Transcriptomic landscapes of effective and failed liver regeneration in humans.
Transcriptomic landscapes of effective and failed liver regeneration in humans.
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人类有效和失败肝再生的转录组景观。
DOI：
10.1016/j.jhepr.2023.100683
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发表时间：
2023-04
期刊：
影响因子：
8.3
通讯作者：
Assinger, Alice
中科院分区：
文献类型：
--
作者：
Starlinger, Patrick;Brunnthaler, Laura;McCabe, Chantal;Pereyra, David;Santol, Jonas;Steadman, Jessica;Hackl, Matthias;Skalicky, Susanna;Hackl, Hubert;Gronauer, Raphael;O'Brien, Daniel;Kain, Renate;Hirsova, Petra;Gores, Gregory J.;Wang, Chen;Gruenberger, Thomas;Smoot, Rory L.;Assinger, Alice
虽然关于肝脏再生过程的大量实验证据已经存在，但在人类身上，验证在很大程度上是缺乏的。然而，肝脏再生受到潜在肝病的严重影响。在这个项目中，我们的目标是系统地评估人类肝再生过程中的早期转录变化，并进一步评估这些过程在肝再生功能障碍的人中有何不同。收集了154例肝切除患者的血液样本和46例肝切除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，21名患者的匹配队列被用于RNA测序。对样本进行循环细胞因子、基因表达动态、肝内中性粒细胞聚集和空间转录分析。肝再生功能障碍的个体表现出转录炎症反应的加重，细胞内黏附分子-1的诱导更高。这种关键的白细胞黏附分子的诱导增加与肝再生障碍患者在诱导肝再生时肝内中性粒细胞聚集和激活的增加有关。比较有和没有肝再生功能障碍患者的基线基因表达谱，我们发现双特异性磷酸酶4(DUSP4)的表达在肝再生功能障碍患者中显著减少，双特异性磷酸酶4(DUSP4)是内皮细胞内黏附分子-1表达的关键调节因子。模仿肝脏再生功能障碍的临床危险因素，我们发现两个肝病模型的肝窦内皮细胞显著降低了DUSP4的基线水平。探索人类肝脏再生早期转录变化的图景，我们观察到再生功能障碍的人经历了压倒性的肝内炎症。亚临床肝病可能是肝窦内皮细胞DUSP4减少的原因，最终导致肝脏出现严重的炎症反应。利用一种独特的人类生物信息库，专注于肝再生(LR)，我们探索了与功能和功能失调的肝再生相关的循环和组织水平的改变。与实验动物模型相比，LR功能障碍患者在LR诱导后表现为转录炎症反应加重，细胞内黏附分子-1(ICAM-1)诱生，肝内中性粒细胞聚集和激活。虽然炎症反应在肝切除后迅速出现，但功能不全的LR患者的炎症反应似乎与LSEC DUSP4水平降低有关，这挑战了现有的切除后LR的概念。我们探讨了与功能性和功能失调性肝再生(DLR)相关的循环和组织水平的改变。与实验动物模型相比，患有DLR的个体有严重的转录炎症反应，挑战现有概念。这种反应似乎与LSEC中DUSP4水平的降低有关。
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. 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. 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. 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. 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. We explored circulating and tissue-level alterations associated with functional and dysfunctional liver regeneration (DLR). In contrast to experimental animal models, individuals with DLR had an aggravated transcriptional inflammatory response, challenging existing concepts. This response appears to be related to decreased levels of DUSP4 in LSECs.
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在人肝脏再生的背景下，AXL/GAS-6的免疫学方面。
影响因子：
5.1
作者：
Ortmayr G;Brunnthaler L;Pereyra D;Huber H;Santol J;Rumpf B;Najarnia S;Smoot R;Ammon D;Sorz T;Fritsch F;Schodl M;Voill-Glaninger A;Weitmayr B;Födinger M;Klimpfinger M;Gruenberger T;Assinger A;Mikulits W;Starlinger P
通讯作者：
Starlinger P
影响因子：
25.7
作者：
OHIRA, H;UENO, T;TANIKAWA, K
通讯作者：
TANIKAWA, K
影响因子：
--
作者：
CORNELL, RP
通讯作者：
CORNELL, RP
影响因子：
13.5
作者：
Jin, XL;Zimmers, TA;Koniaris, LG
通讯作者：
Koniaris, LG
影响因子：
4.8
作者：
Lubos, Edith;Kelly, Neil J.;Handy, Diane E.
通讯作者：
Handy, Diane E.