Clonal analysis of differentiating embryonic stem cells reveals a hematopoietic progenitor with primitive erythroid and adult lymphoid-myeloid potential

Embryonic stem (ES) cells differentiate into multiple hematopoietic lineage s during embryoid body formation in vitro, but to date, an ES-derived hemat opoietic stem cell has not been identified and subjected to clonal analysis in a manner comparable with hematopoietic stem cells from adult bone marro w. As the chronic myeloid leukemia-associated BCR/ABL oncogene endows the a dult hematopoietic stem cell with clonal dominance without inhibiting pluri potent lymphoid and myeloid differentiation, we have used BCR/ABL as a tool to enable engraftment and clonal analysis. We show that embryoid body-deri ved hematopoietic progenitors expressing BCR/ABL maintain a primitive hemat opoietic blast stage of differentiation and generate only primitive erythro id cell types in vitro. These cells can be cloned, and when injected into i rradiated adult mice, they differentiate into multiple myeloid cell types a s well as T and B lymphocytes. While the injected cells express embryonic ( beta -H1) globin, donor-derived erythroid cells in the recipient express on ly adult (beta -major) globin, suggesting that these cells undergo globin g ene switching and developmental maturation in vivo. These data demonstrate that an embryonic hematopoietic stem cell arises in vitro during ES cell di fferentiation that constitutes a common progenitor for embryonic erythroid and definitive lymphoid-myeloid hematopoiesis.