Extramedullary erythropoiesis in the adult liver requires BMP-4/Smad5-dependent signaling

Objective: In mice, homeostatic erythropoiesis occurs primarily in the bone marrow. However, in response to acute anemia, bone morphogenetic proteins 4 (BMP-4)-dependent stress erythropoiesis occurs in the adult spleen. BMP-4 can also regulate stress erythropoiesis in the fetal liver. In humans, erythropoiesis occurs in the bone marrow. However, in certain pathological conditions, extramedullary erythropoiesis is observed, where it can occur in several organs, including the liver. Given these observations, we propose to investigate whether the BMP-4-dependent stress erythropoiesis pathway can regulate extramedullary erythropoiesis in the livers of splenectomized mice. Materials and Methods: Using splenectomized wild-type and flexed-tail (f) mice, which have a defect in BMP-4 signaling, we compared their recovery from phenylhydrazine-induced hemolytic anemia and characterized the expansion of stress burst-forming unit-erythroid in the livers of these mice during the recovery period. Results: Our analysis indicates that in the absence of a spleen, stress erythropoiesis occurs in the murine liver. During the recovery, stress burst-forming unit-erythroid are expanded in the livers of splenectomized mice in response to BMP-4 expressed in the liver. f/f mice, which exhibit a defect in splenic stress erythropoiesis do not compensate for this defect by upregulating liver stress erythropoiesis. Furthermore, splenectomized f/f mice exhibit a defect in liver stress erythropoiesis, which demonstrates a role for the BMP-4-dependent stress erythropoiesis pathway in extramedullary erythropoiesis in the adult liver. Conclusions: Our data indicate that the BMP-4-dependent stress erythropoiesis pathway regulates extramedullary stress erythropoiesis, which occurs primarily in the murine spleen or in the case of splenectomized mice, in the adult liver.