Immune-Mediated Hepatitis Drives Bone marrow to Hepatocyte Plasticity.

Liver dysfunction is a major health burden world-wide. Future cell-based therapies for liver regeneration may benefit from the fact that bone marrow cells can fuse with or transdifferentiate into hepatocytes. All models demonstrating bone marrow to hepatocyte plasticity presented so far, however, have used highly artifical conditions of liver regeneration - applying toxins, genetic pressure models or liver resection. We have set up a model of transgenic T cell induced bystander hepatitis in bone marrow chimeras to assess the effect of hepatitis, a common liver pathology in humans, as an enhancer of bone marrow to hepatocyte plasticity events.

MHC haplotype (Kb) transgenic bone marrow from 178.3 mice or control bone marrow from B10.BR (Kk) mice was transplanted into sublethally irradiated B10.BR (Kk) mice. Hepatitis was induced by repeated injections of Des Kk T cell receptor transgenic T cells against the Kb antigen. In additonal groups Retrorsine was used as an agent inhibiting endogenous hepatocyte proliferation and GCSF for mobilisation of bone marrow stem cells.

Repeated injections of transgenic T cells induced subsequent waves of hepatitis in recipients of MHC haplotype transgenic bone marrow but not in control animals confirmed by serum ALT levels. Hepatocyte single cell suspensions from animals suffering from hepatitis revealed an increased expression of donor bone marrow derived antigen. This could be further enhanced by either increasing the number of circulating stem cells or by inhibiting the endogenous response of resident hepatocytes. FISH analysis showed fusion nuclei on a single cellular level.

T cell receptor transgenic T cells induce bystander hepatitis in an antigen specific manner. This inflammatory response drives the plasticity of bone marrow cells to hepatocytes and their potential contribution to liver regeneration. Fusion between donor cells and resident hepatocytes is the underlying mechanism of liver regeneration in this model mimicking a common liver pathology.