1. Research projects for development of differentiation technology from human stem cells to functional hepatocytes
  1. Research projects for the development of technology for the differentiation of human mesenchymal stem cells to functional hepatocytes
     Our research project was adopted by the project for realization of regenerative medicine in 2008 [http://www.jst.go.jp/saisei-nw/stemcellproject/index.html](Japanese). We are currently engaged in the development of operational stem cell technology. To realize regenerative medical technology, we seek to develop efficient differentiation technology that can be practically applied in clinical settings, differentiating human stem cells into functional hepatocytes. This project focuses on selecting the most effective low molecular weight compounds inhibiting Wnt/β-catenin pathways, combining cell sheets with compounds, and finally developing safe differentiation methods with maximum efficiency.
  2. Differentiation from iPS cells to functional hepatocytes
     We are developing the differentiation technology from mouse iPS cells, human iPS cells, and the ES cells to the functional hepatocytes besides a human mesenchymal stem cells.

2. Development of a promotional program for translational researchers involved in gene and cell therapy

 This project was adopted for Special Coordination Funds for Promoting Science and Technology in 2007. As for these projects, Okayama University, Kagawa University, Kawasaki Medical School, Tottori University, Yamaguchi University, and Shikoku Cancer Center are cooperating. We operate the basic research so that new medical treatment seeds created from the fundamental studies tie to the clinical application, and develop seeds concerning gene and cell therapy. Moreover, we will finish the preclinical trial (test on animals) in three years, and aim to develop the program to promote the young researchers by the process of advancing these projects. In this project, we research new gene therapy to liver cancer by using sensitising genes to anticancer agents.

3. Analysis of effects of retinoic acids in the liver and development of new treatment method by identifying the target genes

 Retinoic acids, metabolites of vitamin A, play a role in development, immunity, cell growth, and cell death. Most of the vitamin A in the body is stored in hepatic stellate cells. Hepatic stellate cells move along the space of Disse and communicate with hepatocytes.
 During the process of chronic liver disease, hepatic stellate cells are activated and transdifferentiated into myofibroblasts, resulting in the loss of fatty droplets containing vitamin A. Retinoic acid (RA), a metabolite of vitamin A, plays one function of vitamin A with RAR/RXR heterodimer as a transcription factor, regulating hundreds of downstream genes. Based on the assumption that a decreased supply of vitamin A from myofibroblasts to hepatocytes causes enhanced hepatocarcinogenesis (since vitamin A has an antioxidative action), we demonstrated that transgenic mice expressing a dominant negative form of retinoic acid receptor specific to the liver developed liver cancer (Hepatology 40,366-75,2004). Since vitamin A is expected to be important for the prevention and treatment of liver cancer, we currently seek to identify RA-inducible genes as targets of cancer therapy (Gastroenterology 136, 341-350, 2009). We have found that retinoic acids bind to the consensus sequence of five voluntary nucleotides inserted between direct repeats of AGGTCT, known as DR5. We are currently attempting to identify RA-inducible genes using DR5 as a clue. Such genes could be useful for the treatment and prevention of human liver cancer.