HIF1 synergizes with glucocorticoids to promote BFU-E progenitor self-renewal

Anemia due to chronic renal insufficiency is often treated with recombinant erythropoietin (Epo). However, anemia caused by a lack of erythropoietin-sensitive CFU-E progenitors does not respond to Epo. A drug that can increase the number of CFU-E progenitors could be useful for treating this Epo-resistant anemia.

To explore potential therapies, we studied how glucocorticoids (GCs) promote the production of CFU-E progenitors in vitro. This process, which also requires stem cell factor (SCF), mimics the physiological process of stress erythropoiesis (SE), where CFU-E progenitors are replenished during chronic anemia. GCs stimulate erythropoiesis by activating specific genes, rather than by gene repression.

Response of BFU-E Progenitors to Glucocorticoids In this study, we used cultured BFU-E and CFU-E progenitors isolated from mouse fetal liver. We found that BFU-E progenitors, not CFU-E progenitors, respond to GCs by increasing their self-renewal capacity. Over time, this results in a ten-fold increase in the number of CFU-E progenitors and, consequently, erythroblast production.

We also identified that the promoter regions of several genes regulated by GC receptor (GCR) activation in BFU-E cells contain binding sites for hypoxia-induced factor 1α (HIF1α), a transcription factor involved in cellular response to oxygen levels. HIF1α activation can enhance gene expression, which suggests that HIF1α may work in conjunction with GCR to amplify the response of BFU-E progenitors to GCs.

HIF1α Activation and Glucocorticoid Synergy To further investigate the role of HIF1α, we used dimethyloxalylglycine (DMOG), a prolyl hydroxylase inhibitor (PHI), to activate HIF1α. Combining DMOG with dexamethasone (Dex), a glucocorticoid, resulted in a synergistic increase in BFU-E proliferation and self-renewal. This combination led to a 300-fold increase in erythroblast production, seven times greater than the effect of Dex alone.

This demonstrates that the combined activation of GCR and HIF1α can stimulate the regeneration of CFU-E progenitors, which enhances erythroblast production. These findings suggest a potential therapeutic strategy for Epo-resistant anemia by using PHIs in combination with low concentrations of GCs.

The combination of HIF1α activation and glucocorticoid signaling can enhance BFU-E progenitor self-renewal and increase the production of CFU-E progenitors, offering a potential strategy for treating Epo-resistant anemia. By using prolyl hydroxylase inhibitors (PHIs) to activate HIF1α along with glucocorticoids, we can pharmacologically stimulate CFU-E regeneration, which could lead to improved therapeutic approaches for anemia management.

To explore the detailed mechanisms and experimental methods behind the synergistic effect of HIF1α and glucocorticoids in promoting BFU-E progenitor self-renewal, we recommend reading the full research paper available in PDF format. This document provides an in-depth analysis of the experimental approaches, results, and implications for potential therapeutic applications in treating Epo-resistant anemia. Please refer to the PDF for comprehensive insights into the study.