Deconstructing the influences of combinatorial microenvironmental cues on human non-parenchymal liver cells in models of liver fibrosis

Liver disease is a major public health concern, and one of the key sources of tissue and organ dysregulation in liver disease is the onset of fibrosis. Liver fibrosis produces changes in the composition of the liver and has profound repercussions for cell behavior and function, especially in tissue microenvironments. The makeup and configuration of the microenvironment is critical in directing cell behaviors due to the myriad extracellular cues it presents. Cellular microarray technology is a powerful platform for efficiently and robustly dissecting the effects of multiple microenvironmental parameters simultaneously. In this dissertation, I describe the use of high-throughput cellular microarrays to investigate the role of combinatorial microenvironments in regulating the phenotypes of two important cell types of the liver, hepatic stellate cells (HSCs) and liver sinusoidal endothelial cells (LSECs), in models of liver fibrosis. We discovered that these cells are highly sensitive to microenvironmental context, and in testing various combinations of extracellular matrix (ECM) proteins, substrate stiffness, and soluble factors, we revealed and characterized previously undescribed patterns and trends in HSC and LSEC phenotype plasticity and heterogeneity. We also demonstrated that HSC-LSEC interactions are regulated by microenvironmental context and present a new framework for understanding how these cells respond to each other and their microenvironments in fibrosis. Taken together, these findings will assist with development of therapeutics for liver fibrosis and deepen our knowledge and understanding of fundamental cell biology in healthy and fibrotic livers.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Bioengineering

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2022

Author dc:creator

• Brougham-Cook, Aidan James

Contributors dc:contributor

• Underhill, Gregory H
• Perez-Pinera, Pablo
• Harley, Brendan
• Khetani, Salman R

• ECM
• Stiffness
• soluble factors
• HSC
• LSEC
• high-throughput
• microenvironment

Statement dc:rights

• Copyright 2022 Aidan Brougham-Cook

Language dc:language

en, eng

Handle dc:identifier

https://hdl.handle.net/2142/115568

OAI record oai:identifier

https://www.ideals.illinois.edu/oai-pmh?verb=GetRecord&metadataPrefix=etdms&identifier=oai%3Awww.ideals.illinois.edu%3A2142%2F115568