Session: 101. Red Cells and Erythropoiesis, Structure and Function, Metabolism, and Survival, Excluding Iron: Mechanisms and Regulation of Erythropoiesis
Hematology Disease Topics & Pathways:
Biological Processes, erythropoiesis, hematopoiesis, inflammation, microenvironment
To test this hypothesis, we isolated EBIs from the bone marrow of both wild-type and Irf5-/- littermate mice at 3 months and 9 months. While no difference was found at 3 months of age, we found that at steady state in the 9-month old cohort, Irf5-/- mice had a significantly decreased number of EBIs with an altered structure – decreased CD71 (erythroid marker) and increased CD11b and Ly6G (myeloid markers). Moreover, analysis of terminal erythroid differentiation based on CD44/Ter119 and CD44/FSC in the bone marrow revealed that the Irf5-/- mice had a higher reticulocyte count (mean 38.61%) than wild-type mice (mean 26.28%, p value 0.032). Accordingly, the precursor populations were reduced in the bone marrow and the spleens of the Irf5-/- mice characteristic of stress erythropoiesis. Using colony-forming assays, we observed that Irf5-/- mice also had a higher number of early progenitor BFU-E when compared to wild-type mice (p value 0.0003 for 3 month-old and 0.038 for 9 month-old mice) as well as CFU -GEMM.
We then induced stress erythropoiesis through submandibular bleeding on 2 consecutive days and found that recovery from stress anemia was delayed in the Irf5-/- mice accompanied with a decreased number of EBIs. 5 days after inducing stress anemia, the Irf5-/- mice had a significantly lower number of bone marrow EBIs (mean 25.29% of the total cells) when compared to wild-type mice (mean 40.47% of the total cells, p value 0.03). Response to stress was also delayed, and the reticulocyte count was lower in the knockout mice compared to the wild-type 5 days post bleeding.
Altogether, these data identify Irf5 as a novel regulator of mammalian erythropoiesis under steady-state and stress conditions.
Disclosures: Kalfa: Forma Therapeutics, Inc: Research Funding; Agios Pharmaceuticals, Inc: Consultancy, Research Funding.
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