Stress erythropoiesis: definitions and models for its study

Abstract

Steady-state erythropoiesis generates new erythrocytes at a constant rate, and it has enormous productive capacity. This production is balanced by the removal of senescent erythrocytes by macrophages in the spleen and liver. Erythroid homeostasis is highly regulated to maintain sufficient erythrocytes for efficient oxygen delivery to the tissues, while avoiding viscosity problems associated with overproduction. However, there are times when this constant production of erythrocytes is inhibited or is inadequate; at these times, erythroid output is increased to compensate for the loss of production. In some cases, increased steady-state erythropoiesis can offset the loss of erythrocytes but, in response to inflammation caused by infection or tissue damage, steady-state erythropoiesis is inhibited. To maintain homeostasis under these conditions, an alternative stress erythropoiesis pathway is activated. Emerging data suggest that the bone morphogenetic protein 4 (BMP4)-dependent stress erythropoiesis pathway is integrated into the inflammatory response and generates a bolus of new erythrocytes that maintain homeostasis until steady-state erythropoiesis can resume. In this perspective, we define the mechanisms that generate new erythrocytes when steady-state erythropoiesis is impaired and discuss experimental models to study human stress erythropoiesis.

Figure 1.. Schematic of alternate responses to anemia.

Left, steady state erythropoiesis is increased by increased levels of erythropoietin (Epo). Right, Inflammation compromises steady state erythropoiesis, which leads to activation of the BMP4 dependent stress erythropoiesis pathway. MPP-multipotential progenitors, CMP- common myeloid progenitor, MEP-megakaryocyte erythroid progenitor, GMP- granulocyte macrophage progenitor, BFU-e- burst-forming units- erythroid, CFU-E- colony forming units-erythroid. The megakaryocyte pathway is not shown in order to simplify the diagram.

Figure 2.. Model of BMP4 dependent stress erythropoiesis.

A. Schematic of the four steps from migration of ST-HSCs into the spleen until terminal differentiation. After specification, the status of Epo receptor expression in the SEPs is indicated. Cell surface markers that identify the populations of SEPs are shown. KSL stands for Kit+Sca1+Lineage negative. The signals known to participate at each stage are indicated below. B. Schematic of the development of the stress erythropoiesis niche in the spleen.