Pluripoietin effects on CFU-S lineage determination: possible mechanisms

Regulation of pluripotent stem cell (CFU-S) proliferation kinetics by humoral factors is now well documented. However, the mechanism of choice of CFU-S differentiation pathways is still a controversial issue. We suggest that long-range humoral factors (pluripoietins) are capable of preferentially channelling CFU-S towards one of the cell lineages after various perturbations such as irradiation and drug treatment. The differentiation pathway depends on the treatment protocol. We present data concerning one of the protocols: injection of 20 mg of cytosine arabinoside (Ara-C). When conditioned medium from bone marrow of treated mice is incubated with normal marrow, CFU-S of the latter generate spleen colonies with an E/G ratio above normal values. Clonal analyses of spleen colonies demonstrate that they are generated by pluripotent stem cells. Therefore, any modification in the E/G ratio is due to modifications of CFU-S channelling and not to the variations of committed cells. It was of interest to determine the mechanism of pluripoietin activity. This was studied at three levels: membrane receptors, gene activation and protein synthesis. These studies suggest that CFU-S have receptors for pluripoietins which activate genes responsible for specific mRNA synthesis. De novo synthesis of proteins is a necessary prerequisite for pluripoietin activity to be expressed. Hypotheses for these mechanisms are presented.