Cell competition leads to a high level of normal liver reconstitution by transplanted fetal liver stem/progenitor cells

Background & Aims: A critical property of stem cells is their ability to repopulate an organ or tissue under nonselective conditions. The aims of this study were to determine whether we could obtain reproducible, high levels of liver repopulation by transplanted fetal liver stem/progenitor cells in normal adult liver and the mechanism by which liver replacement occurred. Methods: Wild-type (dipeptidyl peptidase IV [DPPIV+]) embryonic day (ED) :14 fetal liver cells underwent transplantation into DPPIV- mutant F344 rats to follow the fate and differentiation of transplanted cells. To determine the mechanism for repopulation, proliferation and apoptosis of transplanted and host liver cells were also followed. Results: Transplanted ED 14 fetal liver cells proliferated continuously for 6 months, differentiated into mature hepatocytes, and replaced 23.5% of total liver mass. The progeny of transplanted cells were morphologically and functionally indistinguishable from host hepatocytes and expressed unique liver-specific genes commensurate with their location in the hepatic lobule. Repopulation was based on greater proliferative activity of transplanted cells and reduced apoptosis of their progeny compared with host hepatocytes, coupled with increased apoptosis of host hepatocytes immediately adjacent to transplanted cells. This process, referred to as cell-cell competition, has been described previously in Drosophila during wing development. Conclusions: We show for the first time that cell-cell competition, a developmental paradigm, can be used to replace functional organ tissue in an adult mammalian species under nonselective conditions and may serve as a strategy for tissue reconstitution in a wide variety of metabolic and other disorders involving the liver, as well as other organs.