Decline of colony-forming units with serial bone marrow cell passages: intrinsic or extrinsic causation?

A series of experiments were conducted to approach the question of whether CFU-S decline in self-replicative potential and in life saving potential in the serial transplant recipient were the result of events intrinsic to the CFU-S lineage or were the direct result of incidental external events. Specifically, the possibilities of CFU-S death or loss of potential related to in vitro manipulation, related to failure of the most capable CFU-S to lodge in the bone marrow, related to failure of accessory cells to lodge or related to and coincident with increased CFU-S cycling were all examined. Only the last named factor was associated with CFU-S decline. The results were compatible with the generation age concept i.e., that the loss of CFU-S self replicative potential was due to a permanent shift of the most "primitive" CFU-S to a more differentiated and less self-replicative status when an extreme and prolonged demand for replenishment of the more differentiated CFU-S pools exists.