The extent to which primitive embryonic blood progenitors contribute to definitive lymphoid-myeloid hematopoiesis in the adult remains uncertain. In an effort to characterize factors that distinguish the definitive adult hematopoietic stem cell (HSC) and primitive progenitors derived from yolk sac or embryonic stem (ES) cells, we examined the effect of ectopic expression of HoxB4, a homeotic selector gene implicated in self-renewal of definitive HSCs. Expression of HoxB4 in primitive progenitors combined with culture on hematopoietic stroma induces a switch to the definitive HSC phenotype. These progenitors engraft lethally irradiated adults and contribute to long-term, multilineage hematopoiesis in primary and secondary recipients. Our results suggest that primitive HSCs are poised to become definitive HSCs and that this transition can be promoted by HoxB4 expression. This strategy for blood engraftment enables modeling of hematopoietic transplantation from ES cells.
Bibliographical noteFunding Information:
This work was supported by grants from the National Institutes of Health (CA86991 and DK59279), the National Science Foundation, MIT Biotechnology Process Engineering Center, the Canadian Institutes of Health Research, and the Alberta Heritage Foundation for Medical Research. G.Q.D. is the Birnbaum Scholar of the Leukemia and Lymphoma Society of America. We thank Keith Humphries for providing the HoxB4 cDNA, Anton Wutz for assistance in reengineering the inducible ES cell line, and Rudolf Jaenisch, William Rideout, Konrad Hochedlinger, and Andrew Chess for helpful comments on the manuscript.