The LIF-LIFR Axis Promotes Liver Regeneration via Modulation of Angiogenesis and HGF Release from LSECs.

UNLABELLED: Liver sinusoidal endothelial cells (LSECs) play essential roles in liver regeneration after injury, but the underlying mechanisms remain incompletely defined. Here we report that leukemia inhibitory factor (LIF), which is rapidly induced after liver injury, acts as a key regulator of LSECs-driven liver regeneration through interaction with LSECs-enriched LIF receptor (LIFR). LIF directly stimulates LSECs proliferation and induces hepatocyte growth factor (HGF) release in a dose-dependent manner via LIFR signaling in LSECs, thereby indirectly promoting hepatocyte proliferation. Systemic LIF neutralization or endothelial cells (ECs)-specific Lifr loss impairs liver regeneration, whereas low-titer AAV-mediated LIF expression increases vascular density, elevates circulating HGF, and improves early liver recovery after partial hepatectomy (PHx) in mice. Together, these findings establish LIF-LIFR as a previously unrecognized endothelial axis to promote hepatocyte proliferation and suggest potential therapeutic strategies to enhance liver repair in patients.

HIGHLIGHTS: LIF is upregulated after liver injury and LIF neutralization impairs liver recovery. LIFR displays the highest expression in ECs; endothelial-specific Lifr deletion delays liver regeneration after injury. LIF mediates a positive feedback loop including LSECs proliferation as well as HGF release via LIFR pathway.LIF overexpression increases liver-to-body weight ratio in a dose-dependent manner and accelerates liver regeneration at early stage.