UC San Diego

Hematopoietic stem cells (HSCs) can give rise to all terminally differentiated cells of the blood, and are used in therapeutic approaches to treat hematopoietic cancers and disorders. Patient-specific HSCs derived from pluripotent precursors have long been a goal of the field, but despite tireless efforts it is not yet possible to derive therapy-grade HSCs in vitro. Here, I utilize the zebrafish as a model system in which to identify critical molecular cues that are required for normal HSC development. I have identified the Wnt signaling pathway to be critical for the intra-aortic expansion of zebrafish HSCs, and Wnt9a to be the ligand that mediates this signal. In the zebrafish, this

requirement is highly specific; loss of Wnt9a cannot be compensated for by the exogenous expression of Wnt9b or Wnt3a. The function of Wnt9a is conserved across species; exogenous expression of WNT9A during in vitro hematopoietic progenitor differentiation improves the efficiency of generating CD34+/CD45+ hematopoietic progenitor cells from human embryonic stem cells. My data indicates that Wnt9a is a conserved regulator of hematopoietic stem and progenitor cell development. Inclusion of WNT9A in protocols to derive hematopoietic stem and progenitor cells from pluripotent precursors could more accurately mimic the molecular cues that drive HSC development in vivo.