Prometheus' myth revisited: transgenic mice as a powerful tool to study liver regeneration

Abstract

In this review, we present examples of the contribution of transgenic mice to our knowledge concerning the type of cells that are able to repopulate a damaged liver and information on the factors and mechanisms involved in postnatal liver growth and regeneration. The transgenic technology offers the opportunity to evaluate the physiological consequences of perturbating expression of a given gene in vivo. It has provided insights into the concerted action of extracellular (HGF/SF, TGF-alpha, EGF, TGF-beta) and intracellular factors (c-myc, c-fos, c-jun, p53, c-met, and others) in liver regeneration. Transgenic mice can also contribute to the dissection of the molecular mechanisms responsible for the regulated expression of these factors, both at the transcriptional and the posttranscriptional level. An illustration of such a strategy is given by the study of the sequences involved in the posttranscriptional regulation of the c-myc proto-oncogene. The recent improvement of gene targeting, in which endogenous genes are inactivated by homologous recombination, represents a further step toward the study of the function of a particular gene. Inactivation of most of the factors described in this review has been undertaken. However, further studies of their role in liver growth control are impeded by the fact that the corresponding knockout mice die prematurely. This problem could be overcome by the advent of new techniques, which will be briefly presented, aimed at turning genes on and off at will and in a tissue-specific manner.

Proteomic analysis of regenerating mouse liver following 50% partial hepatectomy

“…Among them, over 25 are located at the mitochondria, and the majority is reported to be associated with liver regeneration for the first time. Consistent with the documented regulatory roles of c-Myc during the G 1 phase of liver regeneration [67] and in the "priming" of hepatocytes [17,68], 18 of the identified differentially-expressed proteins are connected to c-Myc in a complex signaling network via multiple modes, and thus placing c-Myc as one of the master factors regulating liver regeneration under our experimental conditions. Importantly, the functional roles of some newly identified proteins in liver regeneration await further clarification, and whether they are differentially regulated specifically with 50% PH but not with other volume of PH is currently under investigation.…”

Cloning and characterization of a mouse liver-specific gene mfrep-1, upregulated in liver regeneration

“…To investigate the potential role of MFREP-1 in cell proliferation regulation, we used mouse liver regeneration model to analyze the expression kinetics of mfrep-1. The processes of liver regeneration reflect very important events in the cell cycle such as initiation of cell division, termination of cell growth and cell differentiation [19], [20].…”

Aberrant Cell Cycle Progression and Endoreplication in Regenerating Livers of Mice That Lack a Single E-Type Cyclin

“…In this model, resection of intact liver lobes induces a tightly regulated growth response resulting in synchronous replication of hepatocytes. After PH, DNA synthesis starts at 24 h and peaks after 36–40 h. The original liver mass is restored within 12-15 days, reflecting an average of 1.6 division cycles per hepatocyte16.…”