Peripheral human red blood cell development in human immune system mouse model with heme oxygenase-1 deficiency.

A challenge for human immune system (HIS) mouse models has been the lack of human red blood cell (hRBC) survival after engraftment of these immune-deficient mice with human CD34+ hematopoietic stem cells (HSCs). This limits the use of HIS models for preclinical testing of targets directed at hRBC-related diseases. Although human white blood cells can develop in the peripheral blood of mice engrafted with human HSCs, peripheral hRBCs are quickly phagocytosed by murine macrophages upon egress from the bone marrow. Genetic ablation of murine myeloid cells results in severe pathology in resulting mice, rendering such an approach to increase hRBC survival in HIS mice impractical. Heme oxygenase-1 (HMOX-1)-deficient mice have reduced macrophages due to toxic buildup of intracellular heme upon engulfment of RBCs, but do not have an overall loss of myeloid cells. We took advantage of this observation and generated HMOX-1-/- mice on a humanized M-CSF/SIRPα/CD47 Rag2-/- IL-2Rγ-/- background. These mice have reduced murine macrophages but comparable levels of murine myeloid cells to HMOX-1+/+ control mice in the same background. Injected hRBCs survive longer in HMOX-1-/- mice than in HMOX-1+/+ controls. Additionally, upon human HSC engraftment, hRBCs can be observed in the peripheral blood of HMOX-1-/- humanized M-CSF/SIRPα/CD47 Rag2-/- IL-2Rγ-/- mice, and hRBC levels can be increased by treatment with human erythropoietin. Given that hRBC are present in the peripheral blood of engrafted HMOX-1-/- mice, these mice have the potential to be used for hematologic disease modeling, and for testing therapeutic treatments for hRBC diseases in vivo.