Generation of Hematopoietic Stem and Progenitor Cells from Multiple Source-Derived Endothelial Cells

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Hematopoietic stem cells (HSCs) are the central organizers of the entire blood system throughout the lifetime of an individual. Recent findings strongly support the concept that HSCs are formed from hemogenic endothelial cells (HECs) in mid-gestation mouse embryos by a process termed endothelial-to-hematopoietic transition (EHT). Therefore, a deeper understanding of the underlying processes controlling EHT and the subsequent maturation of HSCs during embryonic development presumably is a key prerequisite for the efficient generation of HSCs from non-hematopoietic cell sources, such as induced pluripotent stem (iPS-) cells. iPSC-derived HSCs may hold great promise for patient-tailored, autologous HSC-based cell therapies in future by eliminating the risk of a life-threatening graft-versus-host disease associated with allogeneic stem cell transplantation.The aim of this joint Chinese-German project is to generate HSCs from endothelial cells of embryonic, postnatal and pluripotent stem cell (PSC) - derived sources, based on insights into the regulatory mechanisms of their ontogeny. In a coordinated step-by-step approach, we will first purify hemogenic endothelium subpopulations both from embryos and differentiating PSCs, define their molecular identity by transcriptome analysis and determine their developmental potencies. Because extrinsic niche cells are known to control HSC development at different anatomical sites and during different developmental stages, we will investigate the suitability of a set of stroma cells to support a full maturation of the post-EHT/pre-HSCs of mice and humans. Genes found to be specifically and concordantly expressed both in the in vitro and in vivo systems, including two recently identified candidates, will be interrogated for their role in the emergence, maturation and expansion of HSCs by ectopic expression and tissue-specific knockouts in endothelial and hematopoietic cells.