Haber B A, Mohn K L, Diamond R H, Taub R
Department of Genetics, University of Pennsylvania, School of Medicine, Philadelphia 19104-6145.
J Clin Invest. 1993 Apr;91(4):1319-26. doi: 10.1172/JCI116332.
Liver regeneration is an important process that allows for recovery from hepatic injuries caused by viruses, toxins, ischemia, surgery, and transplantation. Previously, we identified > 70 immediate-early genes induced in regenerating liver after hepatectomy, 41 of which were novel. While it is expected that the proteins encoded by these genes may have important roles in regulating progression through the G1 phase of the cell cycle during regeneration, we were surprised to note that many of these "early" genes are expressed for extended periods during the hepatic growth response. Here we define several patterns of expression of immediate-early, delayed-early, and liver-specific genes during the 9-d period after hepatectomy. One pattern of induction parallels the major growth period of the liver that ends at 60-72 h after hepatectomy. A second pattern has two peaks coincident with the first and second G1 phases of the two hepatic cell cycles. A third group, which includes liver-specific genes such as C/EBP alpha, shows maximal expression after the growth period. Although the peak in DNA synthesis in nonparenchymal cells occur 24 h later than in hepatocytes, most of the genes studied demonstrate similar induction in both cell types. This finding suggests that the G0/G1 transition occurs simultaneously in all cells in the liver, but that the G1 phase of nonparenchymal cells may be relatively prolonged. Finally, we examined the expression of > 70 genes in clinical settings that could induce liver regeneration, including after perfusion in a donor liver, hepatic ischemia, and fulminant hepatic failure. We found that a small number of early and liver-specific genes were selectively activated in human livers under these conditions, and we thereby provide a potential means of measuring the caliber of the regenerative response in clinical situations.
肝再生是一个重要过程，可使肝脏从病毒、毒素、缺血、手术及移植所导致的肝损伤中恢复。此前，我们鉴定出肝切除术后再生肝脏中诱导表达的70多个立即早期基因，其中41个是新基因。虽然预计这些基因编码的蛋白质可能在调节再生过程中细胞周期G1期的进程中发挥重要作用，但我们惊讶地注意到，这些“早期”基因中的许多在肝脏生长反应期间会持续表达很长时间。在此，我们定义了肝切除术后9天内立即早期、延迟早期和肝脏特异性基因的几种表达模式。一种诱导模式与肝脏的主要生长时期平行，该时期在肝切除术后60 - 72小时结束。第二种模式有两个峰值，与两个肝细胞周期的第一个和第二个G1期重合。第三组包括如C/EBPα等肝脏特异性基因，在生长时期后显示出最大表达。尽管非实质细胞中DNA合成的峰值比肝细胞晚24小时出现，但大多数研究的基因在两种细胞类型中都表现出相似的诱导。这一发现表明肝脏中所有细胞的G0/G1转变同时发生，但非实质细胞的G1期可能相对延长。最后，我们在临床环境中研究了70多个可诱导肝再生的基因的表达，包括供体肝脏灌注后、肝缺血和暴发性肝衰竭后。我们发现在这些条件下，少数早期和肝脏特异性基因在人类肝脏中被选择性激活，从而为在临床情况下测量再生反应的程度提供了一种潜在方法。
