Erythropoietin affects B cell maturation and induces B cell-to-erythroid transition in mice
2Department of Hematology, Assuta Ashdod University Hospital, Israel
3Department of Anatomy and Anthropology, Tel-Aviv University, Israel
4Center for Healthy Aging, Technische universitat Dresden, Germany
5Institute of Clinical Chemistry and Laboratory Medicine, Department of Clinical Pathobiochemistry, Technische universitat Dresden, Germany
6Department of Hematology, Tel-Aviv Souraski Medical Center, Israel
7Internal Medicine A, Tel-Aviv Souraski Medical Center, Israel
Erythropoietin (EPO) is a key regulator of erythropoiesis with a myriad of extraerythropoietic effects. It was shown that EPO reduces bone marrow (BM) B cell population by inducing an egress of IgM+ cells out of BM. Here we addressed the effect of EPO on IgM- B cell precursors, including the possibility of their transdifferentiation into erythroid cells.
First, we showed that EPO treatment led to 2.4-fold reduction in BM B cells (both IgM+ and IgM-) while in peripheral blood (PB) we observed a 2-fold increase in IgM- B cells with no change in IgM+ fraction. The observed downregulation of CXCR4 adhesion molecule by BM Pro-B cells could explain the egress of these cells out of BM. We hypothesized that EPO induces a maturation delay at the level of Pre/Pro-B cell stages. Using both MB1-Cre; EPO-Rfl/fl and Osx-Cre; EPO-Rfl/fl mouse models we showed that this maturation delay is independent of EPO-EPO-R signaling in both early B cells and osteoblasts. However, we found significant changes in the key regulators of B cell lymphopoiesis, namely, PAX5 and IL-7 as well as reduced expression of IL-7 receptor. Finally, applying immunofluorescence microscopy, we detected eYFP+ BM cells (derived from MB1-Cre;R26-eYFP mice) that co-expressed TER119, thus demonstrating that a fraction of BM B cells can transdifferentiate into erythroid cells upon EPO stimulation.
We conclude that besides its effect on erythropoiesis, EPO compromises BM B cell compartment by multiple mechanisms, including BM egress, delay in maturation and transdifferentiation into erythroid lineage.