Timing of hepatocyte entry into DNA synthesis after partial hepatectomy iscell autonomous

After surgical removal of two-thirds of the liver, remaining hepatocytes re plicate and restore hepatic mass within 2 weeks. This process must be initi ated by signals extrinsic to the hepatocyte, but it remains unclear whether subsequent events leading to DNA synthesis (S phase) are regulated by circ ulating or locally produced growth factors (a noncell autonomous response), or by a program intrinsic to the hepatocyte itself (a cell autonomous resp onse). To identify the type of mechanism regulating passage to S, we exploi ted the difference between rat and mouse hepatocytes in the timing of DNA s ynthesis after partial hepatectomy, which peaks 12-16 h earlier posthepatec tomy in rat compared with mouse. Four groups of animals received two-thirds partial hepatectomies: rats, mice, mice with chimeric livers composed of b oth transplanted rat hepatocytes and endogenous mouse hepatocytes. and mice with chimeric livers composed of both transplanted and endogenous mouse he patocytes. Following two-thirds partial hepatectomy. both donor and endogen ous hepatocytes in mouse/ mouse chimeric livers displayed kinetics of DNA s ynthesis characteristic of the mouse, indicating that transplantation per s e did not affect the response to subsequent partial hepatectomy. In contras t, rat hepatocytes in chimeric mouse livers displayed rat kinetics despite their presence in a mouse host. Thus, factors intrinsic to the hepatocyte m ust regulate the timing of entry into DNA synthesis. This result defines th e process as cell autonomous and suggests that locally or distantly produce d cytokines or growth factors may have a permissive but not an instructive role in progression to S.