Pathologic angiogenesis in the bone marrow of humanized sickle cell mice is reversible by blood transfusion

Sickle cell disease (SCD) is a monogenic red blood cell (RBC) disorder with high morbidity and mortality. Here we report for the first time the impact of SCD on the bone marrow (BM) vascular niche, which is critical for hematopoiesis. In SCD mice, we find a disorganized and structurally abnormal BM vascular network of increased numbers of highly tortuous arterioles occupying the majority of the BM cavity, as well as fragmented sinusoidal vessels filled with aggregates of erythroid and myeloid cells. By in vivo imaging, sickle and control RBC have significantly slow intravascular flow speeds in sickle cell but not in control BM. In sickle BM, we find increased ROS production in expanded erythroblast populations and elevated levels of HIF-1a. The SCD BM exudate exhibits increased levels of pro-angiogenic growth factors and sVCAM1. Transplantation of SCD mouse BM cells into wild-type mice recapitulates the SCD vascular phenotype. Our data provide a model of SCD BM, where slow RBC flow and vaso-occlusions further diminish local oxygen availability in the physiologic hypoxic BM cavity. These events trigger a milieu conducive to aberrant vessel growth. The distorted neovascular network is completely reversed by a 6-week blood transfusion regimen targeting HbS to <30%, highlighting the plasticity of the vascular niche. A better insight into the BM microenvironments in SCD might provide opportunities to optimize approaches towards efficient and long-term hematopoietic engraftment in the context of curative therapies.