A multi-niche culture method for mimicking human bone marrow

Abstract

Bone marrow is a complex, heterogeneous, primary immune tissue that is composed of distinct microenvironments. The stromal cells that make up these microenvironments regulate normal hematopoietic function and are instrumental in the tissue’s response during illness or therapeutic intervention. These stromal cells create the two primary niches in bone marrow: the endosteal and perivascular niches. While there are a sizeable number of examples of in vitro culture methods that recreate aspects of the bone marrow microenvironment using biomaterials, co-cultures, or ectopic implants, there are relatively few examples that recreate both the endosteal and perivascular niches in a single, defined culture. It is critical for both in vitro modeling of disease and furthering our understanding of the normal physiological processes of the bone marrow that we can recapitulate these basic structures of bone marrow together in a single platform. The overall goal of this dissertation was to create a multi-niche bone marrow mimic to study the role of the endosteal and perivascular niches in hematopoietic stem cell biology. In Aim 1, we designed, fabricated, and developed a microfluidic device, human bone marrow-on-a-chip (hBM-on-a-chip) that recreates the endosteal surface with adjacent microvasculature. In Aim 2, we assessed the utility of the hBM-on-a-chip as a platform for studying hematopoietic stem cell mobilization and the effects of radiation on the bone marrow microenvironment. The work presented in this dissertation provides tools for the in vitro study of human bone marrow, the hematopoietic system, and therapeutics that aim to alter its physiologic state.