Actions of the haemopoietic stem cell proliferation inhibitor

There is a minimum threshold dose for effective inhibition which varies inversely with the duration of exposure to the inhibitor, and two possible models to explain these results are suggested.

Abstract

An inhibitor of haemopoietic stem cell proliferation has been prepared (a) by making extracts of haemopoietic tissue containing slowly proliferating colony-forming units-spleen (CFU-S) and fractioning by molecular ultrafiltration; and (b) by preparing “conditioned” supernatant media of such tissue. Dose-response studies of the effects of these inhibitors on the proportion of proliferating CFU-S which are synthesizing DNA have been carried out for different periods of exposure to the inhibitor. It was found that there is a minimum threshold dose for effective inhibition which varies inversely with the duration of exposure to the inhibitor. Two possible models to explain these results are suggested. First, at the threshold dose, the inhibitor is effective only at the start of the G1 phase. This permits the G1 cells present to progress normally into the S phase and, therefore, prevents an immediate observation of the inhibition. As the dose is increased, the effect is extended throughout the G1 phase to the G1-S boundary, effectively blocking the entry of cells into the S-phase and resulting in immediate inhibition. Second, the threshold dose is effective early in the G2 period, which is long compared to the G1 phase, but the affected cells continue their progress only up to the end of that cycle. The block, therefore, is not seen until this time has elapsed. Higher doses of inhibitor affect later G2 cells, also resulting in early recognition of the block. The effects of the inhibitor are not lost simply by washing the cells, so that once it has become effective the stem cells remain in a switched off state until such time as they are switched on again by an applied proliferation stimulator.