Liver regeneration: a picture emerges from the puzzle

Liver regeneration remains a fascinating enigma. Many pieces of the puzzle have been elucidated, but as each piece is discovered, it is found to be composed of many smaller pieces, some of which are missing, and the multiple interlocking edges with other pieces of the puzzle remain poorly understood. The true initiating event or events remain unclear. The essential requirement for activation of immediate early genes is generally unchallenged. C-jun is essential for normal hepatogenesis in mouse development and it appears to be required for proliferation in response to injury, as well. Yet, nefenopin and cyproterone acetate induce hyperplastic responses in the liver with no induction of c-fos, c-myc, or c-jun. HGF is the single most potent liver mitogen yet discovered. However, levels of HGF do not correlate with the degree of liver regeneration, and high concentrations exist in conditions such as those in chronic hemodialysis patients who have no evidence of regeneration and minimal evidence of liver injury. Numerous conditions exist that induce immediate early genes and yet do not lead to cell proliferation. Thus, the availability of mitogens by themselves is not sufficient to induce regeneration, and the induction of immediate early genes is not sufficient to lead to regeneration. Whereas the isolated parenchymal cell culture system has been extremely valuable in identifying an increasing number of stimulatory and inhibitory substances and identifying the initial steps in their mechanisms of action, this simple system does not take into account the extremely complex interactions of these multiple growth factors in vivo and the interaction of the parenchymal cell with the other cellular and structural components of the liver. All must be accounted for in a complete model of liver regeneration. Parenchymal cell growth itself appears to be controlled by a series of steps, each of which requires the presence of specific growth regulators, which may be stimulators or inhibitors. There is a strictly defined sequence that must be followed, and if one or more of the factors is missing at the essential time point, growth will not progress and the cell will return to the G0 phase or proceed to apoptosis and death. While all this is occurring, the liver must also continue to carry out its essential life-supporting functions. And, finally, the liver must somehow know when to stop. Over-expression of some growth factors, such as TGF alpha, appears to produce tumors, whereas overexpression of others, such as HGF, does not.(ABSTRACT TRUNCATED AT 400 WORDS)