Angiogenic growth factors and notch signaling regulate liver sinusoidal endothelial cell phenotype in combination with matrix stiffness and ECM composition

Liver sinusoidal endothelial cells (LSECs) are the first liver cells that allow metabolites to pass from the bloodstream to the hepatocytes, and as such, are important targets when detangling the effects of extracellular matrix proteins and mechanical cues on overall liver disease progression. Soluble growth factors such as VEGF and FGF have been shown to play complex roles in both inflammatory pathways (as part of liver disease), but also in liver regeneration via angiogenesis. In this study, a high throughput protein microarray based on polyacrylamide hydrogels of different stiffnesses was used to simultaneously look at the effects of time, stiffness, protein combination, soluble factors, and mechanical inhibition on LSEC phenotype using the markers VE-Cadherin (VECAD), CD-31, and LYVE-1. It was found that time increased expression of phenotypic markers, and enhanced the differences between the 1 and 25 kPa stiffness conditions for LYVE-1 expression. Stiffness was found to consistently increase VE-Cadherin localization, and decrease CD31 and LYVE-1 expression. Moreover, the ECM combination Collagen1/Hyaluronic Acid (C1HA) consistently had the highest LYVE-1 expression across many different conditions. Notably, VEGF caused an increase in LYVE-1 expression on the soft 1kPa stiffness condition, but caused a decrease in the 25kPa condition. FGF followed a similar, if nonsignificant trend. DAPT, a Notch inhibitor drug, also unilaterally caused a decrease in LYVE-1 expression across the board, and in combination with VEGF, unilaterally increased VECAD localization and decreased LYVE-1 expression in relation to every other condition. This data could partially suggest that VEGF’s positive effects on LYVE-1 expression, and LSEC phenotype could be in part modulated by Notch, and in inhibiting Notch, VEGF has negative effects on LSEC phenotype.

Name thesis:degree_name

M.S.

Level thesis:degree_level

Thesis

Discipline thesis:degree_discipline

Bioengineering

Grantor

University of Illinois Urbana-Champaign

Year dc:date

2025

Author dc:creator

• Acharya, Ash

Contributors dc:contributor

• Underhill, Gregory H

• Notch Signaling
• VEGF
• FGF
• LSEC

Statement dc:rights

• Copyright 2025 Ash Acharya

Language dc:language

en, eng

Handle dc:identifier

https://hdl.handle.net/2142/129315

OAI record oai:identifier

https://www.ideals.illinois.edu/oai-pmh?verb=GetRecord&metadataPrefix=etdms&identifier=oai%3Awww.ideals.illinois.edu%3A2142%2F129315