Regulation of hepatic growth

Abstract

The liver is a conditional renewal system, which in the adult organism undergoes minimal cell production and/or cell renewal. However, a reduction in liver cell mass, because of either actual cell loss or cell atrophy, evokes a rapid regenerative response tailored to replace the lost tissue. Synthesis of DNA begins as early as 15 h after a two-thirds hepatectomy, and the fact that all the remaining hepatocytes enter DNA synthesis within the next 48 h does indicate they are all potentially proliferative, and it is unlikely that a distinct stem cell compartment exists. The temporal sequelae of events can be best explained by the semisynchronous passage of cells from G0 into the proliferative cycle (see Fig. 2) where they undergo one or more rounds of cell division before decycling back into the proliferatively quiescent G0 state. The age of the animal and its nutritional and hormonal status are all important modifiers of the response, but none of them is critical to the regenerative process. Experiments involving the administration of sera or the transfer of blood between animals strongly favor the existence of humoral regulatory factors; the liver is apparently capable of producing both inhibitory and stimulatory molecules that act by negative and positive feedback mechanisms, respectively, to control tissue homeostasis, whereas other organs, notably the pancreas, are important sources of facilitatory molecules. A chemical mechanism of self inhibition is a very intellectually appealing hypothesis, but at present there is no consistent message as to the identity of the inhibitory molecule, although most studies suggest the target site for its action is the G1-S transition. Unless the whole field is one of multilateral analysis of an artifact, then endogenous growth inhibitors do exist, but the problem now is one of biochemical isolation and characterization. The field compares rather badly with the many success stories in recent years in which new hormones and peptides have been speedily isolated and purified. A reduction in liver size appears to be associated with a decrease in the concentration of an hepatic growth inhibitor and the production and/or unmasking of a stimulatory factor(s) that is also of hepatic origin. Once again, there is little information about the biochemical nature of the principle and much less on its mode of action. We all assume that such stimulators, and for that matter inhibitors as well, act on "restriction points" or "mitosis operons" and so on.(ABSTRACT TRUNCATED AT 400 WORDS)