Hydrogel platform to investigate the coordinated impact of niche signals on hematopoietic stem cell fate

Hematopoietic stem cells (HSCs) regulate the process of hematopoiesis, which is the formation and development of all the body’s blood and immune cells. The HSCs ability to either self-renew or differentiate in order to produce these populations is determined by a number of known as well as hypothesized regulators of HSC biology in specific microenvironments, termed as ‘niches’, in vivo. However, in order to explore their therapeutic potential, controlling HSC fate in vitro is important. Current culture approaches lack the capacity to incorporate combinations of instructive signals to guide desired HSC fate decisions. Furthermore, approaches to examine in detail signaling mechanisms involved in cross-talk between multiple signals are largely underdeveloped. In this thesis, I describe the development of a gradient hydrogel platform that enables co-culture of HSCs with multiple niche components, namely exogenous niche cells, extracellular matrix proteins, and matrix-tethered biomolecular signals. Gradients in microenvironmental signals are common across the marrow; these gradients are thought to play a critical role in HSC signaling and migration. The biomaterial fabrication platform described here enables creation and subsequent analysis of gradient environments in an attempt to understand the effects of niche components on HSC fate. Building upon the gradient platform, we will also discuss the development of an approach to functionalize the biomaterial with proteins that provide an additional degree of instructive signals to manipulate HSC response. Finally, using a diffusion-limited hydrogel network we alter the balance of niche-cell mediated paracrine and HSC-mediated autocrine signals as a novel approach to manipulate HSC response. Balancing these signals in an in vitro platform may eventually offer a path for improved control over HSC self-renewal versus lineage specification for a range of clinical applications. An ultimate goal is developing the capacity to engineer HSC fate in vitro, enabling better clinical therapies and providing insights into blood-related cancers and disorders.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Chemical Engineering

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2014

Author dc:creator

• Mahadik, Bhushan Prakash

Contributors dc:contributor

• Harley, Brendan A.
• Kenis, Paul J.A.
• Kong, Hyun Joon
• Bashir, Rashid

• Hematopoietic stem cell
• Hydrogel: Biomaterial
• gradient
• microfluidic

Statement dc:rights

• Copyright 2014 Bhushan Mahadik

Language dc:language

en

Handle dc:identifier

http://hdl.handle.net/2142/50454

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/50454