Vascular damage and excessive proliferation compromise liver function after extended hepatectomy in mice

Abstract Surgical resection remains the gold standard for liver tumor treatment, yet the emergence of post-operative liver failure, known as the small for size syndrome (SFSS), poses a substantial challenge. The activation of hypoxia sensors in a SFSS liver remnant initiated early angiogenesis, improving vascular architecture, safeguarding against liver failure and reducing mortality. The study aimed to elucidate vascular remodeling mechanisms in SFSS, its impact on hepatocyte function and subsequent liver failure. Mice underwent extended partial hepatectomy to induce SFSS, a subset were exposed to hypoxia immediately after surgery. Hypoxia bolstered post- hepatectomy survival rates. Early proliferation of liver sinusoidal cells coupled with augmented recruitment of endothelial progenitor cells (EPC) via the VEGF/SDF-1α pathway resulted in heightened vascular density, improved lobular perfusion, and limited hemorrhagic events in the regenerating liver under hypoxia. The administration of G-CSF mimicked the effects of hypoxia on vascular remodeling and EPC recruitment, though it failed to rescue survival. Compared to normoxia, hypoxia restrained hepatocyte proliferation yet improved the function of the regenerating remnant, favoring functional preservation in the liver remnant. Injection of AAV8- TBG-HNF4α virus for hepatocyte-specific overexpression of HNF4α, the master regulator of hepatocyte function, enforced functionality in proliferating hepatocytes. The combination, only, of HNF4α overexpression and G-CSF treatment rescued survival post-SFSS-setting hepatectomy. In summary, SFSS arises due to imbalance and desynchronized interplay between functional regeneration and vascular restructuring. To enhance survival following SFSS-hepatectomy, a two- pronged strategy is essential, addressing the preservation of function in the proliferating parenchymal cells alongside the simultaneous mitigation of vascular harm. One Sentence Summary Combined treatment with G-CSF and HNF4α overexpression rescues vascular damage and function to improve survival after extended hepatectomy in mice.