Adenosine Signaling-Mediated Metabolic Reprogramming Regulates Erythropoiesis

Erythropoiesis is an extremely dynamic process finely regulated by cytokines, hormones, and growth factors at transcriptional and translational levels. Stress-induced erythropoiesis is defined as a stimulated basal erythropoiesis with expansion of the erythroid progenitor pool, associated with reticulocytosis and splenomegaly. Stress erythropoiesis is stimulated under the condition of insufficient oxygen availability such as high altitude, blood loss, infection, and anemia. Thus, stress erythropoiesis is an important stress adaptive response for survival. Although stress erythropoiesis has been long speculated to be linked with increased metabolic requirements, until recent two years with innovative metabolomics profiling and state of art isotopically labelled metabolic flux approaches, the filed has evolved and revealed that enhanced glucose and glutamine metabolism is essential for stress erythropoiesis. However, molecular basis underlying metabolic reprogramming to enhance glucose metabolism and subsequently stress erythropoiesis remains unclear.

To address this question, we conducted both human and mouse studies. First, we found that plasma adenosine is rapidly induced and associated with stress erythropoiesis features including increased hematocrit (HCT), hemoglobin (Hb) mass and reticulocytes in healthy human volunteers at high altitude and in mice exposed to hypoxia mimicking high altitude. Follow-up mouse genetic studies showed that activation of adenosine signaling via erythroid ADORA2B promotes the survival and expansion of proerythroblasts both in spleen and bone marrow and in this way contributes to hypoxia-induced stress erythropoiesis independent of erythropoietin. Using unbiased high-throughput metabolic profiling, we identified that erythroid ADORA2B contributes to an overall hypoxia metabolic reprogramming with substantial increased glycolysis in proerythroblast progenitors in mice. Finally, using primary human CD34⁺ hematopoietic stem cells culture, we showed that adenosine analogue and ADORA2B agonist promote the survival and expansion of erythroid progenitors in a time and dose-dependent manner. Taken together, both human and mouse studies identify that adenosine ADORA2B is a previously unrecognized purinergic signaling underlying hypoxia-induced erythropoiesis by facilitating expansion and survival of proerythroblasts, and highlight that enhancing this pathway is a potential strategy to induce erythropoiesis.