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Hematopoietic stem cells (HSCs) must exhibit tight regulation of both self‐renewal and differentiation to maintain homeostasis of the hematopoietic system as well as to avoid aberrations in growth that may result in leukemias or other disorders. In this study, we sought to understand the molecular basis of lineage determination, with particular focus on factors that influence megakaryocyte/erythrocyte‐lineage commitment, in hematopoietic stem and progenitor cells. We used intracellular flow cytometry to identify two novel hematopoietic progenitor populations within the mouse bone‐marrow cKit(+) Lineage (−) Sca1(+) (KLS) Flk2 (+) compartment that differ in their protein‐level expression of GATA1, a critical megakaryocyte/erythrocyte‐promoting transcription factor. GATA1‐high repopulating cells exhibited the cell surface phenotype KLS Flk2(+ to int), CD150(int), CD105(+), cMPL(+), and were termed “FSE cells.” GATA1‐low progenitors were identified as KLS Flk2(+), CD150(−), and cMPL(−), and were termed “Flk(+) CD150(−) cells.” FSE cells had increased megakaryocyte/platelet potential in culture and transplant settings and exhibited a higher clonal frequency of colony‐forming unit–spleen activity compared with Flk(+) CD150(−) cells, suggesting functional consequences of GATA1 upregulation in promoting megakaryocyte and erythroid lineage priming. Activation of ERK and AKT signal‐transduction cascades was observed by intracellular flow cytometry in long‐term HSCs and FSE cells, but not in Flk(+) CD150(−) cells in response to stimulation with thrombopoietin, an important megakaryocyte‐promoting cytokine. We provide a mechanistic rationale for megakaryocyte/erythroid bias within KLS Flk2(+) cells, and demonstrate how assessment of intracellular factors and signaling events can be used to refine our understanding of lineage commitment during early definitive hematopoiesis. S TEM  C ELLS  2011;29:1774–1782

Novel Hematopoietic Progenitor Populations Revealed by Direct Assessment of GATA1 Protein Expression and cMPL Signaling Events