In addition to well-characterised CD34+ Haematopoietic Stem and Progenitor Cells (HSPCs), the human HSC hierarchy contains a rare CD34− population with a severely combined immunodeficiency-repopulating capacity. However, little is known about the molecular characteristics of these CD34− cells or their relationship to the CD34+ populations.
We have recently shown that the self-renewing Lin−CD34−CD38−CD93hi population contains cells that not only function as HSCs, but can also be placed above the CD34+ populations in the haematopoietic hierarchy. These cells have an active Notch pathway, in which signalling through Delta4 is crucial for maintenance of the primitive state, and the combined signals from Jagged1 and TGF-β are important in controlling its quiescence. They are also refractory to proliferative signals, and show a repressed canonical Wnt pathway, in part regulated by Notch.
Overall, therefore, CD34− cells represent an immature and quiescent human HSC population maintained through a distinctive network of cellular signalling interactions. Future work will aim to define the ontogeny of these cells, the role of this fraction under stress conditions, and ways to expand these cells (Anjos-Afonso et al., 2013; Cell Stem Cell. 13(2): 161-74).