Altered hematopoiesis in murine sickle cell disease

We investigated the mechanisms of sickle cell disease (SCD) hematopoietic/e rythropoietic defects using bone marrow, spleen, and/or peripheral blood fr om the transgenic SAD mouse model, which closely reproduces the biochemical and physiological disorders observed in human SCD. First, the erythropoiet ic lineage late precursors (polychromatophilic normoblasts to the intramedu llary reticulocytes) of SAD mouse bone marrow were significantly altered mo rphologically. These anomalies resulted from high levels of hemoglobin poly mers and were associated with increased cell fragmentation occurring during medullary endothelial migration of reticulocytes. Secondly, analysis of bo ne marrow erythropoiesis in earlier stages showed a marked depletion in SAD erythroid burst-forming units (BFU-E; of similar to 42%) and erythroid col ony-forming units (CFU-E; of similar to 23%) progenitors, despite a signifi cant increase in their proliferation, suggesting a compensatory mechanism. In contrast to the bone marrow progenitor depletion, we observed (1) a high mobilization/relocation of BFU-E early progenitors (similar to 4-fold incr ease) in peripheral blood of SAD mice as well as of colony-forming units-gr anulocyte-macrophage (CFU-GM) and (2) a 7-fold increase of SAD CFU-E in the spleen. Third, and most importantly, SAD bone marrow multipotent cells (sp leen colony-forming units [CFU-S], granulocyte-erythroid-macrophage-megakar yocyte colony-forming units [CFU-GEMM], and Sca(+)Lin(-)) were highly mobil ized to the peripheral blood (similar to 4-fold increase), suggesting that peripheral multipotent cells could serve as proliferative and autologous ve hicles for gene therapy. Therefore, we conclude the following. (1) The abno rmal differentiation and morphology of late nucleated erythroid precursors result in an ineffective sickle erythropoiesis and likely contribute to the pathophysiology of sickle cell disorders; this suggests that transfer of n ormal or modified SCD bone marrow cells may have a selective advantage in v ivo. (2) A hematopoietic compensatory mechanism exists in SAD/SCD pathology and consists of mobilization of multipotent cells from the bone marrow to the peripheral blood and their subsequent uptake into the spleen, an extram edullary hematopoietic site for immediate differentiation. Altogether, thes e results corroborate the strong potential effectiveness of both autologous acid allogeneic bone marrow transplantation for SCD hematopoietic therapy. (C) 1999 by The American Society of Hematology.