Most current theories assume that self-renewal and differentiation of hematolymphoid stem cells (HSCs) is randomly regulated by intrinsic and environmental influences. A direct corollary of these tenets is that self-renewal will continuously generate functionally heterogeneous daughter HSCs. Decisions about self-renewal versus commitment are made by individual, single HSCs and, thus, require examination on the clonal level. We followed the behavior of individual, clonally derived HSCs through long-term, serial repopulation experiments. These studies showed that daughter HSCs derived from individual clones were remarkably similar to each other in the extent and kinetics of repopulation. Moreover, daughter HSCs within a clone showed equivalent contributions to the myeloid or lymphoid lineages. Lineage contribution could be followed because of the discovery of a new subset of HSCs that gave rise stably to skewed ratios of myeloid and lymphoid cells. Overall, the data argue that self-renewal does not contribute to the heterogeneity of the adult HSC compartment. Rather, all HSCs in a clone follow a predetermined fate, consistent with the generation-age hypothesis. By extension, this suggests that the self-renewal and differentiation behavior of HSCs in adult bone marrow is more predetermined than previously thought.

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