PDF(Pubmed)
Abstract：
UNASSIGNED: The prevalence of non-alcoholic fatty liver disease (NAFLD) and its severe form, non-alcoholic steatohepatitis (NASH), is increasing. Individuals with NASH often develop liver fibrosis and advanced liver fibrosis is the main determinant of mortality in individuals with NASH. We and others have reported that STAT3 contributes to liver fibrosis and hepatocellular carcinoma in mice.
UNASSIGNED: Here, we explored whether STAT3 activation in hepatocyte and non-hepatocyte areas, measured by phospho-STAT3 (pSTAT3), is associated with liver fibrosis progression in 133 patients with NAFLD. We further characterized the molecular and cellular determinants of STAT3 activation by integrating spatial distribution and transcriptomic changes in fibrotic NAFLD livers.Results: pSTAT3 scores in non-hepatocyte areas progressively increased with fibrosis severity (r = 0.53, p <0.001). Correlation analyses between pSTAT3 scores and expression of 1,540 immune- and cancer-associated genes revealed a large effect of STAT3 activation on gene expression changes in non-hepatocyte areas and confirmed a major role for STAT3 activation in fibrogenesis. Digital spatial transcriptomic profiling was also performed on 13 regions selected in hepatocyte and non-hepatocyte areas from four NAFLD liver biopsies with advanced fibrosis, using a customized panel of markers including pSTAT3, PanCK+CK8/18, and CD45. The regions were further segmented based on positive or negative pSTAT3 staining. Cell deconvolution analysis revealed that activated STAT3 was enriched in hepatic progenitor cells (HPCs) and sinusoidal endothelial cells. Regression of liver fibrosis upon STAT3 inhibition in mice with NASH resulted in a reduction of HPCs, demonstrating a direct role for STAT3 in HPC expansion.
UNASSIGNED: Increased understanding of the spatial dependence of STAT3 signaling in NASH and liver fibrosis progression could lead to novel targeted treatment approaches.
UNASSIGNED: Advanced liver fibrosis is the main determinant of mortality in patients with NASH. This study showed using liver biopsies from 133 patients with NAFLD, that STAT3 activation in non-hepatocyte areas is strongly associated with fibrosis severity, inflammation, and progression to NASH. STAT3 activation was enriched in hepatic progenitor cells (HPCs) and sinusoidal endothelial cells (SECs), as determined by innovative technologies interrogating the spatial distribution of pSTAT3. Finally, STAT3 inhibition in mice resulted in reduced liver fibrosis and depletion of HPCs, suggesting that STAT3 activation in HPCs contributes to their expansion and fibrogenesis in NAFLD.
UNASSIGNED: Here, we explored whether STAT3 activation in hepatocyte and non-hepatocyte areas, measured by phospho-STAT3 (pSTAT3), is associated with liver fibrosis progression in 133 patients with NAFLD. We further characterized the molecular and cellular determinants of STAT3 activation by integrating spatial distribution and transcriptomic changes in fibrotic NAFLD livers.Results: pSTAT3 scores in non-hepatocyte areas progressively increased with fibrosis severity (r = 0.53, p <0.001). Correlation analyses between pSTAT3 scores and expression of 1,540 immune- and cancer-associated genes revealed a large effect of STAT3 activation on gene expression changes in non-hepatocyte areas and confirmed a major role for STAT3 activation in fibrogenesis. Digital spatial transcriptomic profiling was also performed on 13 regions selected in hepatocyte and non-hepatocyte areas from four NAFLD liver biopsies with advanced fibrosis, using a customized panel of markers including pSTAT3, PanCK+CK8/18, and CD45. The regions were further segmented based on positive or negative pSTAT3 staining. Cell deconvolution analysis revealed that activated STAT3 was enriched in hepatic progenitor cells (HPCs) and sinusoidal endothelial cells. Regression of liver fibrosis upon STAT3 inhibition in mice with NASH resulted in a reduction of HPCs, demonstrating a direct role for STAT3 in HPC expansion.
UNASSIGNED: Increased understanding of the spatial dependence of STAT3 signaling in NASH and liver fibrosis progression could lead to novel targeted treatment approaches.
UNASSIGNED: Advanced liver fibrosis is the main determinant of mortality in patients with NASH. This study showed using liver biopsies from 133 patients with NAFLD, that STAT3 activation in non-hepatocyte areas is strongly associated with fibrosis severity, inflammation, and progression to NASH. STAT3 activation was enriched in hepatic progenitor cells (HPCs) and sinusoidal endothelial cells (SECs), as determined by innovative technologies interrogating the spatial distribution of pSTAT3. Finally, STAT3 inhibition in mice resulted in reduced liver fibrosis and depletion of HPCs, suggesting that STAT3 activation in HPCs contributes to their expansion and fibrogenesis in NAFLD.
摘要：
未经证实：非酒精性脂肪性肝病（NAFLD）的患病率及其严重形式，非酒精性脂肪性肝炎（NASH），正在增加。患有NASH的个体通常发展为肝纤维化,并且晚期肝纤维化是患有NASH的个体的死亡率的主要决定因素。我们和其他人报道STAT3有助于小鼠的肝纤维化和肝细胞癌。
未经评估：这里，我们探讨了肝细胞和非肝细胞区域的STAT3激活，通过磷酸-STAT3（pSTAT3）测量，与133例NAFLD患者的肝纤维化进展相关。通过整合纤维化NAFLD肝脏中的空间分布和转录组变化，我们进一步表征了STAT3激活的分子和细胞决定因素。结果：非肝细胞区域的pSTAT3评分随着纤维化严重程度而逐渐增加（r=0.53，p<0.001）。pSTAT3评分与1,540个免疫和癌症相关基因的表达之间的相关性分析揭示了STAT3激活对非肝细胞区域基因表达变化的巨大影响，并证实了STAT3激活在纤维形成中的主要作用。数字空间转录组分析也在肝细胞和非肝细胞区域选择从四个NAFLD肝活检与晚期纤维化的13个区域进行，使用定制的标记物组，包括pSTAT3、PanCK+CK8/18和CD45。基于阳性或阴性pSTAT3染色进一步分割区域。细胞去卷积分析显示活化的STAT3富集在肝祖细胞(HPCs)和窦内皮细胞中。在NASH小鼠中STAT3抑制后肝纤维化的回归导致HPCs减少，证明STAT3在HPC扩展中的直接作用。
UNASSIGNED：增加对NASH和肝纤维化进展中STAT3信号传导的空间依赖性的理解可能导致新的靶向治疗方法。
未经证实：晚期肝纤维化是NASH患者死亡率的主要决定因素。这项研究表明，使用来自133名NAFLD患者的肝活检，非肝细胞区域的STAT3激活与纤维化严重程度密切相关，炎症,并发展到NASH。STAT3激活富集在肝祖细胞（HPCs）和肝窦内皮细胞（SECs），由研究pSTAT3空间分布的创新技术决定。最后,小鼠中的STAT3抑制导致肝纤维化减少和HPCs的消耗，表明HPCs中的STAT3激活有助于其在NAFLD中的扩张和纤维化形成。
未经评估：这里，我们探讨了肝细胞和非肝细胞区域的STAT3激活，通过磷酸-STAT3（pSTAT3）测量，与133例NAFLD患者的肝纤维化进展相关。通过整合纤维化NAFLD肝脏中的空间分布和转录组变化，我们进一步表征了STAT3激活的分子和细胞决定因素。结果：非肝细胞区域的pSTAT3评分随着纤维化严重程度而逐渐增加（r=0.53，p<0.001）。pSTAT3评分与1,540个免疫和癌症相关基因的表达之间的相关性分析揭示了STAT3激活对非肝细胞区域基因表达变化的巨大影响，并证实了STAT3激活在纤维形成中的主要作用。数字空间转录组分析也在肝细胞和非肝细胞区域选择从四个NAFLD肝活检与晚期纤维化的13个区域进行，使用定制的标记物组，包括pSTAT3、PanCK+CK8/18和CD45。基于阳性或阴性pSTAT3染色进一步分割区域。细胞去卷积分析显示活化的STAT3富集在肝祖细胞(HPCs)和窦内皮细胞中。在NASH小鼠中STAT3抑制后肝纤维化的回归导致HPCs减少，证明STAT3在HPC扩展中的直接作用。
UNASSIGNED：增加对NASH和肝纤维化进展中STAT3信号传导的空间依赖性的理解可能导致新的靶向治疗方法。
未经证实：晚期肝纤维化是NASH患者死亡率的主要决定因素。这项研究表明，使用来自133名NAFLD患者的肝活检，非肝细胞区域的STAT3激活与纤维化严重程度密切相关，炎症,并发展到NASH。STAT3激活富集在肝祖细胞（HPCs）和肝窦内皮细胞（SECs），由研究pSTAT3空间分布的创新技术决定。最后,小鼠中的STAT3抑制导致肝纤维化减少和HPCs的消耗，表明HPCs中的STAT3激活有助于其在NAFLD中的扩张和纤维化形成。
