P-selectin deficiency protects SCD mice from baseline hepatic vaso-occlusion, but does not prevent chronic liver injury.
P-selectin deficiency contributes to increased cellular senescence in the liver of SCD mice.
Sickle cell disease (SCD) is caused by a homozygous mutation in the β-globin gene, which leads to erythrocyte sickling, vaso-occlusion, and intense hemolysis. P-selectin inhibition has been shown to prevent vaso-occlusive events in SCD patients, however, the chronic effect of P-selectin inhibition in SCD remains to be determined. Here, we used quantitative liver intravital microscopy in our recently generated P-selectin deficient SCD mice to show that chronic P-selectin deficiency attenuates liver ischemia, but fails to prevent hepatobiliary injury. Remarkably, we find that this failure in resolution of hepatobiliary injury in P-selectin deficient SCD mice is associated with the increase in cellular senescence and reduced epithelial cell proliferation in the liver. These findings highlight the importance to investigate the long-term effects of chronic P-selectin inhibition therapy on liver pathophysiology in SCD patients.