Modelling Human Developmental Hematopoiesis. Towards in vitro Generation of Human Hematopoietic Stem Cells

The possibility to manufacture hematopoietic stem cells (HSCs) in the laboratory would provide an indefinite source of cells for patients requiring bone marrow transplantation. Moreover, combined with the progress in gene editing techniques, it would provide a novel platform for gene and cell replacement therapies for a range of currently incurable congenic and acquired disorders. During my PhD, I worked with an optimized protocol for in vitro blood generation from human Pluripotent Stem Cells (hPSCs). It was designed to mimic human hematopoietic development, and allowed us to explore some aspects that could elicit in vitro generation of HSCs. Using single-cell transcriptional analysis, we could explore the gene expression dynamics driving the endothelial-to-hematopoietic transition that occurs during in vitro differentiation. We also used this platform to explore the role of adrenergic signaling in human hematopoietic development, and identified reactive oxygen species as a major hurdle likely impairing the generation of functional HSCs from hPSCs. In this thesis, I present these studies in the context of the development of the hematopoietic system as it occurs during embryonic development, and in the framework of the latest progress in the quest of in vitro generation of HSCs.