Trading iPS efficiency for tumorigenicity?

Five recent publications in Nature show the reprogramming of somatic cells to pluripotency is blocked by the p53 pathway and the INK4/ARF locus (encoding the tumor suppressors p16^Ink4a, p19^Arf, p15^Ink4b) (Hong et al., 2009; Kawamura et al., 2009; Li et al., 2009; Marion et al., 2009; Utikal et al., 2009). Each group demonstrated that knocking down p53 expression increased iPS cell generation dramatically, whether in a p53-/- background or by using shRNA, both in mouse and human cells. shRNA-mediated knockdown of p53  could rescue the ability to produce iPS cells in otherwise incapable cells (Utikal et al., 2009). And, Shinya Yamanaka's group was able to reprogram cells using only two factors (Oct4 and Sox2) in the absence of p53. One of the larger issues preventing the use of stem cells therapeutically for PD is the inability to generate large enough numbers to be useful. Decreasing p53 activity clearly can increase the efficiency of iPS cell generation - but at what cost? Without p53, would those stem cells actually be useful? In our quest to tweak iPS cells for therapeutic use, are we trading efficiency for tumorgenicity?

Li et al. show the INK4/ARF locus is upregulated with age and cite that reprogramming is less efficient in older organisms. Utikal et al. also demonstrate that the efficiency of iPS cell generation decreased after serial passages and the onset of senescence. The barriers that keep the genome intact and prevent tumorgenicity in older age are possibly the same barriers preventing reprogramming to pluripotency. Marion et al. propose that the action of p53 is required to prevent the generation of iPS cells containing DNA damage, including short telomeres, DNA repair deficiency and exogenously inflicted DNA damage. Cells closer to pluripotency have a lower tolerance for DNA damage - removing the tumor suppressor p53 can allow these abnormalities to be passed on to reprogrammed cells. Therefore, p53 is likely an important regulator preventing the generation of stem cells from damaged sources.

With the recent demonstration that iPS cells can produce healthy mice (Zhao et al., 2009; Kang et al., 2009), some of the fear over the tumorgenicity of iPS cells has been assuaged, but this latest work only strengthens the link between induced pluripotency and tumorgenicity. Even if you could transiently knockdown p53 to generate iPS cells - that may not prevent inheriting damaged DNA. Would iPS cells generated by inhibiting p53 (even transiently) still be able to generate tumor-free, healthy mice? Though we have taken a step forward in improving the efficiency of producing induced pluripotent stem cells, whether these cells will be useful in modeling or transplantation therapy for Parkinson's disease is yet to be determined.