MODIFIED THROMBOPOIETIC RESPONSE TO 5-FU IN MICE FOLLOWING TRANSPLANTATION IN LIN(-)SCA-1(-MARROW CELLS() BONE)

An experimental murine model of bone marrow transplantation (BMT) has been used to study the mechanisms of platelet production following tra nsplantation. A defined primitive population of hematopoietic bone mar row cells (1000 Lin(-)Sca-1(+)) was isolated and transplanted into let hally irradiated (13 Gy) syngeneic recipient mice. Platelet counts, bu t neither red nor white blood cell (WBC) counts, were low 30 days afte r transplantation. By 90 days, platelet levels had normalized in trans planted mice, but this occurred from a reduced megakaryocyte progenito r (CFU-Mk) pool, implying that altered bone marrow control was involve d in platelet production. To assess the capacity of the bone marrow of these compensated mice to sustain platelet production, the rate and d egree of recovery were examined following administration of 150 mg/kg of 5-fluorouracil (5-FU) 90 days after transplantation. Transplanted m ice showed a delay, both in platelet recovery and rebound thrombocytos is, after 5-FU administration when compared to normal littermates trea ted with 5-FU. The regeneration and expansion of bone marrow CFU-Mk an d mature megakaryocytes was retarded in the transplanted mice and expl ained the altered platelet kinetics. The onset of increased platelet a nd mature megakaryocyte size, however, was not different between the t wo groups, indicating that the transplanted mice responded normally to the mechanisms controlling megakaryocyte development and platelet for mation. The data suggest that following BMT a limitation in the prolif erative capacity of primitive hematopoietic cells results in a smaller pool of megakaryocyte precursors. Compensatory adjustment within the megakaryocyte lineage, nevertheless, results in normalization of megak aryocyte and platelet number. The ability of transplanted mice to sust ain platelet production when challenged with increased platelet demand is not limited by megakaryocytic maturation but by a restriction in p roliferation or differentiation from the stem cell pool.