Thymus Cell Antigen-1-Expressing Cells in the Oval Cell Compartment

Thymus cell antigen-1 (Thy-1)-expressing cells proliferate in the liver during oval cell (OC)-mediated liver regeneration. We characterized these cells in normal liver, in carbon tetrachloride-injured liver, and in several models of OC activation. The gene expression analyses were performed using reverse-transcriptase polymerase chain reaction (RT-PCR), quantitative RT-PCR (Q-RT-PCR) of cells isolated by fluorescence-activated cell sorting (FACS), and by immunofluorescent microscopy of tissue sections and isolated cells. In normal liver, Thy-1(+) cells are a heterogeneous population: those located in the periportal region do not coexpress desmin or alpha smooth muscle actin (alpha-SMA). The majority of Thy-1(+) cells located at the lobular interface and in the parenchyma coexpress desmin but not alpha-SMA, i.e., they are not resident myofibroblasts. Although Thy-1(+) cells proliferate moderately after carbon tetrachloride injury, in all models of OC-mediated liver regeneration they proliferate quickly and expand significantly and disappear from the liver when the OC response subsides. Activated Thy-1(+) cells do not express OC genes but they express genes known to be expressed in mesenchymal stem cells (CD 105, CD73, C1329), genes considered specific for activated stellate cells (desmin, collagen I-a2, Mmp2, Mmp14) and myofibroblasts (alpha-SMA, fibulin-2), as well as growth factors and cytokines (Hgf, Tweak, IL-1b, IL-6, IL-15) that can affect OC growth. Activated in vitro stellate cells do not express Thy-1. Subcloning of Thy-1(+) cells from OC-activated livers yield Thy-1(+) fibroblastic cells and a population of E-cadherin(+) mesenchymal cells that gradually discontinue expression of Thy-1 and begin to express cytokeratins. However, upon transplantation these cells do not differentiate into hepatocytes or cholangiocytes. Activated Thy-1(+) cells produce predominantly latent transforming growth factor beta. Conclusion: Thy-1(+) cells in the OC niche are activated mesenchymal-epithelial cells that are distinct from resident stellate cells, myofibroblasts, and oval cells. (HEPATOGY 2009,50:601-611.)