STEM-CELL FACTOR HAS CONTRASTING EFFECTS IN COMBINATION WITH 5-FLUOROURACIL OR TOTAL-BODY IRRADIATION ON FREQUENCIES OF DIFFERENT HEMATOPOIETIC-CELL SUBSETS AND ENGRAFTMENT OF TRANSPLANTED BONE-MARROW

The effect of stem cell factor (SCF) given at 24, 12 and 2 h before ei ther 5-fluorouracil (5-FU) or total-body irradiation (TBI) was investi gated on a range of bone marrow hemopoietic cell subsets that included primitive stem cells capable of longterm repopulation in bone marrow transplant (BMT) recipients. At 24 h after treatment, the femoral cont ent of transient and permanent repopulating stem cell subsets was asse ssed 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-1(a) --> B6-Gpi-1(b)) were transplanted and the level of erythr oid engraftment was followed over 1 year. Analysis of the frequencies of CAFCs in host bone marrow after treatment with SCF demonstrated a r emarkable increase in the number of early-developing CAFC subsets by a bout 10-fold, At the same time SCF conferred a sensitization of these subsets after treatment with 5-FU, which indicated an enhanced prolife rative activity, The SCF-induced increase in the number of progenitor cells, however, was the more dominant process in the irradiated animal s, resulting in less overall depletion of CAFCs. These contrasting res ults provide an explanation for the sensitization by SCF of 5-FU-induc ed lethality and its converse protection against radiation-induced let hality as reported by others. Nevertheless, the number of the more pri mitive CAFC subsets appearing at 28 and 35 days in culture and their s ensitivity to 5-FU or radiation remained unaffected by this short SCF treatment. The number of CAFCs that remained in the bone marrow largel y predicted the subsequent patterns of donor marrow engraftment in the treated BMT recipients: SCF enhanced short-term engraftment after tre atment with 5-FU while it reduced the need for short-term engraftment after irradiation, Only irradiation afforded long-term engraftment thr ough depletion of primitive host stem cells, and this was moderately i mproved by prior treatment with SCF. (C) 1997 by Radiation Research so ciety.