Global gene expression prolife of primary cultured murine stress erythroid progenitors.

Inflammation inhibits steady state erythropoiesis, while at the same time it induces stress erythropoiesis to maintain erythroid homeostasis. Stress erythropoiesis relies on the rapid expansion of early progenitors that do not differentiate until the increase in serum Epo promotes a transition in progenitors to enable their synchronous differentiation. RNA-seq analysis allows us to identify an inflammatory transcriptome signature in early progenitors that induces iNOS-derived NO production. The accumulation of NO establishes a metabolism that promotes cell proliferation while inhibiting the differentiation of early progenitors. In contrast, the transition of progenitors to differentiation is marked by the suppressed inflammatory responses and a consequent decrease of iNOS-derived NO. We show that Epo initiates this transition response by altering progenitor metabolism to support itaconate production, resulting in the activation of Nrf2 that suppresses the inflammatory responses, which in turn alleviates the NO-mediated inhibition of erythroid program. Consequent differentiation of stress erythroid progenitors generates a bolus of new erythrocytes to maintain erythroid homeostasis until steady state erythropoiesis can resume. Overall design: mRNA profiles of primary cultured stress erythroid progenitors in five conditions: WT expansion cultures treated with vehicle or 1400w, WT differentiation cultures treated with vehicle or 1400w, and Nrf2-/- differentiation cultures treated with vehicle.