Abstract

Liver regeneration is initiated by rapid vascular changes, yet how blood flow-derived mechanical cues are decoded by liver sinusoidal endothelial cells (LSECs) remains unclear. Here, we found that partial hepatectomy generates temporally distinct mechanical cues in vivo, with a transient rise in shear stress followed by progressive sinusoidal dilation and endothelial stretch. To dissect these forces, we developed a liver regeneration chip that reconstructs sinusoidal architecture and enables independent or coupled manipulation of shear stress and mechanical stretch. Shear-dominant, stretch-dominant, and coupled mechanical modalities induce divergent LSEC regenerative programs involving extracellular matrix remodeling, cell-cycle regulation, cytoskeletal organization, and angiocrine signaling. Mechanistically, force-specific pathways, including Wnt, HIF-1, NF-{kappa}B, and Piezo1-associated signaling, mediate these outputs. Inhibition of these pathways after partial hepatectomy impairs hepatocyte proliferation and survival. These findings reveal that LSECs temporally decode blood flow-derived mechanical forces into distinct regenerative outputs, establishing endothelial mechanotransduction as an upstream regulator of liver regeneration.