A major thrust within this sub-theme is to realise the translational potential of induced pluripotent stem cells (iPS cells) and their differentiated cell types, not only as a source of cells and tissue for transplantation, but as models for understanding mechanisms of disease. Somatic cells can be reprogrammed into iPS cells by overexpressing combinations of factors such as Oct4, Sox2, Klf4, and c-Myc but reprogramming is slow and stochastic. We have identified senescence as an important barrier to reprogramming and shown that expression of the four reprogramming factors triggers senescence by up-regulating p53, p16(INK4a), and p21(CIP1). Induction of DNA damage response and chromatin remodeling of the INK4a/ARF locus are two of the mechanisms behind senescence induction. Crucially, ablation of different senescence effectors improves the efficiency of reprogramming, suggesting novel strategies for maximizing the generation of iPS cells.
The power of iPS cells as models for human disease is exemplified by our recent success in the area of metabolic liver disease. Dermal fibroblasts from patients with various inherited metabolic diseases of the liver were used to generate patient-specific human iPS cell lines that were differentiated into hepatocytes using a novel 3-step differentiation protocol in chemically defined conditions. The resulting cells exhibited functional properties of mature hepatocytes and cells generated from patients with 3 of the inherited metabolic conditions studied (alpha1-antitrypsin deficiency, familial hypercholesterolemia, and glycogen storage disease type 1a) were found to recapitulate key pathological features of the diseases affecting the patients from which they were derived. The simple and effective platform for hepatocyte generation from patient-specific human iPS cells is proof of principle that it is possible to model diseases whose phenotypes are caused by pathological dysregulation of key processes within adult cells. Collaborations have now been initiated with investigators within several of the different themes within the BRC to use iPS cells to model human diseases that result from pathological disturbances within a variety of other cell types.
Sub-theme leads: Roger Pedersen and Ludovic Vallier
