Routes to repopulation--a unification of the stochastic model and separation of stem-cell subpopulations.

In summary, we propose that the haemopoietic system consists of a hierarchy of clonogenic stem and progenitor cells and that the stochastic effect is superimposed upon these compartments. This means that (i) considerable heterogeneity can exist within major compartments without the need to invoke the existence of numerous subpopulations, and (ii) that the stochastic effect and the separation of stem cells are not totally incompatible. The unifying model offers a reasonable explanation of the situations summarized above. The clear implication of the disappearance of stem cell clones as a result of the stochastic effect is a requirement for multiple stem cells to ensure long-term repopulation in cell replacement or gene therapy. The necessary multiplicity may not be great, possibly 3-fold according to the results of Lemishka, and the scheme shown in Figure 1, but should be considered in the design and interpretation of experimental and therapeutic strategies. Other implications are concerned with the degree to which it is necessary to select 'subpopulations' of haemopoietic stem cells for transplantation or experimental work.