The Role of Endothelial Cells in Sickle Cell Hemoglobin Clearance: What Do We Know So Far?

Presentation Date: 6/8/2024 Presentation Start Time: 6:00 PM Sickle cell disease (SCD) is a monogenic disorder that affects 100,000 African Americans and millions of people worldwide. Intra-erythrocytic polymerization of sickle hemoglobin (HbS) promotes erythrocyte sickling, impaired rheology, ischemia and hemolysis, leading to the development of progressive organ injury in SCD. Liver resident Kupffer cells and monocytes are known to enable the clearance of HbS, however, the role of liver sinusoidal endothelial cells (LSECs) in HbS clearance and liver injury in SCD remains unknown. We used real-time intravital imaging, flow cytometry analysis, and confocal imaging of human and mouse primary endothelial cells to investigate their potential function in hemoglobin clearance. We show for the first time that LSECs are capable of HbS clearance. Hb uptake by LSECs was mediated by micropinocytosis. We show that accumulation of HbS in LSECs promotes endothelial senescence. Hepatic monocytes were observed to attenuate LSEC senescence by accelerating HbS clearance in the liver of SCD mice, however, this protection was impaired in P-selectin-deficient SCD mice secondary to reduced monocyte recruitment in the liver. These findings are the first to suggest that LSECs contribute to HbS clearance and HbS induced LSEC-senescence promotes progressive liver injury in SCD mice. Our results provide a novel insight into the pathogenesis of hemolysis induced chronic liver injury in SCD caused by LSEC senescence. Identifying the regulators of LSEC mediated HbS clearance may lead to new therapies to prevent the progression of liver injury in SCD.