INDUCTION-PATTERNS OF 70 GENES DURING 9 DAYS AFTER HEPATECTOMY DEFINETHE TEMPORAL COURSE OF LIVER-REGENERATION

Liver regeneration is an important process that allows for recovery fr om 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 nove l. While it is expected that the proteins encoded by these genes may h ave important roles in regulating progression through the G1 phase of the cell cycle during regeneration, we were surprised to note that man y of these ''early'' genes are expressed for extended periods during t he hepatic growth response. Here we define several patterns of express ion 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 hepate ctomy. A second pattern has two peaks coincident with the first and se cond G1 phases of the two hepatic cell cycles. A third group, which in cludes liver-specific genes such as C/EBPalpha, shows maximal expressi on after the growth period. Although the peak in DNA synthesis in nonp arenchymal cells occur 24 h later than in hepatocytes, most of the gen es studied demonstrate similar induction in both cell types. This find ing suggests that the G0/G1 transition occurs simultaneously in all ce lls in the liver, but that the G1 phase of nonparenchymal cells may be relatively prolonged. Finally, we examined the expression of > 70 gen es in clinical settings that could induce liver regeneration, includin g after perfusion in a donor liver, hepatic ischemia, and fulminant he patic failure. We found that a small number of early and liver-specifi c genes were selectively activated in human livers under these conditi ons, and we thereby provide a potential means of measuring the caliber of the regenerative response in clinical situations.