Development of an in vitro model to mimic the human vascular stem cell niche
The human body constantly requires new blood cells to remain viable. The hematopoietic stem cells (HSCs) located in the red bone marrow take over this essential function. Due to their self-renewing and multipotent differentiation properties, they are able to reconstitute all cells of the human blood system. In vivo, HSCs retain their stemness due to the complex and highly specialized three-dimensional microenvironment in their so-called “niches”. The vascular stem cell niche is located in the perisinusoidal space in close proximity to blood vessels. Here, endothelial cells (ECs) and mesenchymal stem/stromal cells (MSCs) are the most essential supporter cell types for the HSCs. ECs, which line blood vessels, are responsible for the uptake of nutrients and oxygen from the blood, but inside the vascular niche they also serve as instructive cells and are involved in maintenance and regeneration of HSCs.
The aim of this study is to find a suitable model to mimic the human vascular stem cell niche as this would enable fundamental studies in this field and serve applications such as HSC multiplication. Recreating the tiny blood vessels typical for the vascular niche will be a crucial step that could also help solving problems regarding perfusion and vascularization of engineered tissue, which are as yet without satisfying solutions.
To design a model for the vascular niche, cell sheet engineering is used. The cells are cultured on thermoresponsive polymers, which allow detaching the cells as one sheet, keeping them within their extracellular matrix. In this study, it is planned to culture bone marrow derived MSCs as a cell sheet, covered with a thin layer of endothelial cells on thermoresponsive polymers. By lowering the temperature, the cells can be detached and rolled to achieve a 3D structure. For stabilization, the cell sheet will be embedded into a hydrogel after rolling. To complete the triculture of cells that are found in the vascular niche vivo, HSCs will be seeded on top of the embedded cell sheet. In a last step, it is planned to perfuse the created artificial tissue by the implementation of vascular structures to ensure a sufficient delivery of nutrients and oxygen.
With this 3D model of the vascular niche, it is then possible to gain more knowledge about the behavior and interaction of the different cell types in future studies. Furthermore, it could be used to achieve perfusion and vascularization of tissue in tissue engineering applications.