Cellular aspects of liver regeneration1

Acta Cirurgica Brasileira, 2006

This paper has the objective to analyze the cellular aspects of liver regeneration (LR). Upon damage in this organ, the regenerative capacity of hepatocyte is sufficiently able to reestablish the parenchyma as a whole. Taking into account the regenerative capacity of hepatocyte, the need of a progenitor or a liver trunk cell was not obvious. Nowadays it is well-established that precursor cells take part in the liver regenerative process. The liver trunk cell, oval cell, acts as a bypotential precursor, contributing for the liver restoration, mainly when the hepatocytes are unable to proliferate. Another precursor, trunk cell of hematopoetic origin (HSC), takes part in the regenerative process, originating cells of the hepatocitic lineage and colangiocytes, as well as the oval cell. The way the trans-differentiation takes place is not established yet. A number of studies must be undertaken in order to clarify questions, such as the possible occurrence of cellular fusion process between the HSC and the hepatic cells and the possibility of application as a new therapeutic procedure in the treatment of diseases associated with insufficiency of this noble organ.

Biochimie, 1986

Liver regeneration is a good system for studying cell proliferation in an in vivo, physiologically controlled situation. Various hepatotrophic factors, neuromediators, hormones and growth factors, presumably acting in synergy, seem necessary to induce the switch from quiescence to proliferation. As a consequence of this activation, a number of changes occurs in the hepatocyte: (I) modifications of the plasma membrane proteins; (II) metabolic changes such as variations in albumin and fibrinogen concentrations, and induction of the acute phase proteins; (III) induction of several specific mRNAs; (IV) variations in cAMP concentrations, and consequently in the activity of protein kinases and several other enzymes; (V) modifications in chromosomal proteins; (VI) induction of proteins involved in DNA replication. A model has been constructed which is more a basis for reflexion than a theoretical model. It takes ' into account the possible connections between the 'different molecular events cited above. It is hypothesized that DNA replication is at least partly uncoupled from mitosis, and that the initial events of the proliferative response may be triggered by nutritional elements. rat liver / hepatic regeneration / DNA replication / mitosis / cell proliferation Resume-Biologie moleculaire de la regeneration hepatique, La regeneration hepatique apres une hepatectomie partielle a ete longuement etudiee d'un point de vue physiologique. Quelques facteurs hepatotrophiques (hormones, neuromediateurs, facteurs protetques) ont ete identifies, mais les apports recents de la biologie moleculaire permettent de mieux comprendre les evenements qui precedent 10 replication et fa mitose. Au cours de la regeneration, bien que toutes les fonctions differenciees de fa cellule hepatique soient maintenues, son metabolisme est affecte (en particulier la synthese d'albumine, de fibrinogene et des proteines de stress). Le role de l'AMPc se degage clairement: it est necessaire pour que fa synthese d'ADN ail lieu; it active les proteines kinases AMPc dependantes qui, apres translocation du cytoplasme vers Ie noyau , phosphorylent les proteines chromatiniennes, dont I'histone Hl. D'autres evenements ont ete decrits: activation de pro Mines appartenant au complexe de replication, modification de proteines membran aires, augmentation du niveau de certains ARN messagers (parmi lesquels des oncogenes). Par ai/leurs, il apparait que dans ce systeme, la replication peut eIre decouplee de 10 mitose. Tous ces elements sont integres dans un schema final qui se veut etre davantage une base de reflexion qu 'un modele theorique du controle de la multiplication cellulaire. regeneration hepatique / proliferation cellulaire / mitose I joie de rat .. This article is dedicated to th e memory of J .M. Sala-Trepat.

Acta Cirurgica Brasileira, 2006

The purpose of this review was to carry out an analysis of the liver regenerative process focusing on the molecular interactions involved in this process. The authors undertook a review of scientific publications with a focus on the liver regeneration.The cellular processes involved in liver regeneration require multiple systematic actions related to cytokines and growth factors. These interactions result in the initiation of mitogenic potential of the hepatocytes. The action of these modulators in the regenerative process require a processing in the extra-cellular matrix. Serines and metal proteins are responsible for the bio availability of cytokines and growth factors so that they can interact as receptors in the cellular membrane generating signaling events for the beginning and end of the liver regenerative process. The exact mechanism of interaction between cells, cytokines and growth factors is not well established yet. A series of ordered events that result in the hepatic tissue regeneration has been described. The better understanding of these interactions should provide a new approach of the treatment for liver diseases, aiming at inducing the regenerative process.

International Journal of Surgery, 2013

Background: Rodent models have been used to evaluate aspects of liver regeneration. The aim of the present study was to investigate the natural history of liver regeneration in healthy rats. Methods: A 70% partial hepatectomy was performed in 64 rats. The animals were randomised into 8 groups and evaluated on postoperative days one to eight. Hepatocyte proliferation was evaluated by immunohistochemistry using unbiased stereological principles. Results: The mean rat body weight was 238 g (211e287). The mean weight of the resected liver was 6.3 g (5.2e7.3) and the estimated mean total liver weight was 8.9 g (7.4e10.4). Both liver weight analysis and regeneration rate showed an ascending curve, with a maximum slope on postoperative days 1e4, reaching a steady state on days 5e8. Hepatocyte proliferation (positive Ki-67 cell profiles pr. mm 2 ) was high (250 cell profiles/mm 2 ) on postoperative days 1e3 and tapered off on day 5. Conclusion: Seventy percent partial hepatectomy in healthy rats induces a rapid regenerative response and PODs 2, 4 and 8 seems optimal for assessing hepatic growth in future studies.

Bulletin of Experimental Biology and Medicine, 1973

Restoration of the normal parenchyma during reparative regeneration of the liver was studied by histological, cytological, biochemical, and immunochemical methods in rats with experimental cirrhosis and hepatitis. Analysis of the mitotic activity of the hepatocytes, the dynamics of the change in the number of binuclear cells, and the change in size and ploidy of the mononuclear hepatocytes revealed some general and specific rules governing reparative regeneration and the reversibility of the pathological changes in these conditions. Somatic polyploidization is suggested as playing an essential role in the reparative regeneration of the pathologically changed liver.

2011

Even if the Greeks probably anticipated rather than discovered the extraordinary regenerative capacity of the liver with the Prometheus myth, this phenomenon still fascinates scientists nowadays with the same enthusiasm. There are good reasons to decipher this process other than to find an answer to our fantasy of immortality: it could indeed help patients needing large liver resections or living-donor liver transplantation, it could increase our understanding of liver pathology and finally it could enable novel cell-therapy approaches. For decades, most of our knowledge about the mechanisms involved in liver regeneration came from the classic twothirds partial hepatectomy (PH) model. In this scenario, hepatocytes play the leading role, which raises the question of the simple existence of a stem cell population. Recently however, hepatic progenitor cells come again under the limelight, seeming to play a role in liver physiology and in various liver diseases such as steatosis or cirrhosis. Excellent reviews have recently addressed liver regeneration. Our goal is therefore to focus on recent improvements in the field, highlighting data mostly published in the last two years in order to draw a putative picture of what the future research axes on liver regeneration might look like.

The International Journal of Biochemistry & Cell Biology, 2011

Loss of hepatic tissue triggers a regenerative response in the whole organ. Under typical normal conditions, all hepatic cells (epithelial: hepatocytes and biliary epithelial cells; non-epithelial: stellate cells, macrophages and endothelial cells) undergo one to three rounds of replication to establish the original number of cells and restore organ size. The review summarizes the literature of regenerative patterns in situations in which proliferation of either hepatocytes or biliary epithelial cells is inhibited. The evidence strongly suggests that under these circumstances, hepatocytes or biliary epithelial cells can function as facultative stem cells for each other and replenish the inhibited cellular compartment by a process of trans-differentiation, involving complex signaling pathways. These pathways are activated under experimental conditions in rodents and in fulminant hepatitis associated with liver failure in humans. Mechanistic analysis of these pathways has implications for liver biology and for potential therapeutic modalities in human liver disease.

Acta Medica (Hradec Kralove, Czech Republic), 2016

Liver regeneration in mammals is a unique phenomenon attracting scientific interest for decades. It is a valuable model for basic biology research of cell cycle control as well as for clinically oriented studies of wide and heterogeneous group of liver diseases. This article provides a concise review of current knowledge about the liver regeneration, focusing mainly on rat partial hepatectomy model. The three main recognized phases of the regenerative response are described. The article also summarizes history of molecular biology approaches to the topic and finally comments on obstacles in interpreting the data obtained from large scale microarray-based gene expression analyses.

The International Journal of Developmental Biology, 2018

The liver is structurally and functionally heterogeneous and complex, and it accomplishes crucial functions for the organism. Its most remarkable potential is its capacity to regenerate after injury in order to maintain whole body homeostasis and guarantee the survival of the individual. Under normal conditions, liver regeneration (LR) is attributed to adult hepatocytes, the main cells in the liver which are able to proliferate in response to different stimuli or injuries. Nevertheless, when liver injury is severe and/or hepatocytes are prevented from proliferation, liver stem/progenitor cells (LS/PCs) participate directing LR to maintain liver mass and functions. Different mechanisms have been shown to guide this second line of LR, such as intrahepatic and extrahepatic liver progenitor cells, as well as transdifferentiation processes between hepatocytes and other liver cells. For this reason, many efforts have been made to elucidate the specific molecular mechanisms which orchestrate this process; this in turn would improve the prognosis and treatment of liver diseases. In this review, we revisit the fascinating process of LR, also with a short overview about liver development, the process from which arises the concept of LS/PCs participating in LR, and very important nowadays when considering cell therapy and tissue bioengineering for the treatment of patients suffering from liver disease.

Annals of Surgery, 2002

To investigate whether liver regeneration is an angiogenesisassociated phenomenon.