Maintenance of the mammalian blood system is dependent on hematopoietic stem cells (HSCs). HSCs are long-living multipotent stem cells with the potential to differentiate into all blood cell lineages. In mammals, hematopoiesis takes place in different sites during embryogenesis. These sites include the yolk sac, aorta-gonad mesonephros (AGM), and fetal liver. In adults, the differentiation of blood cells takes place primarily in bone marrow.

 

The classical model of hematopoiesis is viewed as a tree in which HSCs sequentially branch out into lineage-restricted progenitors of erythroid, myeloid, lymphoid, and megakaryocytic lineages. In this model, each progenitor is believed to represent a homogeneous population of cells with the equal potential to give rise to multiple lineages simultaneously.

 

However, despite evidence for hierarchical hematopoietic differentiation, recent studies have provided evidence suggesting there is clonal heterogeneity of multipotent and oligopotent progenitors. For example, it has been shown that on a population level, mouse CMPs are able to produce cells of myeloid, erythroid, and megakaryocytic lineages. Single-cell differentiation analysis of CMPs suggest that each clone is programmed to give rise to one type of blood cell only (i.e., macrophage, neutrophil, erythrocyte, megakaryocyte, etc.) Similar studies have also been done on other mouse and human progenitors including LMPP and GMPs.