ESCs and hematopoietic fate: mixing the perfect “cocktail”

The relatively recent availability of human embryonic stem cell (ESC) lines holds tremendous potential for a variety of therapeutic applications. ESCs are self-renewing and pluripotent, capable of generating cells of all tissue types. The ability to coax ESCs in vitro toward lineage-specific differentiation by varying culture conditions has been demonstrated in several mammalian species. But detailed characterization of the culture conditions required for differentiation of human ESCs has not been elucidated. Comparison of undifferentiated mouse and human ESCs has revealed important differences in morphology, marker gene expression, and culture conditions, further emphasizing the need for the precise characterization of human ESCs.

In this issue, Chadwick and colleagues (page 906) report that BMP-4, together with a specific combination of cytokines, can reproducibly induce multilineage hematopoietic fate from human ESCs under embroid body (EB) culture conditions. These results are consistent with the early role of BMP-4 in inducing ventral mesoderm, the tissue that gives rise to all embryonic blood lineages. Chadwick and colleagues further demonstrate that BMP-4, either alone or in combination with cytokines, promotes an increase in self-renewal of hESC-derived hematopoietic precursors, without significantly affecting their differentiation.

The detailed characterization presented here extends previous findings and represents an important step in defining a “cocktail” of factors capable of efficiently inducing hematopoietic differentiation from human ESCs. Recent studies have shown that the Wnt (Reya et al, Nature. 2003;423: 409-414) and FGF (de Haan et al, Dev Cell. 2003;4:241-251) signaling pathways can promote expansion and self-renewal of murine HSCs. Do these signaling pathways interact or synergize with the BMP-4 pathway to enhance multilineage hematopoietic differentiation from human ESCs? Future studies addressing the identification of the precise target populations acted upon under specific culture conditions and the further assessment of the long-term repopulating ability of these cells will be critical. Such studies lead the way toward a better understanding of the early development of human ESCs and provide a basis for tapping into their tremendous clinical potential.