In Vitro Bone Marrow Niches for Hematopoietic Cells: to have and to hold, in sickness and in health

Abstract

The bone marrow is a complex tissue within the bones, responsible for the production of blood cells. Within the bone marrow, different types of blood cells arise from so-called stem cells. The bone marrow plays an important role in the support and regulation of these hematopoietic stem and progenitor cells. Several malignancies can also develop in the bone marrow, including multiple myeloma, a cancer of plasma cells. Both cell types cannot survive outside the bone marrow and are therefore dependent on their surrounding, supportive environment: the bone marrow niche. By mimicking the bone marrow niche in vitro (outside the body), both hematopoietic stem and progenitor cells and multiple myeloma cells can be cultured and thus be used for further research. The studies described in this thesis investigate the possibilities to develop an artificial bone marrow niche model in vitro that can be used as a platform to culture hematopoietic stem and progenitor cells as well as myeloma cells. For both cell types, the components of a supportive bone marrow niche model were optimized. Various combinations of primary stromal cell types, hydrogels and biofabricated architectures were investigated, in search of the most essential components of these complex environments. The developed myeloma bone marrow niche model was further validated, analyzing the genetic stability of the cultured myeloma cells. Also the feasibility of using the model to assess therapeutic responses was analyzed. T cell therapy, liposomal drug therapy, as well as conventional chemotherapy were tested in the model, analyzing their effect on both myeloma cells and the supporting stromal cells. Lastly, the capability of the developed myeloma bone marrow niche model to predict clinical treatment outcomes was evaluated. The developed model will be used in further research to look at the effects of multiple myeloma cells and given anticancer therapies on the surrounding bone and bone marrow, as well as further research into the metastatic bone marrow niche environment, investigating cancer-niche interactions.