Gareth Sullivan group
Current models employed by the pharmaceutical industry and academia to investigate disease, drug discovery/ safety/ efficacy, and toxicity are inadequate, as they do not faithfully recapitulate the human physiology, metabolism or cellular behavior. Consequently, there is a pressing need to improve this. With the recent development of human induced pluripotent stem cell (hiPSC) technology, this provides a novel way to model human disease and offers an alternative to current cell-based systems, most importantly as a potentially limitless supply of genetically defined stem cells that can be potentially differentiated into any cell type under defined conditions. This also decreases dependency, usage and overall numbers of animal models, in compliance with the 3R's (Reduction, Refinement and Replacement). Current hiPSC technology itself has its own limitations, which include the use of lenti-/ retroviral approaches that lead to unwanted perturbation of the genome, therefore the key challenge to address is the establishment of non-integrative methods of reprogramming, that will allow the potential use of the derived hiPSCs in disease modeling, toxicity studies, drug discovery/ safety/ efficacy and in the long term, potential therapeutic application.
The long-term goal of our work is to improve current methods of reprogramming while gaining insight into the mechanistic processes involved. In addition we will utilize these technologies to derive disease specific models to investigate the disease process in the dish. To reach these goals, we are (ii) establishing novel methods of reprogramming, (ii) improving current methodologies of differentiation towards endoderm, and (iii) applying these to disease models.
- Non-integrative methods of nuclear reprogramming to derive pluripotent and multipotent cell populations.
- Derivation of human hepatocytes from hiPSCs/ hESCs that recapitulate adult primary hepatocytes in function.
- Establishing 3D Organotypic models of the liver.