The current model for the lineage commitment of haematopoietic stem cells (HSCs) proposes that the first decisive step is the complete separation of myelopoiesis and lymphopoiesis through the generation of common myeloid progenitors (CMPs) and common lymphoid progenitors (CLPs). But a recent paper in Cell indicates that this might be preceded by a branch point separating cells that have erythroid and megakaryocytic potential from otherwise multipotent progenitors.

HSCs are defined by the phenotype lineage (Lin)−SCA1+KIThi (LSK) and can be subdivided by their expression of CD34 and FLT3 (fms-related tyrosine kinase 3) into a developmental progression of long-term HSCs (LT-HSCs; LSKCD34−FLT3−), short-term HSCs (ST-HSCs; LSKCD34+FLT3−) and a population of LSKCD34+FLT3+ HSCs. Jacobsen and colleagues first confirmed previous results showing that the LSKFLT3+ population has combined myeloid and lymphoid potential, being able to generate B cells, T cells and granulocyte/monocyte (GM) progenitors under the appropriate culture conditions. So, according to the current model, LSKFLT3+ cells should also be able to generate megakaryocytic and erythroid lineages, which are classically considered to be derived, together with GM progenitors, from CMPs.

However, a series of in vitro and in vivo experiments showed that LSKFLT3+ cells lack significant megakaryocytic and erythroid potential. Whereas 57% of single ST-HSCs produced megakaryocytes in response to culture with thrombopoietin, only 2% of LSKFLT3+ cells did so under the same conditions. Similarly, 53% of ST-HSCs generated erythroid progeny under appropriate culture conditions, compared with only 3% of LSKFLT3+ cells. Therefore, LSKFLT3+ cells lack in vitro megakaryocytic and erythroid potential beyond that which could be expected from sorting impurities. In vivo transplant experiments following myeloablation were then used to compare the reconstitution capacity of ST-HSCs and LSKFLT3+ cells. Whereas more than 80 megakaryocyte progenitors were generated per transplanted ST-HSC, transplanted LSKFLT3+ cells did not generate detectable numbers of megakaryocytes. And ST-HSCs substantially contributed to erythrocyte reconstitution in all mice tested, in contrast to a contribution from LSKFLT3+ cells in only 1 of 13 mice.

Consistent with their GM potential, quantitative reverse-transcriptase PCR showed that both ST-HSCs and LSKFLT3+ cells express high levels of mRNA encoding PU.1 and granulocyte colony-stimulating-factor receptor. By contrast, LSKFLT3+ cells had no expression of GATA1 (GATA-binding protein 1) or erythropoietin receptor and reduced expression of thrombopoietin receptor compared with ST-HSCs, all of which are known to be required for megakaryocyte and erythrocyte development.

The authors therefore conclude that the first HSC restriction step involves the loss of megakaryocytic and erythroid potential by ST-HSCs, which form LSKFLT3+ cells with both GM and CLP potential, and a population of megakaryocyte/erythrocyte progenitors. This new model is consistent with the fact that erythrocyte-like myeloid cells appear earlier in evolution and ontogeny than lymphoid cells.