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Another Blow to the iPSC Field?



A recent report in Nature (Lister et al.) has suggested that human induced pluripotent stem cells (iPSC), the great hope for personalised cellular therapy, are not as similar to embryonic stem cells (ESCs) as hoped, and that this may affect their use as a replacement for ESC in disease modelling and cellular therapy.

Centromeric and telomeric regions in iPSCs were found to maintain a DNA methylation state similar to that of their cell of origin, and were further linked to changes in methylation of histone H3 and transcriptional activity.   Some regions of difference were shared between the multiple iPSC lines studied, suggesting that certain loci may be “inherently susceptible to aberrant methylation” while other regions of difference were iPSC specific, also suggesting “a stochastic element to reprogramming”.   It was also observed that these differences are transmitted through differentiation of iPSC towards a trophoblastic lineage.

However, the authors do note that DNA methylation patterns in somatic cells do become remarkably reconfigured during reprogramming to iPSC, to generate a methylome which is very similar to that observed in human ESC.

This epigenetic “memory” of iPSC origin has also been demonstrated in mice by various other research groups (Kim et al and Polo et al), as previously reported on the Stem Cell Portal (iPSC don´t Forget their Origins). Some results have also previously indicated that human iPSCs and ESCs are not equivalent (Doi et aland Ohm et al) although other studies suggest a great degree of similarity (Guenther et al), while yet others propose that differences may merely reflect differing techniques, be they laboratory or analytical, used in each separate laboratory (Chin et al and Newman et al).

Overall, this suggests that while reprogramming, as it is today, can generate cells that are similar to ESC, pieces of the reprogramming puzzle are still missing. Can we find these pieces and lay them in the correct place? The research continues…………..


Original Paper

Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cells.

Lister R, Pelizzola M, Kida YS, Hawkins RD, Nery JR, Hon G, Antosiewicz-Bourget J, O'Malley R, Castanon R, Klugman S, Downes M, Yu R, Stewart R, Ren B, Thomson JA, Evans RM, Ecker JR.

Nature. 2011 Feb 2.


Flaw in induced-stem-cell model

Elie Dolgin

Nature 470, 13-13 (2 February 2011) doi:10.1038/470013a News