Aging reprogramming liver endothelial zonation triggers steatohepatitis by inactivating pericentral endothelium-derived C-kit

Abstract Aging leads to systemic metabolic disorders including nonalcoholic steatohepatitis (NASH). Here, we showed that aging-induced liver sinusoidal endothelial cell (LSEC) senescence accelerated liver sinusoid capillarization and promoted steatohepatitis by reprogramming liver endothelial zonation and inactivating pericentral endothelium-derived C-kit. Abrogation of endothelial C-kit triggered cellular senescence which disturbed LSEC homeostasis. During diet-induced NASH development, C-kit deletion aggravated hepatic steatosis and exacerbated NASH-associated fibrosis and inflammation. Mechanistically, CXCR4/SDF-1 signaling was inhibited by C-kit. Blocking CXCR4/SDF-1 signaling by AMD3100 abolished LSEC-macrophage crosstalk and recovered the aggravated NASH in C-kit deficient mice. For therapeutic purpose, C-kit+ LSECs were implanted into NASH or aged mice, which counteracted LSEC senescence and improved diet or aging-induced NASH by restoring the homeostasis of pericentral liver endothelium.