Acetylation Modulation for Cell Reprogramming and Regenerative Medicine

Generation of iPS (induced pluripotent stem) cells by ectopic expression of four transcription factors, Oct4, Sox2, Klf4, and c-Myc (Takahashi and Yamanaka 2006), has been rapidly adopted to generate such cells from various cell types in mice, humans, and other mammals (Jaenisch and Young 2008; Stadtfeld and Hochedlinger 2010; Yamanaka and Blau 2010). Because of its great promise and potential for in vitro disease modeling and autologous stem cell therapy, this has generated lots of excitement. One challenge is to increase the efficiency of iPS cell generation. In this regard, HDAC inhibitors have been found to promote iPS clone formation. Among the tested inhibitors, valproic acid (VPA), suberoylanilide hydroxamic acid (SAHA), and trichostatin A (TSA), VPA was shown to be the most potent that could increase iPS clone production by 100-fold (Huangfu et al. 2008a). As a result, VPA enables reprogramming of primary human fibroblasts with only Oct4 and Sox2 (Huangfu et al. 2008b). In addition, VPA was found to synergize with vitamin C in promoting iPS clone production (Shi et al. 2010). Interestingly, VPA has also been used in a protein-based reprogramming protocol (Zhou et al. 2009). In addition, butyrate was found to stimulate programming dramatically (Mali et al. 2010). As VPA and butyrate are less specific inhibitors than TSA, it is unclear whether they have activity other than HDAC inhibition accounting for the high efficiency. On the other hand, it is reasonable to assume that HDAC inhibition promotes histone hyperacetylation and opens up chromatin for cell reprogramming.

In addition to iPS clone production, a recent study has demonstrated that HDAC inhibition stimulates direction conversion of germ cells to neurons in C. elegans (Tursun et al. 2011), suggesting the utility of HDAC inhibitors in promoting transdifferentiation, another type of cell reprogramming that is also important for regenerative medicine.

0 0

Post a comment