Differentiation and proliferation of hematopoietic stem cells.

Available evidence indicates that qualitative changes in hematopoietic stem cells and progenitors, such as the decision of stem cells to self-renew or differentiate, or selection of lineage potentials by the multipotential progenitors during differentiation (commitment), are intrinsic properties of the progenitors and are stochastic in nature. In-contrast, proliferative kinetics of the progenitors, namely survival and expansion of the progenitors, appear to be controlled by a number of interacting cytokines. While proliferation and maturation of committed progenitors is controlled by late-acting lineage-specific factors such as Ep, M-CSF, G-CSF, and IL-5, progenitors at earlier stages of development are controlled by a group of several overlapping cytokines. IL-3, GM-CSF, and IL-4 regulate proliferation of multipotential progenitors only after they exit from G0 and begin active cell proliferation. Triggering of cycling by dormant primitive progenitors and maintenance of B-cell potential of the primitive progenitors appears to require interactions of early acting cytokines including IL-6, G-CSF, IL-11, IL-12, LIF, and SF. Currently, this simple model fits our understanding of the interactions of growth factors with hematopoietic progenitors. Naturally the model risks oversimplification of a very complex process. However, because the model is testable, it will hopefully challenge investigators to design new experiments to examine its validity.