The (intra-aortic) hematopoietic cluster cocktail: what is in the mix?

The adult-definitive hematopoietic hierarchy and hematopoietic stem cells (HSCs) residing in the bone marrow are established during embryonic development. In mouse, human, and many other mammals, it is the sudden formation of so-called intra-aortic/arterial hematopoietic clusters (IAHCs) that best signifies and visualizes this de novo generation of HSCs and hematopoietic progenitor cells (HPCs). Cluster cells arise through an endothelial-to-hematopoietic transition and, for some time, express markers/genes of both tissue types, whilst acquiring more hematopoietic features and losing endothelial ones. Among several hundreds of IAHC cells, the midgestation mouse embryo contains only very few bona fide adult-repopulating HSCs, suggestive of a challenging cell fate to achieve. Most others are HPCs of various types, some of which have the potential to mature into HSCs in vitro. Based on the number of cells that reveal hematopoietic function, a fraction of IAHC cells is uncharacterized. This review aims to explore the current state of knowledge on IAHC cells. We will describe markers useful for isolation and characterization of these fleetingly produced, yet vitally important, cells and for the refined enrichment of the HSCs they contain, and speculate on the role of some IAHC cells that are as-yet functionally uncharacterized.