Vascular damage and axcessive proliferation compromise liver function after extended hepatectomy in mice
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 significant 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, with a subset  exposed to hypoxia immediately after surgery. Hypoxia bolstered post-hepatectomy survival rates. Early proliferation of liver sinusoidal cells coupled with recruitment of putative endothelial progenitor cells (EPC) via the VEGF/SDF-1a pathway, increased vascular density, improved lobular perfusion, and limited hemorrhagic events in the regenerating liver under hypoxia. Administration of G-CSF in hepatectomized mice mimicked the effects of hypoxia on vascular remodeling and EPC recruitment, but failed to rescue survival. Compared to normoxia, hypoxia favored hepatocyte function over proliferation, , promoting functional preservation in the regenerating remnant. Injection of AAV8-TBG-HNF4a virus for hepatocyte-specific overexpression of HNF4a, the master regulator of hepatocyte function, enforced functionality in proliferating hepatocytes but did not rescue survival. Only the combination of HNF4a overexpression and G-CSF treatment rescued survival afterSFSS-setting hepatectomy. In summary, SFSS arises from an 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. Overall design: RNA-seq experiment was performed to compare the gene expression level in 4 different conditions: PHx70% (n=3), PHx80% (n=3), PHx80%-HC (n=3), G-CSF+HNF4a-PHx80% (n=3).