University of Illinois Urbana-Champaign

Developing a biomaterial model of the bone marrow perivascular niche for the study of hematopoietic stem cells

Barnhouse, Victoria Rae

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BARNHOUSE-DISSERTATION-2022.pdf

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https://hdl.handle.net/2142/115673

Description

Title
Developing a biomaterial model of the bone marrow perivascular niche for the study of hematopoietic stem cells
Author(s)
Barnhouse, Victoria Rae
Issue Date
2022-03-31
Director of Research (if dissertation) or Advisor (if thesis)
Harley , Brendan AC
Doctoral Committee Chair(s)
Harley , Brendan AC
Committee Member(s)
  • Boppart, Marni
  • Underhill, Gregory
  • Cunningham , Brian
Department of Study
Bioengineering
Discipline
Bioengineering
Degree Granting Institution
University of Illinois at Urbana-Champaign
Degree Name
Ph.D.
Degree Level
Dissertation
Keyword(s)
  • hematopoietic stem cells
  • perivascular niche
  • biomaterials
  • hypoxia
Abstract
Hematopoietic stem cells (HSCs) are responsible for producing the body’s full complement of blood and immune cells through the process of hematopoiesis. These rare cells (0.007% of the bone marrow) can self-renew and differentiate to produce multiple cell lines. HSCs primarily reside in the bone marrow in specific microenvironments termed niches. The niche environment provides biophysical, cellular, and biochemical cues to guide HSC fate decisions such as proliferation, mobilization, self-renewal, and differentiation. HSCs are used clinically as a curative therapy for malignancies and disorders of the blood and immune system, such as leukemia and lymphoma. However, these transplants still have a high rate of failure, typically due to relapse of the primary disease but can also be caused by issues related to transplants, including low stem cell dose, failure to engraft, and graft vs host disease. Transplant success is correlated with the number of cells infused, thus methods to expand HSCs prior to transplant are under investigation. A better understanding of the native HSC niche will aid in the development of ex vivo expansion methods. One niche known to be important for retention of primitive HSCs is the perivascular niche, the region existing within ~20μm of blood vessels within the marrow. In this work, we describe the development of a tissue engineering model of the bone marrow perivascular niche to provide cellular, biophysical, and biochemical cues to HSCs. We first investigate the ability for angiocrine signals from the perivascular niche to maintain primitive HSPCs. We then report a microfluidic approach to create vascular gradients then investigate dose-dependent effects of vascular network density on Akt vs. MAPK signaling as well as Notch signaling through Jagged-1. We then describe a murine bone marrow-derived perivascular niche model, characterizing metrics of network formation, basement membrane deposition, and secretome to consider the arteriolar vs sinusoidal nature of the model. Direct co-culture of perivascular cells and HSCs is then examined for the potential to support expansion of differentiated hematopoietic cells while also maintaining a subpopulation of HSCs. Finally, we investigate the role of hypoxia on murine bone marrow perivascular network formation as well as subsequent proliferation versus maintenance of HSCs. Together, this thesis describes a series of new engineered microphysiological models to provide insight into how the bone marrow perivascular environment may influence HSC fate decisions.
Graduation Semester
2022-05
Type of Resource
Thesis
Handle URL
https://hdl.handle.net/2142/115673
Copyright and License Information
Copyright 2022 Victoria Barnhouse

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Graduate Dissertations and Theses at Illinois PRIMARY
Graduate Theses and Dissertations at Illinois