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.

Critical function for the Ras-GTPase activating protein RASA3 in vertebrate erythropoiesis and megakaryopoiesis

“…Spleen erythropoiesis increases significantly under stress conditions (20). An increased number of total cells in the spleen was observed in scat animals in crisis due to the expansion of the red All mice 3-4 wk of age.…”

miR-214 protects erythroid cells against oxidative stress by targeting ATF4 and EZH2

“…There is elevated formation of free radicals and increased oxidative stress in erythroid precursors due to enhanced demand of iron for hemoglobin synthesis and accumulated hemoglobin content [20,66,67], and erythroid precursors may be also subjected to oxidative stress from foreign chemicals including drugs for medicinal purposes and environmental toxicants [19,22,68]. Therefore, erythroid cells are highly sensitive to oxidative stress, and aberrant ROS accumulation incurs impaired erythropoiesis, shortened lifespan of RBCs and even hemolysis [66,69,70].…”

“…However, whether Nrf2 also conducts cytoprotection through miRNA-dependent mechanisms is still largely unknown thus far. During the maturation of proerythroblasts into red blood cells (RBCs), erythroid precursors experience various stresses from both inside and outside [19][20][21][22]. The increased demand of iron for hemoglobin synthesis in erythroblast results in enhanced formation of labile iron and consequently generation of free radicals, oxidative stress and cytotoxicity [19][20][21].…”

“…During the maturation of proerythroblasts into red blood cells (RBCs), erythroid precursors experience various stresses from both inside and outside [19][20][21][22]. The increased demand of iron for hemoglobin synthesis in erythroblast results in enhanced formation of labile iron and consequently generation of free radicals, oxidative stress and cytotoxicity [19][20][21]. In addition, erythroid precursors may be also subjected to diverse stresses in bone marrow, such as hypoxia, mechanical stress, radiation, foreign chemicals and environmental toxicants [23][24][25][26].…”

Bone morphogenetic protein 4 expression in multiple normal and tumor tissues reveals its importance beyond development

“…12 Bmp4 is expressed in the endocrine pancreas regulating insulin metabolism, and in the spleen during stressinduced erythropoiesis. 13,14 Furthermore, BMP4 has been implicated in the idiopathic pulmonary fibrosis of the lung. 15 Increased BMP4 expression has been observed in esophagitis and Barrett's esophagus where BMP4 induces the metaplastic transformation of squamous epithelial cells to columnar cells.…”