Stem Cell Migration and Proliferation During Severe Anemia

The pluripotential stem cell (CFU) compartment of marrow and spleen wasevaluated in mice subjected to an intense erythroid stimulus associated withphenylhydrazine-induced anemia. Erythroid hyperplasia occurred in both marrow and spleen. CFU in the marrowgradually declined to approximately 50per cent of control levels (day 5) whiletheir numbers in the spleen increased(fourfold) by day 3 and were maintainedat this level for several days. Thesechanges in numbers of marrow andsplenic CFU were not associated withCFU proliferation. Thereafter, CFU inthe marrow, but not in the spleen, entered active cell cycle. The data suggestthat CFU migrate from marrow to spleenduring the demands of severe anemia.The induction of marrow CFU into cyclefurther suggests a negative feedback,which, perhaps through cell-cell interaction, maintains stem cells at a criticalcompartment size. The failure of splenicCFU to cycle may reflect the converseeffect, i.e. an inhibition on stem cell proliferation in the wake of an expandedstem cell pool.

Submitted on March 17, 1970 Revised on May 14, 1970 Accepted on June 9, 1970     

The Pattern of Stem Cell Repopulation in Heavily Irradiated Mice Receiving Transplants of Fetal Liver

Pluripotential cells derived from fetal liver had a lower plating efficiencythan adult marrow cells, but estimates of the generation time derived fromthe growth curve are significantly shorter and may account for the earliererythroid population.

Submitted on June 18, 1969 Accepted on August 12, 1969     

Relationship of Erythropoietin Effectiveness to the Generative Cycle of Erythroid Precursor Cell

Hydroxyurea, a cytotoxic agent that kills cells in DNA synthesis, was usedto study the relationship between erythropoietin and the generative cycle of theimmediate erythroid precursor cell. When OHU and EP were administeredsimultaneously to hypertransfused mice, the resultant erythroid response wasdiminished relative to EP treated controls. OHU given at intervals after EPresulted in a progressively greater diminution of erythroid response.

From these studies, then, we would suggest that in the suppressed animal thecommitted stem cell compartment is in cycle but with a prolonged G₁.After EP there is a shortening of the generation time and an increase in therate of turnover of the committed stem cells. The data also indicate that cellsin cycle are differentiated into the pronormoblast compartment. It furthermay be suggested that erythropoietin is effective throughout the bulk of thegenerative cycle although it seems unlikely that differentiation is accomplishedduring the mitotic phase. Whether erythropoietin must be present in both G₁and S as suggested by Kretchmar cannot be answered by the present studies.The data also indicate that cells of the pluripotential compartment are normallyin G₀ or perhaps a prolonged G₁. Damage to the committed compartment appears to be in part repaired by the influx of cells from the pluripotentialcompartment.

Submitted on July 9, 1969 Accepted on September 8, 1969