Biostatistics, Epidemiology, and Scientific Computing Department, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
Department of Surgery and Organ Transplantation Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
Sci Rep. 2020 Mar 23;10(1):5213. doi: 10.1038/s41598-020-61826-1.
The liver is a unique organ that has a phenomenal capacity to regenerate after injury. Different surgical procedures, including partial hepatectomy (PH), intraoperative portal vein ligation (PVL), and associated liver partition and portal vein ligation for staged hepatectomy (ALPPS) show clinically distinct recovery patterns and regeneration. The observable clinical differences likely mirror some underlying variations in the patterns of gene activation and regeneration pathways. In this study, we provided a comprehensive comparative transcriptomic analysis of gene regulation in regenerating rat livers temporally spaced at 24 h and 96 h after PH, PVL, and ALPPS. The time-dependent factors appear to be the most important determinant of post-injury alterations of gene expression in liver regeneration. Gene expression profile after ALPPS showed more similar expression pattern to the PH than the PVL at the early phase of the regeneration. Early transcriptomic changes and predicted upstream regulators that were found in all three procedures included cell cycle associated genes (E2F1, CCND1, FOXM1, TP53, and RB1), transcription factors (Myc, E2F1, TBX2, FOXM1), DNA replication regulators (CDKN1A, EZH2, RRM2), G1/S-transition regulators (CCNB1, CCND1, RABL6), cytokines and growth factors (CSF2, IL-6, TNF, HGF, VEGF, and EGF), ATM and p53 signaling pathways. The functional pathway, upstream, and network analyses revealed both unique and overlapping molecular mechanisms and pathways for each surgical procedure. Identification of molecular signatures and regenerative signaling pathways for each surgical procedure further our understanding of key regulators of liver regeneration as well as patient populations that are likely to benefit from each procedure.
肝脏是一种具有非凡再生能力的独特器官。不同的手术程序，包括部分肝切除术（PH）、术中门静脉结扎术（PVL）和相关的肝分割和门静脉结扎分期肝切除术（ALPPS），显示出明显不同的恢复模式和再生能力。可观察到的临床差异可能反映了基因激活和再生途径的某些潜在变化。在这项研究中，我们对 PH、PVL 和 ALPPS 后 24 和 96 小时的大鼠肝脏进行了时间间隔的全面比较转录组分析，以研究基因调控。时间依赖性因素似乎是肝再生中损伤后基因表达改变的最重要决定因素。ALPPS 后的基因表达谱在再生的早期阶段与 PH 比 PVL 更相似。在所有三种手术中，早期转录组变化和预测的上游调控因子包括细胞周期相关基因（E2F1、CCND1、FOXM1、TP53 和 RB1）、转录因子（Myc、E2F1、TBX2、FOXM1）、DNA 复制调控因子（CDKN1A、EZH2、RRM2）、G1/S 过渡调控因子（CCNB1、CCND1、RABL6）、细胞因子和生长因子（CSF2、IL-6、TNF、HGF、VEGF 和 EGF）、ATM 和 p53 信号通路。功能途径、上游和网络分析揭示了每种手术的独特和重叠的分子机制和途径。每种手术的分子特征和再生信号通路的鉴定进一步加深了我们对肝脏再生关键调控因子以及可能从每种手术中受益的患者群体的理解。
