in vitro share the highest similarity with native intestinal ECs relative to kidney and lung. Together, these data show that HIOs can co-differentiate a native EC population that are properly patterned with an intestine-specific EC transcriptional signature in vitro.

developmental biology↗