Investigating the Cell Type- and Receptor-Specific Effects of Erythropoietin that Mediate Erythropoiesis and Thrombopoiesis in Primary Human Hematopoietic Progenitor Cells

Chronic kidney disease (CKD) affects 37 million adults in the United States and results in anemia in more than 5 million patients. Patients with anemia due to CKD often require transfusion or pharmaceutical intervention to combat fatigue and hypoxia. The most common pharmaceutical intervention is injection of Erythropoietin (EPO), a cytokine that is produced in the healthy kidney in response to hypoxia. EPO promotes erythropoiesis by enhancing the survival and proliferation of erythroid-committed progenitors in the bone marrow. However, pharmaceutical EPO administration can cause thrombocytosis with an increased risk of stroke. This off-target consequence highlights an understudied role for EPO in non-erythroid-committed cell types and emphasizes the need for further research to clarify the effect of EPO on hematopoietic progenitors such as the Megakaryocytic-Erythroid bipotent progenitor and Megakaryocytic-committed progenitor. Furthermore, the receptors and downstream signaling pathways activated by EPO have not been fully elucidated in subpopulations of hematopoietic progenitors. Our preliminary results indicate that EPO supports survival and self-renewal of MEP. The research proposed in this application will investigate the cell-autonomous effects of EPO on bipotent human Megakaryocytic-Erythroid progenitors, Megakaryocytic-committed progenitors, and Erythroid- committed progenitors ex vivo by measuring activation of signaling mediators, transcriptional expression, and phenotypic changes. It will also clarify the receptors and targets that are activated in response to EPO signaling in defined hematopoietic subpopulations utilizing novel receptor-specific EPO mimetics. We hypothesize that in response to EPO, Megakaryocytic-Erythroid progenitors expand to increase the pool of progenitors capable of giving rise to erythroid and platelet-producing megakaryocytes, resulting in increased production of both platelets and red blood cells. Successful completion of these studies will resolve the molecular mechanism of the action of EPO on specific populations of cells in the bone marrow, which will aid in the development of more targeted and effective therapies for patients with chronic anemia.