A mouse model for an erythropoietin-deficiency anemia

Abstract

In mammals, the production of red blood cells is tightly regulated by the growth factor erythropoietin (EPO). Mice lacking a functional Epo gene are embryonic lethal, and studying erythropoiesis in EPO-deficient adult animals has therefore been limited. In order to obtain a preclinical model for an EPO-deficient anemia, we developed a mouse in which Epo can be silenced by Cre recombinase. After induction of Cre activity, Epo(KO/flox) mice experience a significant reduction of serum EPO levels and consequently develop a chronic, normocytic and normochromic anemia. Furthermore, compared with wild-type mice, Epo expression in Epo(KO/flox) mice is dramatically reduced in the kidney, and expression of a well-known target gene of EPO signaling, Bcl2l1, is reduced in the bone marrow. These observations are similar to the clinical display of anemia in patients with chronic kidney disease. In addition, during stress-induced erythropoiesis these mice display the same recovery rate as their heterozygous counterparts. Taken together, these results demonstrate that this model can serve as a valuable preclinical model for the anemia of EPO deficiency, as well as a tool for the study of stress-induced erythropoiesis during limiting conditions of EPO.

A mouse model of adult-onset anaemia due to erythropoietin deficiency

“…1b and Table 1). Epo -/-embryos suffered from severe anaemia and died around E12.5, consistent with previous reports 23,25 . In contrast, the transgene sustained fetal liver erythropoiesis and rescued the Epo -/-embryos from the lethal anaemia (Fig.…”

“…Null mutations of either the Epo or EpoR gene cause embryonic lethal anaemia around day 12.5 (E12.5) in mice, clearly demonstrating the significance of Epo-EpoR signalling for fetal erythropoiesis 23,24 . In addition, conditional inactivation of either the Epo or Hif2a genes results in moderate anaemia (20-30% reduction in RBC numbers) in adult mice, suggesting the significance of Epo for adult erythropoiesis 25,26 . None of these mutants, however, represent good models of renal/Epo-deficiency anaemia.…”

Acute hematopoietic stress in mice is followed by enhanced osteoclast maturation in the bone marrow microenvironment

“…In our mouse model, we confirmed that blood loss of 10% total blood content is sufficient to significantly increase the number of reticulocytes and serum Epo levels, which are both good estimators of induced erythropoiesis [43,51]. This increase lead to an elevated number of TER119 + cells in BM and spleen as early as 3 days after bleeding.…”

“…After an hematological stress in adult mice, both BM and spleen niches are activated and stimulate HSC proliferation [22] to maintain the RBC count and oxygenation homeostasis [42]. The main regulator of RBC production is erythropoietin (Epo), produced mostly by kidneys, which serves as a good estimator of the extent of erythropoietic activity [43].…”

FGF-23 Is a Negative Regulator of Prenatal and Postnatal Erythropoiesis

“…These observations suggest that Fgf-23 affects mainly early rather than late erythroid progenitors; the mechanism of this finding requires further investigation. Similarly, although mice lacking functional Epo (40), Epo-R (41), HIF-1␣ (42), or HIF-2␣ (43) genes are embryonically lethal, studies have shown that conditional inactivation of either the Epo (44) or Hif-2␣ (45) genes postnatally results in extremely low serum Epo levels that are associated with moderate anemia (20 -30% reduction in RBC numbers, hemoglobin, and hematocrit) in adult mice, demonstrating the significance of Epo/HIF for adult erythropoiesis.…”