Abstract
Proliferation of hepatocytes is known to be the main process in the hepatectomy-induced liver regrowth; however, in cases of extensive loss it may be insufficient for complete recovery unless supported by some additional sources e.g. mobilization of undifferentiated progenitors. The study was conducted on rat model of 80% subtotal hepatectomy; the objective was to evaluate contributions of hepatocytes and resident progenitor cells to the hepatic tissue recovery via monitoring specific mRNA and/or protein expression levels for a panel of genes implicated in growth, cell differentiation, angiogenesis, and inflammation. Some of the genes showed distinctive temporal expression patterns, which were loosely associated with two waves of hepatocyte proliferation observed at 2 and 7 days after the surgery. Focusing on genes implicated in regulation of the progenitor cell activity, we came across slight increases in expression levels for Sox9 and two genes encoding tumor necrosis factor-like cytokine TWEAK (Tnfsf12) and its receptor Fn14 (Tnfrsf12a). At the same time, no increase in numbers of cytokeratin 19-positive (CK19+) cells was observed in periportal areas, and no CK19+ cells were found in hepatic plates. Since CK19 is thought to be a specific marker of both cholangiocytes and the hepatic progenitor cells, the data indicate a lack of activation of the resident progenitor cells during recovery of hepatic tissue after 80% subtotal hepatectomy. Thus, proliferation of hepatocytes invariably makes the major contribution to the hepatic tissue recovery, although in the cases of subtotal loss this contribution is distinctively modulated. In particular, induction of Sox9 and TWEAK/Fn14 regulatory pathways, conventionally attributed to progenitor cell activation, may incidentally stimulate mitotic activity of hepatocytes.
Highlights
Regeneration of mammalian liver has inspired a huge amount of research
Most of the studies have been done on laboratory rodents using the partial hepatectomy model, that is, by excision of median and left lobes, which constitute about 70% of the organ volume [1]
This is consistent with an idea that proliferation of hepatocytes after the 80% subtotal hepatectomy is regulated differently as compared to the partial hepatectomy, so that hepatocytes with mitotic figures in subtotally hepatectomized rats can be observed at about 36 h after the surgery, whereas in partially hepatectomized rats they can be observed already within 12 h, and their numbers peak at 24 h after the surgery; the delay is explained by G0 or G2/M cell cycle arrest [24]
Summary
Most of the studies have been done on laboratory rodents using the partial hepatectomy model, that is, by excision of median and left lobes, which constitute about 70% of the organ volume [1]. The procedure is currently standardized and commercially available [2], whereas variations in the removed volume may seem to be less revealing, as long as a much smaller number of studies are dealing with them [3,4]. Resections of an extremely large volume (80–90%) of the organ represent a special interest due to their clinical relevance. A similar response at the systemic level is typical for the patients whose livers have been subjected to extensive resection leaving an extremely small part of the organ, in order to withhold a tumor from spreading [5,6]
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