Are transplantable stem cells required for adult hematopoiesis?

Hematopoietic stem cells (HSCs) have been studied intensely for more than half a century. As a result, the properties of HSCs have become a paradigm of adult stem cell biology and function. The "classical" view of hematopoiesis suggests that the HSCs sit at the top of a hierarchy and that differentiation involves sequential production of multipotent and lineage committed progenitors with limited self-renewal capacity. This view of hematopoiesis is certainly valid after transplantation of HSCs, where, with appropriate support, a single HSC can regenerate the entire hematopoietic system of the recipient. However, it is not clear whether HSCs perform the same function during steady-state hematopoiesis. Indeed, studies have shown that the majority of classical HSCs are not required for ongoing steady-state adult hematopoiesis. Several reports suggest that steady-state hematopoiesis relies on highly proliferative cells with more lineage restricted characteristics, a finding that was not anticipated based on results from transplantation experiments. However, other studies indicate a more substantial HSC contribution. Nevertheless, the notion of HSCs as distinct from progenitors appears to be simplistic in view of ample evidence for heterogeneity within the stem cell compartment. In this review we discuss recent results and controversies surrounding HSCs.