Investigating the role of geometry, mechanics, and microenvironmental cues on liver progenitor cell differentiation

Engineered systems permit investigation of the variety of signals in the microenvironment that direct cells and tissue fates. This work focuses on developing and using such systems to investigate how mechanical characteristics impact liver progenitor cell differentiation. In this dissertation, I will introduce and review relevant concepts of mechanobiology and the 2D and 3D in vitro systems used doe measurement and manipulation. I then describe my work combining microarrays with a semi-automated implementation of TFM analysis to enables evaluation of the impact of substrate stiffness, matrix composition, and tissue geometry on cellular mechanical behavior in high throughput, and the application of this system to circular islands of liver progenitor cells. Here I characterize how peak cell to substrate traction stresses at the island periphery, which is also predicted by mechanical models, coincident with peak biliary fate. Building from this work, I next describe the development of a hydrogel-based microwell platform, which I used to produce arrays of 3D, multicellular liver progenitor cell microtissues in constrained geometries. These generated distinct mechanical profiles which I modeled with finite element method software, which was supported with mechanical measurements. I used this system to correlate patterns of tensile and compressive stress with patterns of progenitor cell fate. Finally, I adapted this system into a coculture platform used to investigate signaling between liver progenitor cells and portal fibroblasts, showing the portal fibroblasts lead to increased biliary differentiation in context-specific ways. This dissertation details the engineering behind these diverse methods for use by the scientific community, along with describing the specific contributions made to understanding liver development.

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

2021

Author dc:creator

• Berg, Ian Charles Edwin

Contributors dc:contributor

• Underhill, Gregory H
• Sirk, Shannon J
• Harley, Brendan
• Saif, Taher

• liver tissue engineering
• microwells
• 3D cell culture
• mechanobiology
• microtissues
• traction force microscopy
• hydrogels
• biomechanics

Statement dc:rights

• © 2021 by Ian C. E. Berg. All rights reserved

Language dc:language

en

Handle dc:identifier

http://hdl.handle.net/2142/110802

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/110802