Thesis Yvonne Dorland

Abstract

The bone marrow consists of many components, including hematopoietic stem and progenitor cells (HSPCs) that produce blood cells, stromal cells which have a supportive function, and endothelial cells forming the interior vascular wall. Mesenchymal stromal cells (MSCs) provide structural support to all bone marrow cells and instructive signals to guide hematopoiesis and are applied in a variety of cellular-based therapies. Matured blood cells cross the vascular wall, out of the bone marrow into the circulation. In this thesis, the interactions between HSPCs, MSCs, the endothelium and the bone marrow microenvironment are investigated. First, we explored the effect of the extracellular matrix protein TGFBI expression by MSCs and hematopoietic cells and found that a balanced expression of TGFBI in the bone marrow niche supports hematopoiesis. Furthermore, we uncovered that Lamin A/C expression defines the nuclear shape and the migration capacity of MSCs in vitro and viable retention of administered MSCs in vivo. During migration of MSCs, hematopoietic or immune cells across the endothelial barrier, an accurate response at the endothelial cell-to-cell contacts is required to protect the vasculature. We found that the F-BAR protein pacsin2 protects endothelial integrity during dynamic remodeling by inhibiting the internalization of cell-cell contact proteins. Finally, we examined how cell density and matrix rigidity affect the formation of the cell-cell contacts between cultured MSCs. In summary, this thesis comprises studies revealing new molecular processes involved in the crosstalk between endothelial, hematopoietic and mesenchymal stromal cells, thereby contributing to our understanding of bone marrow function.