Engineered 3D microenvironments to understand and direct liver progenitor and cancer cell fate

The cellular microenvironment encompasses every chemical and physical factor surrounding a cell, including all other cells, cell-cell and cell-extracellular matrix (ECM) signaling interactions and any detectible change in conditions. As the interplay between every component of the microenvironment synergistically or antagonistically leads to changes in cell function and fate, the use of engineered systems allows for deconstruction of the various cues to understand the roles that they play in cell behavior and to understand how these cues can be used to modulate cell fate. Often these systems take the form of in vitro 2D monolayer cell culture, but there is a concerted effort to integrate 3D engineered systems in cell fate determination studies due to their more in vivo-like structure and the significant changes in microenvironmental cues they provide. In this dissertation, I describe two different 3D engineered systems to examine different processes within the liver. One system was designed to examine liver progenitor development and integrate tunable factors that can be used to change the differentiation trajectory of these progenitors in a 3D aggregate. We found them to be very susceptible to the growth factor TGFβ1 and the introduction of polymer microparticles to push differentiation towards a desired fate. The other system utilized a tunable microarray system to create geometrically controlled hepatocellular carcinoma spheroids and 3D cancer co-culture spheroids with relevant niche cells, showing how manipulating the aggregate size, shape and potential co-culture changed cell behavior and fate. Together, these 3D engineered systems present different methods of deconstructing and manipulating microenvironmental cues to produce targeted cell fate changes within two different aspects of the liver, with many potential uses in other liver and non-liver specific processes.

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

2020

Author dc:creator

• Gentile, Stefan Dell

Contributors dc:contributor

• Underhill, Gregory H
• Wagoner Johnson, Amy J
• Kong, Hyunjoon
• Perez-Pinera, Pablo

• Engineered systems
• Bioengineering
• Microenvironment
• Extracellular matrix
• Hydrogel
• Cellular microarray
• High-throughput
• Confocal microscopy
• Flow cytometry
• Image cytometry
• Liver progenitor
• Liver development
• Hepatoblast
• Hepatocyte
• Cholangiocyte
• Biliary
• TGFβ1
• Cell spheroid
• 3D aggregates
• Hydrogel particles
• Liver cancer
• Hepatocellular carcinoma
• Tumor microenvironment
• 3D cancer culture
• Cancer co-culture
• Microwell array
• Drug response
• Hepatic stellate cells
• Portal fibroblasts
• Collagen

Statement dc:rights

• Copyright 2019 Stefan Gentile

Language dc:language

en

Handle dc:identifier

http://hdl.handle.net/2142/106454

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/106454