Stem Cell Factor Has Contrasting Effects in Combination with 5-Fluorouracil or Total-Body Irradiation on Frequencies of Different Hemopoietic Cell Subsets and Engraftment of Transplanted Bone Marrow

Abstract

The effect of stem cell factor (SCF) given at 24, 12 and 2 h before either 5-fluorouracil (5-FU) or total-body irradiation (TBI) was investigated on a range of bone marrow hemopoietic cell subsets that included primitive stem cells capable of long-term repopulation in bone marrow transplant (BMT) recipients. At 24 h after treatment, the femoral content of transient and permanent repopulating stem cell subsets was assessed from the frequency of early- and late-developing cobblestone area-forming cells (CAFCs) growing in stroma-associated cultures. At this time untreated 3 x 10(6) congenically marked donor bone marrow cells (B6-Gpi-Ia-->B6-Gpi-Ib) were transplanted and the level of erythroid engraftment was followed over 1 year. Analysis of the frequencies of CAFCs in host bone marrow after treatment with SCF demonstrated a remarkable increase in the number of early-developing CAFC subsets by about 10-fold. At the same time SCF conferred a sensitization of these subsets after treatment with 5-FU, which indicated an enhanced proliferative activity. The SCF-induced increase in the number of progenitor cells, however, was the more dominant process in the irradiated animals, resulting in less overall depletion of CAFCs. These contrasting results provide an explanation for the sensitization by SCF of 5-FU-induced lethality and its converse protection against radiation-induced lethality as reported by others. Nevertheless, the number of the more primitive CAFC subsets appearing at 28 and 35 days in culture and their sensitivity to 5-FU or radiation remained unaffected by this short SCF treatment. The number of CAFCs that remained in the bone marrow largely predicted the subsequent patterns of donor marrow engraftment in the treated BMT recipients: SCF enhanced short-term engraftment after treatment with 5-FU while it reduced the need for short-term engraftment after irradiation. Only irradiation afforded long-term engraftment through depletion of primitive host stem cells, and this was moderately improved by prior treatment with SCF.