PDF(Pubmed)
Abstract：
UNASSIGNED: Although extensive experimental evidence on the process of liver regeneration exists, in humans, validation is largely missing. However, liver regeneration is critically affected by underlying liver disease. Within this project, we aimed to systematically assess early transcriptional changes during liver regeneration in humans and further assess how these processes differ in people with dysfunctional liver regeneration.
UNASSIGNED: Blood samples of 154 patients and intraoperative tissue samples of 46 patients undergoing liver resection were collected and classified with regard to dysfunctional postoperative liver regeneration. Of those, a matched cohort of 21 patients were used for RNA sequencing. Samples were assessed for circulating cytokines, gene expression dynamics, intrahepatic neutrophil accumulation, and spatial transcriptomics.
UNASSIGNED: Individuals with dysfunctional liver regeneration demonstrated an aggravated transcriptional inflammatory response with higher intracellular adhesion molecule-1 induction. Increased induction of this critical leukocyte adhesion molecule was associated with increased intrahepatic neutrophil accumulation and activation upon induction of liver regeneration in individuals with dysfunctional liver regeneration. Comparing baseline gene expression profiles in individuals with and without dysfunctional liver regeneration, we found that dual-specificity phosphatase 4 (DUSP4) expression, a known critical regulator of intracellular adhesion molecule-1 expression in endothelial cells, was markedly reduced in patients with dysfunctional liver regeneration. Mimicking clinical risk factors for dysfunctional liver regeneration, we found liver sinusoidal endothelial cells of two liver disease models to have significantly reduced baseline levels of DUSP4.
UNASSIGNED: Exploring the landscape of early transcriptional changes of human liver regeneration, we observed that people with dysfunctional regeneration experience overwhelming intrahepatic inflammation. Subclinical liver disease might account for DUSP4 reduction in liver sinusoidal endothelial cells, which ultimately primes the liver for an aggravated inflammatory response.
UNASSIGNED: Using a unique human biorepository, focused on liver regeneration (LR), we explored the landscape of circulating and tissue-level alterations associated with both functional and dysfunctional LR. In contrast to experimental animal models, people with dysfunctional LR demonstrated an aggravated transcriptional inflammatory response, higher intracellular adhesion molecule-1 (ICAM-1) induction, intrahepatic neutrophil accumulation and activation upon induction of LR. Although inflammatory responses appear rapidly after liver resection, people with dysfunctional LR have exaggerated inflammatory responses that appear to be related to decreased levels of LSEC DUSP4, challenging existing concepts of post-resectional LR.
UNASSIGNED: Blood samples of 154 patients and intraoperative tissue samples of 46 patients undergoing liver resection were collected and classified with regard to dysfunctional postoperative liver regeneration. Of those, a matched cohort of 21 patients were used for RNA sequencing. Samples were assessed for circulating cytokines, gene expression dynamics, intrahepatic neutrophil accumulation, and spatial transcriptomics.
UNASSIGNED: Individuals with dysfunctional liver regeneration demonstrated an aggravated transcriptional inflammatory response with higher intracellular adhesion molecule-1 induction. Increased induction of this critical leukocyte adhesion molecule was associated with increased intrahepatic neutrophil accumulation and activation upon induction of liver regeneration in individuals with dysfunctional liver regeneration. Comparing baseline gene expression profiles in individuals with and without dysfunctional liver regeneration, we found that dual-specificity phosphatase 4 (DUSP4) expression, a known critical regulator of intracellular adhesion molecule-1 expression in endothelial cells, was markedly reduced in patients with dysfunctional liver regeneration. Mimicking clinical risk factors for dysfunctional liver regeneration, we found liver sinusoidal endothelial cells of two liver disease models to have significantly reduced baseline levels of DUSP4.
UNASSIGNED: Exploring the landscape of early transcriptional changes of human liver regeneration, we observed that people with dysfunctional regeneration experience overwhelming intrahepatic inflammation. Subclinical liver disease might account for DUSP4 reduction in liver sinusoidal endothelial cells, which ultimately primes the liver for an aggravated inflammatory response.
UNASSIGNED: Using a unique human biorepository, focused on liver regeneration (LR), we explored the landscape of circulating and tissue-level alterations associated with both functional and dysfunctional LR. In contrast to experimental animal models, people with dysfunctional LR demonstrated an aggravated transcriptional inflammatory response, higher intracellular adhesion molecule-1 (ICAM-1) induction, intrahepatic neutrophil accumulation and activation upon induction of LR. Although inflammatory responses appear rapidly after liver resection, people with dysfunctional LR have exaggerated inflammatory responses that appear to be related to decreased levels of LSEC DUSP4, challenging existing concepts of post-resectional LR.
摘要：
■尽管存在关于肝再生过程的大量实验证据，在人类中,验证在很大程度上是缺失的。然而,肝脏再生受到潜在肝脏疾病的严重影响。在这个项目中,我们旨在系统地评估人类肝脏再生过程中的早期转录变化，并进一步评估这些过程在肝脏再生障碍患者中的差异。
■收集154例患者的血液样本和46例接受肝切除术的患者的术中组织样本，并根据术后肝再生功能障碍进行分类。其中,一个由21例患者组成的配对队列被用于RNA测序.评估样本的循环细胞因子，基因表达动力学，肝内中性粒细胞积累，和空间转录组学。
■具有功能失调的肝脏再生的个体表现出随着更高的细胞内粘附分子-1诱导而加重的转录炎症反应。这种关键的白细胞粘附分子的诱导增加与肝再生功能失调的个体在诱导肝再生时增加的肝内中性粒细胞积累和激活有关。比较有和没有功能失调的肝再生个体的基线基因表达谱，我们发现双特异性磷酸酶4（DUSP4）表达，一种已知的内皮细胞胞内粘附分子-1表达的关键调节剂，在肝脏再生功能失调的患者中明显减少。模仿肝功能异常的临床危险因素，我们发现两种肝病模型的肝窦内皮细胞的DUSP4基线水平显著降低.
■探索人类肝脏再生的早期转录变化的景观，我们观察到功能失调的人经历压倒性的肝内炎症。亚临床肝病可能是肝窦内皮细胞DUSP4减少的原因，最终启动肝脏加重的炎症反应。
■使用独特的人类生物存储库，专注于肝脏再生（LR），我们探索了与功能和功能失调LR相关的循环和组织水平改变的景观。与实验动物模型相反,LR功能失调的人表现出转录炎症反应加重，更高的细胞内粘附分子-1（ICAM-1）诱导，诱导LR时肝内中性粒细胞积累和激活。尽管肝切除术后炎症反应迅速出现，LR功能失调患者的炎症反应过度,这似乎与LSECDUSP4水平降低有关,这对现有的切除后LR概念提出了挑战.
■收集154例患者的血液样本和46例接受肝切除术的患者的术中组织样本，并根据术后肝再生功能障碍进行分类。其中,一个由21例患者组成的配对队列被用于RNA测序.评估样本的循环细胞因子，基因表达动力学，肝内中性粒细胞积累，和空间转录组学。
■具有功能失调的肝脏再生的个体表现出随着更高的细胞内粘附分子-1诱导而加重的转录炎症反应。这种关键的白细胞粘附分子的诱导增加与肝再生功能失调的个体在诱导肝再生时增加的肝内中性粒细胞积累和激活有关。比较有和没有功能失调的肝再生个体的基线基因表达谱，我们发现双特异性磷酸酶4（DUSP4）表达，一种已知的内皮细胞胞内粘附分子-1表达的关键调节剂，在肝脏再生功能失调的患者中明显减少。模仿肝功能异常的临床危险因素，我们发现两种肝病模型的肝窦内皮细胞的DUSP4基线水平显著降低.
■探索人类肝脏再生的早期转录变化的景观，我们观察到功能失调的人经历压倒性的肝内炎症。亚临床肝病可能是肝窦内皮细胞DUSP4减少的原因，最终启动肝脏加重的炎症反应。
■使用独特的人类生物存储库，专注于肝脏再生（LR），我们探索了与功能和功能失调LR相关的循环和组织水平改变的景观。与实验动物模型相反,LR功能失调的人表现出转录炎症反应加重，更高的细胞内粘附分子-1（ICAM-1）诱导，诱导LR时肝内中性粒细胞积累和激活。尽管肝切除术后炎症反应迅速出现，LR功能失调患者的炎症反应过度,这似乎与LSECDUSP4水平降低有关,这对现有的切除后LR概念提出了挑战.
