Activated hepatic stellate cells are required for Hippo-YAP activation and functional liver regeneration following portal vein ligation in mice.

Portal vein ligation (PVL), a preoperative strategy to induce compensatory liver regeneration, is widely applied in clinical practice; however, the cellular and molecular mechanisms underlying PVL-induced liver regeneration remain incompletely understood. Hepatic stellate cells (HSCs), known for their collagen gene expression even in early activation states, have emerged as potential regulators of liver regeneration. To elucidate their role in PVL-induced regeneration, we established a murine PVL model and used Col1a1-GFP reporter mice to visualize collagen gene-expressing HSCs. These cells showed a transient increase after PVL, suggesting activation in response to altered portal flow. To investigate their functional contribution, we selectively ablated activated HSCs using Col1a2-Cre/ERT × ROSA-DTA mice. Despite preservation of total liver mass, activated HSC-deficient mice regenerated their livers through a strikingly different mechanism: hepatocyte proliferation was enhanced, whereas hepatocyte hypertrophy was impaired, resulting in numerous small hepatocytes. Mechanistically, depletion of activated HSCs markedly suppressed YAP nuclear localization and reduced expression of canonical YAP target genes (Cyr61, Ctgf), indicating impaired activation of the Hippo-YAP pathway, whereas mTOR signaling and growth factors remained unchanged. Bulk RNA sequencing further revealed diminished enrichment of metabolic pathways in activated HSC-deficient livers, suggesting impeded functional maturation of hepatocytes. These findings identify activated HSCs as essential mediators of Hippo-YAP-driven hepatocyte hypertrophy and functional maturation after PVL. By redefining activated HSCs as pro-regenerative regulators, this work provides a mechanistic foundation for strategies to enhance preoperative liver regeneration in clinical settings.