Erythropoietin stimulates spleen BMP4-dependent stress erythropoiesis and partially corrects anemia in a mouse model of generalized inflammation

Abstract

Mouse bone marrow erythropoiesis is homeostatic, whereas after acute anemia, bone morphogenetic protein 4 (BMP4)-dependent stress erythropoiesis develops in the spleen. The aim of this work was to compare spleen stress erythropoiesis and bone marrow erythropoiesis in a mouse model of zymosan-induced generalized inflammation, which induces longlasting anemia and to evaluate the ability of erythropoietin (Epo) injections to correct anemia in this setting. The effects of zymosan and/or Epo injections on erythroid precursor maturation and apoptosis, serum interferon-␥ levels, hematologic parameters, and spleen BMP4 expression were analyzed, as well as the effect of zymosan on red blood cell halflife. We found that bone marrow erythropoiesis is suppressed by inflammation and does not respond to Epo administration, despite repression of erythroblast apoptosis. On the contrary, a robust erythropoietic response takes place in the spleen after Epo injections in both control and zymosan-induced generalized in-

Hemolytic anemia repressed hepcidin level without hepatocyte iron overload: lesson from Günther disease model

“…We analyzed the respective contribution of bone marrow and spleen erythropoiesis in compensating the hemolytic anemia in CEP mice ( Figure 2). Using a flow cytometry assay based on cell surface expression of Ter119 and CD71, as previously described, 14 The bone marrow of CEP mice showed an important increase in the number of early erythroblasts (Figure 2A ( Figure 2A). In addition, the number of late erythroblasts was much lower than the intermediate erythroblasts in CEP mice, suggesting increased maturation rate and cellular exit from the bone marrow.…”

From stem cell to red cell: regulation of erythropoiesis at multiple levels by multiple proteins, RNAs, and chromatin modifications

“…109,110 Indeed, during stress erythropoiesis, BMP4 expression is induced by hypoxia in spleen stromal cells. 111,112 For BFU-E cells to be responsive to BMP4, they need to be "primed" with Sonic Hedgehog, a morphogen that is also synthesized and secreted by cells in the spleen microenvironment. 113 BMP4, in turn, activates the transcription factor Smad5 as well as Scl and Gata2, which enhances the probability of BFU-E self-renewal over differentiation (Figure 3).…”

Extrinsic and intrinsic control by EKLF (KLF1) within a specialized erythroid niche

“…As macrophage depletion leads to a reduction of BMP4 activity (Chow et al, 2013), part of the explanation for the lower erythroid numbers after stress induction under these conditions is likely to be that EKLF levels are compromised, leading to a global negative effect on red cell expansion and maturation. Conversely, increased EKLF levels lead to precocious erythroid differentiation (Frontelo et al, 2007); thus secreted BMP4 from the adherent macrophages (Millot et al, 2010;Paulson et al, 2011) can use this molecular pathway to support normal or accelerated red cell production. This suggests that EKLF expression levels in the red cell can be dynamically adjusted based on signals from adjacent macrophage both in normal and stress conditions.…”