Stem cells: The great iPS barrier


into induced pluripotent stem (iPS) cells by the expression of defined transcription factors. However, although iPS cells share many of the features of embryonic stem cells and can be differentiated into multiple cell types, the low efficiency of iPS cell production limits their therapeutic potential. Research from five groups now reveals that the p16INK4A and ARF–p53 pathways function as a barrier against iPS cell generation in mouse and human cells. The INK4/ARF locus encodes p15INK4B (also known as CDKN2B), p16INK4A (also known as CDKN2A) and ARF, which positively regulate the p53 and retinoblastoma tumour suppressor pathways to inhibit cell proliferation and promote cellular senescence. p21 (also known as CDKN1A), which is upregulated by p53, also inhibits proliferation and promotes senescence. Data from the five new studies suggest that depletion of p53, ARF, p16INK4A or p21 can increase the kinetics and efficiency of iPS cell generation. Hong et al. showed that the absence of, or a reduction in, p53 increases the efficiency of iPS cell generation from mouse and human fibroblasts. In fact, all of these studies, using various approaches, showed that p53 depletion enhances iPS cell generation. Kawamura et al. also enhanced the reprogramming of mouse embryonic fibroblasts (MEFs) by reducing the level of p21 or ARF. As ARF inhibits p53 degradation, ARF knockdown might enhance reprogramming by decreasing p53 stability. Li et al. and Utikal et al. observed that the INK4/ARF locus is epigenetically silenced in iPS cells reprogrammed from MEFs, as well as in embryonic stem cells, but not in MEFs. This suggests that the expression of genes at this locus may prevent cellular pluripotency. Indeed, Utikal et al. also observed that older MEFs, which harbour increased levels of p16INK4A, ARF and p21 owing to ageing and the onset of senescence, show a decrease in reprogramming efficiency. Li et al. also linked ageing and expression from the INK4/ARF locus with decreased iPS cell generation. They showed that cells from old mice express genes at this locus at a higher level than cells from young mice and that this is associated with a decreased reprogramming efficiency, which can be rescued by knocking down INK4/ARF. Finally, Marión et al. found that p53 prevents the reprogramming of MEFs that have various types of DNA damage. Although loss of p53 function allows faster and more efficient reprogramming in the presence of DNA damage, it generates iPS cells containing damaged DNA and chromosomal aberrations. This emphasizes that, although these studies provide crucial mechanistic insight into how the generation of iPS cells is regulated, it will be important to determine how the p16INK4A and ARF–p53 tumour suppressor pathways can be silenced to allow the efficient production of iPS cells without increasing the possibility of malignant transformation. Katharine H. Wrighton

DOI: 10.1038/nrm2753

Cite this paper

@article{Wrighton2009StemCT, title={Stem cells: The great iPS barrier}, author={Katharine H. Wrighton}, journal={Nature Reviews Molecular Cell Biology}, year={2009}, volume={10}, pages={578-579} }