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

Berg, Ian Charles Edwin

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https://hdl.handle.net/2142/110802 Copy

Description

Title

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

Author(s)

Berg, Ian Charles Edwin

Issue Date

2021-04-21

Director of Research (if dissertation) or Advisor (if thesis)

Underhill, Gregory H

Doctoral Committee Chair(s)

Underhill, Gregory H

Committee Member(s)

• Sirk, Shannon J
• Harley, Brendan
• Saif, Taher

Department of Study

Bioengineering

Discipline

Bioengineering

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

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

Abstract

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.

Graduation Semester

2021-05

Type of Resource

Thesis

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

Copyright and License Information

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

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