Early B Cell Factor 2 Regulates Hematopoietic Stem Cell Homeostasis in a Cell-Nonautonomous Manner

SummaryHematopoiesis requires the interaction of hematopoietic stem cells (HSCs) with various stromal microenvironments. Here, we examine the role of early B cell factor 2 (Ebf2), a transcription factor expressed in a subset of immature osteoblastic cells. Ebf2−/− mice show decreased frequencies of HSCs and lineage-committed progenitors. This defect is cell nonautonomous, as shown by the fact that transplantation of Ebf2-deficient bone marrow into wild-type hosts results in normal hematopoiesis. In coculture experiments, Ebf2−/− osteoblastic cells have reduced potential to support short-term proliferation of HSCs. Expression profiling of sorted Ebf2−/− osteoblastic cells indicated that several genes implicated in the maintenance of HSCs are downregulated relative to Ebf2+/− cells, whereas genes encoding secreted frizzled-related proteins are upregulated. Moreover, wild-type HSCs cocultured with Ebf2−/− osteoblastic cells show a reduced Wnt response relative to coculture with Ebf2+/− cells. Thus, Ebf2 acts as a transcriptional determinant of an osteoblastic niche that regulates the maintenance of hematopoietic progenitors, in part by modulating Wnt signaling.

► Transcription factor Ebf2 is expressed in a subset of immature osteoblastic cells ► Ebf2-deficient mice show a cell-nonautonomous defect in HSCs and progenitors ► Ebf2−/− osteoblastic cells have a defect in the stromal support of HSCs in vitro ► Ebf2−/− stromal cells upregulate Sfrp-1 and -2, antagonists of Wnt signaling