Metabolic regulation of stress erythropoiesis, outstanding questions, and possible paradigms

Abstract

Steady state erythropoiesis produces new erythrocytes at a constant rate to replace the senescent cells that are removed by macrophages in the liver and spleen. However, infection and tissue damage disrupt the production of erythrocytes by steady state erythropoiesis. During these times, stress erythropoiesis is induced to compensate for the loss of erythroid output. The strategy of stress erythropoiesis is different than steady state erythropoiesis. Stress erythropoiesis generates a wave of new erythrocytes to maintain homeostasis until steady state conditions are resumed. Stress erythropoiesis relies on the rapid proliferation of immature progenitor cells that do not differentiate until the increase in serum Erythropoietin (Epo) promotes the transition to committed progenitors that enables their synchronous differentiation. Emerging evidence has revealed a central role for cell metabolism in regulating the proliferation and differentiation of stress erythroid progenitors. During the initial expansion stage, the immature progenitors are supported by extensive metabolic changes which are designed to direct the use of glucose and glutamine to increase the biosynthesis of macromolecules necessary for cell growth and division. At the same time, these metabolic changes act to suppress the expression of genes involved in erythroid differentiation. In the subsequent transition stage, changes in niche signals alter progenitor metabolism which in turn removes the inhibition of erythroid differentiation generating a bolus of new erythrocytes to alleviate anemia. This review summarizes what is known about the metabolic regulation of stress erythropoiesis and discusses potential mechanisms for metabolic regulation of proliferation and differentiation.

FAM210B is dispensable for erythroid differentiation in adult mice

“…Male Fam210b -/- mice were heavier than wild-type and heterozygote males, although we did not observe any difference in the weights of female Fam210b -/- mice relative to wild-type controls (Figure 2C). Because of our previous studies suggesting that Fam210b is required for erythroid terminal differentiation, we measured splenic weights, as mouse spleens are an extramedullary site of stress erythropoiesis (18). To our surprise, there was no significant difference in the weights (Figure 2D) or gross morphology (Figure 2E) between wild-type and Fam210b -/- spleens.…”

Red blood cell dynamics during malaria infection challenge the assumptions of mathematical models of infection dynamics

“…It is now widely recognized that the inflammatory response, as stimulated by infection, causes “ stress erythropoiesis ” . This response is characterized by the cytokine-mediated suppression of erythropoiesis immediately following infection, an acceleration of erythrophagocytosis and finally the production of a “ pulse ” of RBCs in the spleen, via a heme-mediated signaling cascade (Yap and Stevenson, 1992; Chang and Stevenson, 2004; Paulson et al, 2020; Ruan and Paulson, 2023). Given that malaria infection induces (i) significant inflammation, erythrophagocytosis and heme-accumulation in the spleen, and (ii) the concordance between the timescale of stress erythropoiesis and our RBC supply curve, it is reasonable to hypothesize that similar mechanisms underlie the biphasic RBC supply dynamics we have observed.…”

TFPI from erythroblasts drives heme production in central macrophages promoting erythropoiesis in polycythemia

“…1M, N). New RBCs will be produced rapidly under stress conditions 32 . In stress erythropoiesis induced by phenylhydrazine (PHZ), TFPI f/f;EpoR mice developed more severe erythropoietic impairment and had a delayed RBC recovery response compared to TFPI f/f mice (supplemental Fig.…”