Development of hepatic cell sheet therapy for liver injury

Bone-marrow derived mesenchymal stem cells (BM-MSCs) have a differentiation potential toward hepatocytes besides regenerative effects by producing trophic factors. Therefore, cell-based therapies utilizing BM-MSCs are expected to be an alternative treatment for liver disease. We previously identified small molecule compounds driving hepatic differentiation of BM-MSCs through downregulation of Wnt/β-catenin signals. To maximize the therapeutic effect of BM-MSCs on liver injury, hepatocytes derived from BM-MSCs treated with a Wnt/β-catenin signal inhibitor was transplanted onto liver of liver injury model as a cell sheet. In brief, human BM-MSCs were treated with a Wnt/β-catenin signal inhibitor on PIPAAm-grafted dishes for 8 days, and then the cell sheets were transplanted onto liver surface of acute and chronic liver injury mice. In the acute liver injury model, hepatic cell sheets significantly improved survival rates as well as liver functions such as serum transaminases and total bilirubin. The therapeutic effect was increased with number of cell sheets. The mitotic cells were significantly increased on day 4 in cell sheet-transplanted mice, suggesting cell sheet therapy stimulated liver regeneration. Increased anti-oxidant proteins and decreased oxidative stress in cell sheet-transplanted mice were observed. In the chronic liver injury, transplantation of cell sheets decreased CCl₄-induced α-SMA positive cells and collagen deposition. These data suggest that transplantation of hepatic cell sheets derived from BM-MSCs is a promising therapy for acute and chronic liver injury.