PDF(Pubmed)
Abstract：
Fifty percent of all acute liver failure (ALF) cases in the United States are due to acetaminophen (APAP) overdose. Assessment of canonical features of liver injury, such as plasma alanine aminotransferase activities are poor predictors of acute liver failure (ALF), suggesting the involvement of additional mechanisms independent of hepatocyte death. Previous work demonstrated a severe overdose of APAP results in impaired regeneration, the induction of senescence by p21, and increased mortality. We hypothesized that a discrete population of p21+ hepatocytes acquired a secretory phenotype that directly impedes liver recovery after a severe APAP overdose. Leveraging in-house human APAP explant liver and publicly available single-nuclei RNAseq data, we identified a subpopulation of p21+ hepatocytes enriched in a unique secretome of factors, such as CXCL14. Spatial transcriptomics in the mouse model of APAP overdose confirmed the presence of a p21+ hepatocyte population that directly surrounded the necrotic areas. In both male and female mice, we found a dose-dependent induction of p21 and persistent circulating levels of the p21-specific constituent, CXCL14, in the plasma after a severe APAP overdose. In parallel experiments, we targeted either the putative senescent hepatocytes with the senolytic drugs, dasatinib and quercetin, or CXCL14 with a neutralizing antibody. We found that targeting CXCL14 greatly enhanced liver recovery after APAP-induced liver injury, while targeting senescent hepatocytes had no effect. These data support the conclusion that the sustained induction of p21 in hepatocytes with persistent CXCL14 secretion are critical mechanistic events leading to ALF in mice and human patients.
摘要：
在美国，所有急性肝衰竭（ALF）病例中有50％是由于对乙酰氨基酚（APAP）过量。肝损伤的典型特征的评估，例如血浆丙氨酸氨基转移酶活性是急性肝功能衰竭（ALF）的不良预测因子，提示独立于肝细胞死亡的其他机制的参与。先前的工作表明，严重过量的APAP会导致再生受损，p21诱导衰老，并增加死亡率。我们假设p21肝细胞的离散群体获得了分泌表型，在严重的APAP过量后直接阻碍肝脏恢复。利用内部人类APAP外植体肝脏和公开可用的单核RNAseq数据，我们确定了p21+肝细胞的亚群富含一个独特的分泌组的因子，例如CXCL14。APAP过量小鼠模型中的空间转录组学证实了直接包围坏死区域的p21肝细胞群的存在。在雄性和雌性小鼠中，我们发现p21的剂量依赖性诱导和p21特异性成分的持续循环水平，CXCL14，在血浆中出现严重的APAP过量。在平行实验中,我们用抗衰老药物靶向假定的衰老肝细胞，达沙替尼和槲皮素，或CXCL14与中和抗体。我们发现，靶向CXCL14极大地增强了APAP诱导的肝损伤后的肝脏恢复，而靶向衰老的肝细胞没有影响。这些数据支持以下结论:在具有持续CXCL14分泌的肝细胞中持续诱导p21是导致小鼠和人类患者ALF的关键机制事件。
