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

• Published in: Blood Vol. 135; no. 23; pp. 2071 - 2084
• Main Authors: Park, Shin-Young, Matte, Alessandro, Jung, Yookyung, Ryu, Jina, Anand, Wilson Babu, Han, Eun-Young, Liu, Min, Carbone, Carmine, Melisi, Davide, Nagasawa, Takashi, Locascio, Joseph J., Lin, Charles P., Silberstein, Leslie E., De Franceschi, Lucia
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 04.06.2020; American Society of Hematology
• Subjects: Anemia, Sickle Cell - complications; Animals; Blood Transfusion - methods; Bone Marrow - metabolism; Bone Marrow - pathology; Erythrocytes, Abnormal - metabolism; Erythrocytes, Abnormal - pathology; Female; Hematopoiesis; Humans; Male; Mice; Neovascularization, Pathologic - etiology; Neovascularization, Pathologic - pathology; Neovascularization, Pathologic - prevention & control; Red Cells, Iron, and Erythropoiesis; Splenomegaly - etiology; Splenomegaly - pathology; Splenomegaly - prevention & control
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.2019002227

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 RBCs have significantly slow intravascular flow speeds in sickle cell BM but not in control BM. In sickle cell BM, we find increased reactive oxygen species production in expanded erythroblast populations and elevated levels of HIF-1α. The SCD BM exudate exhibits increased levels of proangiogenic growth factors and soluble vascular cell adhesion molecule-1. Transplantation of SCD mouse BM cells into wild-type mice recapitulates the SCD vascular phenotype. Our data provide a model of SCD BM, in which slow RBC flow and vaso-occlusions further diminish local oxygen availability in the physiologic hypoxic BM cavity. These events trigger a milieu that is conducive to aberrant vessel growth. The distorted neovascular network is completely reversed by a 6-week blood transfusion regimen targeting hemoglobin S to <30%, highlighting the plasticity of the vascular niche. A better insight into the BM microenvironments in SCD might provide opportunities to optimize approaches toward efficient and long-term hematopoietic engraftment in the context of curative therapies. •Slow RBC flow speed and vaso-occlusions trigger an HIF-1α–induced proangiogenic milieu conducive to aberrant vessel growth.•In SCD mice, blood transfusion reverses neoangiogenesis, highlighting the plasticity of the BM vasculature. [Display omitted]