Stress erythropoiesis, defined with expansion of the erythroid progenitor pool associated with reticulocytosis and splenomegaly, is a critical adaptive process in response to the condition of insufficient oxygen availability such as high altitude, blood loss, infection, and anemia. It has been identified that stress erythropoiesis is finely regulated by cytokines, hormones, and growth factors at transcriptional and translational levels. More recently, stress erythropoiesis has been shown to be linked with increased metabolic requirements, but the molecular basis promoting metabolomics reprogramming to enhance energy metabolism to support stress erythropoiesis remains unclear. Our recent studies identify a decisive role of elevated adenosine in stress erythropoiesis. Mouse genetic studies showed that activation of adenosine signaling via erythroid ADORA2B-Hif1a pathway contributes to stress erythropoiesis by driving the differentiation of erythroid lineage independent of erythropoietin level in two independent stress erythropoiesis mouse models. Mechanistically, by using unbiased high-throughput metabolic profiling coupled with isotopically labelled metabolic flux approaches, we identified that erythroid ADORA2B contributes to an overall hypoxia metabolic reprogramming with substantial increased glycolysis, glutaminolysis and TCA cycle intermediates production in erythroid progenitors in mice. Human hematopoietic stem and progenitor cell (HSPC) culture studies showed that pharmacological activation of adenosine ADORA2B signaling promotes differentiation of erythroid progenitors in a Hif1a-dependnent manner. Taken together, both human and mouse studies identify adenosine ADORA2B signaling is a previously unrecognized purinergic signaling underlying stress erythropoiesis by regulation of metabolic reprogramming in erythroid progenitors, and likely discover new therapeutic targets to counteract hypoxia-induced injury by activation of erythropoiesis.
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.