A human pluripotent stem cell-based approach to study human hematopoietic stem cell development

Although hematopoietic stem cell (HSCs) transplantation is routinely used to treat blood disorders, immune incompatibility and donor shortage remain critical clinical barriers. Likewise, since high number of HSC are needed for successful transplants, the absence of reliable expansion protocols prevents the wider application of this cell therapy. Patient-specific induced pluripotent stem cells (PSCs) could serve as a solution to these problems, as they would provide a potentially unlimited, easy to engineer, source of immunologically matched HSCs. However, despite recent advances, the robust de novo generation of HSCs remains unrealized due to an incomplete understanding of how HSCs are generated during embryonic development, a process that, as such, cannot be accurately recapitulated in vitro. To tackle these issues, in this proposal we will leverage on our proven expertise in PSC differentiation and hematopoietic development. In particular, we will determine at the molecular level how HSC precursors control their gene expression to generate blood cells. In addition, we will uncover the molecular regulators of the extensive embryonic self-renewal, thus enabling specification of HSCs from PSCs. This will enable the future design of strategies to resurrect this embryonic self-renewal program in postnatal HSCs for their in vitro expansion. Our unique cellular and molecular tools, combined with our expertise in hematopoietic development and stem cell biology, sets us in an ideal position to understand how we can generate and grow blood cells in a lab.