The Endothelium and the Bone Marrow Microenvironment
Kotha, Surya Shree
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The bone marrow vasculature provides an interface between the circulation and hematopoietic tissue, allowing for hundreds of billions of blood cells to enter the circulation in an adult human every day. Much is unknown, however, about the characteristics of marrow vasculature and interactions of hematopoietic progenitor cells or their progeny with the endothelium. This is largely due to the cellular and architectural complexity in vivo and lack of appropriate in vitro hematopoietic vascular models. The following dissertation reports on the development of in vitro 3D human marrow microvascular platforms to study endothelial cells in the context of the marrow microenvironment. We describe the isolation and characterization of marrow-specific endothelial cells to determine their structural properties and their functional contributions to the marrow microenvironment. We demonstrate the co-culture of human marrow cells and endothelial cells to recapitulate an in vitro marrow microenvironment. To gain insight on thrombopoiesis, differentiating megakaryocytes were cultured in the microvessel platform observed over time. To examine the role of the microenvironment on the vasculature, we assessed the ability of marrow stromal fibroblasts to modify endothelial phenotype and demonstrated a role for fibroblasts and monocytes in directing hematopoietic cell trafficking. The effect of leukemic cells on vasculature was assessed in the microvessel platform to examine disease-induced vascular remodeling. Overall, these studies demonstrate the utility of a marrow-specific microvessel platform to examine hematopoietic cell interactions with vasculature. By guiding the interplay of heterogeneous cell populations, we have demonstrated the capacity to define distinct microenvironment spaces. Further development of this 3D marrow platform will further our understanding of the endothelial role in stem cell trafficking, residence, and differentiation in health and disease.
- Bioengineering