Regulation of cell survival during B lymphopoiesis in mouse bone marrow: Enhanced pre–B-cell apoptosis in CSF-1–deficient op/op mutant mice

Osteopetrotic (op/op) mice are deficient in macrophages and osteoclasts due to a CSF-1 gene mutation. The aim of this study was to evaluate the effect of these deficiencies and of CSF-1–dependent mechanisms on B lymphopoiesis in bone marrow, with special reference to the apoptotic activity of precursor B cells. B-cell development and apoptosis were examined in the bone marrow of op/op mice using immunofluorescence labeling and flow cytometry. Short-term cultures of bone marrow were used to evaluate the effect of recombinant CSF-1 on the rate of B-cell apoptosis. Bone marrow cellularity was greatly reduced in op/op mice compared with normal littermates. However, precursor B cells were disproportionately decreased, most markedly at the pre–B-cell stage. Precursor B cells, particularly pre-B cells, displayed elevated apoptotic incidences both ex vivo and in short-term culture. Addition of recombinant CSF-1 reduced the incidence of apoptosis among precursor B cells in short-term cultures of whole bone marrow suspensions from normal mice but not in cultures of sorted B220 + B-lineage cells. The finding of increased pre–B-cell apoptosis in op/op mice provides evidence that CSF-1–dependent mechanisms can strongly influence the survival of precursor B cells in mouse bone marrow, particularly at the pro-B/pre-B cell transition. It is proposed that the local or systemic levels of CSF-1 during ontogeny may thus play a role in regulating B-cell production within the bone marrow microenvironment.