Rats provide a superior model of human stress erythropoiesis.

Mouse models are widely used to study human erythropoiesis in vivo. One important caveat using mouse models is that mice often develop significant extramedullary erythropoiesis with anemia, which could mask important phenotypes. To overcome this drawback in mice, here we established in vitro and in vivo rat models for the studies of stress erythropoiesis. Using flow cytometry-based assays, we can monitor terminal erythropoiesis in rats during fetal and adult erythropoiesis under steady state and stress conditions. We used this system to test rat erythropoiesis under phenylhydrazine (PHZ)-induced hemolytic stress. In contrast to mice, rats did not have an increased proportion of early-stage erythroid precursors during terminal differentiation in the spleen or bone marrow. This could be explained by the abundant bone marrow spaces in rats that allow sufficient erythroid proliferation under stress. Consistently, the extent of splenomegaly in rats after PHZ treatment was significantly lower than that in mice. The level of BMP4, which was significantly increased in mouse spleen after PHZ treatment, remained unchanged in rat spleen. We further demonstrated that the bone marrow c-Kit positive progenitor population underwent a phenotype shift and became more CD71 positive and erythroid skewed with the expression of maturing erythroid markers under stress in rats and humans. In contrast, the phenotype shift to an erythroid-skewed progenitor population in mice occurred mainly in the spleen. Our study establishes rat in vitro and in vivo erythropoiesis models that are more appropriate and superior for the study of human stress erythropoiesis than mouse models.