Vascular damage and axcessive proliferation compromise liver function after extended hepatectomy in mice. 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-1α 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-HNF4α virus for hepatocyte-specific overexpression of HNF4α, the master regulator of hepatocyte function, enforced functionality in proliferating hepatocytes but did not rescue survival. Only the combination of HNF4α 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).

手术切除仍是肝肿瘤治疗的金标准，但术后肝功能衰竭，即小体积综合征（small for size syndrome, SFSS）的出现是一项重大临床挑战。SFSS残肝中缺氧感受器的激活可启动早期血管生成，改善血管结构，预防肝功能衰竭并降低死亡率。
本研究旨在阐明SFSS中的血管重塑机制，及其对肝细胞功能与后续肝功能衰竭的影响。
研究通过扩大部分肝切除术诱导小鼠出现SFSS，并将部分小鼠在术后立即暴露于缺氧环境。缺氧可提高肝切除术后的存活率。肝窦细胞的早期增殖，加上通过血管内皮生长因子/基质细胞衍生因子1α（VEGF/SDF-1α）通路募集的推定内皮祖细胞（endothelial progenitor cells, EPC），可提高缺氧环境下再生肝脏的血管密度、改善小叶灌注，并减少出血事件。
对肝切除术后小鼠给予粒细胞集落刺激因子（Granulocyte colony-stimulating factor, G-CSF），可模拟缺氧对血管重塑与EPC募集的作用，但无法挽救小鼠的存活率。与常氧环境相比，缺氧更倾向于维持肝细胞功能而非促进增殖，从而促进再生残肝的功能保留。通过注射腺相关病毒8型（adeno-associated virus serotype 8, AAV8）-TBG-HNF4α病毒，实现肝细胞特异性过表达肝细胞核因子4α（hepatocyte nuclear factor 4 alpha, HNF4α）——这是肝细胞功能的核心调控因子——可增强增殖肝细胞的功能，但无法挽救小鼠存活率。仅当同时进行HNF4α过表达与G-CSF治疗时，才可挽救SFSS模型肝切除术后小鼠的存活率。
综上，SFSS源于功能再生与血管重塑之间的失衡及不同步的相互作用。为提高SFSS肝切除术后的存活率，需采用双管齐下的治疗策略：既要维持增殖实质细胞的功能，同时也要减轻血管损伤。
实验整体设计：通过RNA测序（RNA-seq）实验比较4种不同条件下的基因表达水平：70%肝切除术组（PHx70%，n=3）、80%肝切除术组（PHx80%，n=3）、PHx80%-HC组（PHx80%-HC，n=3）以及G-CSF+HNF4α-PHx80%组（G-CSF+HNF4α-PHx80%，n=3）。