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

Barnhouse, Victoria Rae

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

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

Copyright and License Information

Copyright 2022 Victoria Barnhouse

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