Depletion of reserve in the hemopoietic system. II. Decline in CFU-S self-renewal capacity following prolonged cell cycling.

The prolonged induction of pluripotent hemopoietic stem cells into the cell cycle was accomplished by injecting phenylhydrazine hydrochloride which induced a hemolytic anemia. Phenylhydrazine hydrochloride was intraperitoneally administered 3 days/week for 6 weeks (or every 2 days for 17 weeks) during which time the hematocrit fell to a mean of 32% while the reticulocyte count increased from 0.8 to 83%. The number of CFU-S in S-phase at any time increased from a baseline of 7 up to 64%. After prolonged CFU-S cell cycling, serial bone marrow transplantations were conducted. Control serial bone marrow transplantations could be accomplished 5 times, while if prolonged cycling had occurred, only one transplantation could be successfully accomplished, and even then, reversion to host karyotype occurred within 30 days. These data may be interpreted as supporting a CFU-S generation-age hypothesis with an inherent 'Hayflick limit'.