Blood, Vol. 94 No. 4 (August 15), 1999:
pp. 1451-1459
Altered Hematopoiesis in Murine Sickle Cell Disease
Marie-José Blouin,
Monique E. De Paepe, and
Marie Trudel
From the Institut de Recherches Cliniques de Montreal, Molecular
Genetics and Development, Faculte de Medecine de L'Universite de
Montreal, Montreal, Quebec, Canada.
We investigated the mechanisms of sickle cell disease (SCD)
hematopoietic/erythropoietic defects using bone marrow, spleen, and/or
peripheral blood from the transgenic SAD mouse model, which closely
reproduces the biochemical and physiological disorders observed in
human SCD. First, the erythropoietic lineage late precursors
(polychromatophilic normoblasts to the intramedullary reticulocytes) of
SAD mouse bone marrow were significantly altered morphologically. These
anomalies resulted from high levels of hemoglobin polymers and were
associated with increased cell fragmentation occurring during medullary
endothelial migration of reticulocytes. Secondly, analysis of bone
marrow erythropoiesis in earlier stages showed a marked depletion in
SAD erythroid burst-forming units (BFU-E; of ~42%) and
erythroid colony-forming units (CFU-E; of ~23%)
progenitors, despite a significant 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 (~4-fold increase) in peripheral blood of SAD
mice as well as of colony-forming units-granulocyte-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 (spleen
colony-forming units [CFU-S],
granulocyte-erythroid-macrophage-megakaryocyte colony-forming units
[CFU-GEMM], and Sca+Lin
)
were highly mobilized to the peripheral blood (~4-fold increase), suggesting that peripheral multipotent cells could serve as
proliferative and autologous vehicles for gene therapy. Therefore, we
conclude the following. (1) The abnormal 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 normal or modified SCD
bone marrow cells may have a selective advantage in vivo. (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
extramedullary hematopoietic site for immediate differentiation.
Altogether, these results corroborate the strong potential
effectiveness of both autologous and allogeneic bone marrow
transplantation for SCD hematopoietic therapy.
