Stress erythropoiesis: new signals and new stress progenitor cells

Abstract

Purpose of review: Acute anemic stress induces a physiological response that includes the rapid development of new erythrocytes. This process is referred to as stress erythropoiesis, which is distinct from steady state erythropoiesis. Much of what we know about stress erythropoiesis comes from the analysis of murine models. In this review, we will discuss our current understanding of the mechanisms that regulate stress erythropoiesis in mice and discuss outstanding questions in the field.

Recent findings: Stress erythropoiesis occurs in the murine spleen, fetal liver and adult liver. The signals that regulate this process are Hedgehog, bone morphogenetic protein 4 (BMP4), stem cell factor and hypoxia. Recent findings show that stress erythropoiesis utilizes a population of erythroid-restricted self-renewing stress progenitors. Although the BMP4-dependent stress erythropoiesis pathway was first characterized during the recovery from acute anemia, analysis of a mouse model of chronic anemia demonstrated that activation of the BMP4-dependent stress erythropoiesis pathway provides compensatory erythropoiesis in response to chronic anemia as well.

Summary: The BMP4-dependent stress erythropoiesis pathway plays a key role in the recovery from acute anemia and new data show that this pathway compensates for ineffective steady state erythropoiesis in a murine model of chronic anemia. The identification of a self-renewing population of stress erythroid progenitors in mice suggests that therapeutic manipulation of this pathway may be useful for the treatment of human anemia. However, the development of new therapies will await the characterization of an analogous pathway in humans.

Figure 1. Model of the bone morphogenetic protein 4 stress erythropoiesis pathway

(a) Activation by acute anemia. (b) Postrecovery replenishment of stress progenitors. BFU-E, burst forming unit-erythroid; BM, bone marrow; BMP4, bone morphogenetic protein 4; Epo, erythropoietin; SCF, stem cell factor.

Figure 2. Three distinct populations of stress erythroid progenitors develop in the spleen during the recovery from bone marrow transplant

(a) Flow cytometry analysis of spleen cells on the indicated days after transplant. The cells are gated on Kit⁺ cells and the expression of CD71 and Ter119 is analyzed. (b) Populations I, II and III were sorted on day 8 after transplant and plated for burst forming unit-erythroid (BFU-E) and colony forming unit-erythroid (CFU-E). Population II cells did not give rise to BFU-E and Population III cells failed to form colonies of any type. BMP4, bone morphogenetic protein 4; Epo, erythropoietin; SCF, stem cell factor. Adapted from [40^••].