Reprogramming of differentiated somatic cells to a pluripotent embryonic stem (ES) cell-like state can be achieved by somatic cell nuclear transfer or by expressing a combination of four transcription factors. Two studies now show that nuclear transfer ES (ntES) cells and transcription-factor-reprogrammed induced pluripotent stem (iPS) cells show differences in differentiation potential related to their tissue of origin.

Kim et al. tested the capacity of ntES cells, blood-derived iPS (B-iPS) cells, fibroblast-derived iPS (F-iPS) cells and fertilized-embryo-derived ES (fES) cells to differentiate into haematopoietic and osteogenic cells. All stem cell lines expressed pluripotency markers but showed differences in differentiation poten-tial. Fibroblast-nucleus-derived ntES cells and fES cells differentiated with similar efficiency to both cell types, whereas B-iPS cells and F-iPS cells had differentiation potentials

that were biased towards their cell-type of origin. Similarly, Polo et al. found that genetically identical iPS cell lines generated from four differ-ent somatic cell lines had different and biased differentiation potentials that reflected their cells of origin.

What is the molecular basis for these variable differentiation capaci-ties? As reprogramming involves the resetting of genomic methylation, Kim et al. analysed the DNA meth-ylation pattern of the different stem cell lines. They found that ntES cells and fES cells have similar methyla-tion patterns, whereas F-iPS cells and B-iPS cells retain residual methyla-tion marks that are specific to their tissue of origin. Polo et al. compared the transcriptional profiles of the four iPS cells lines and found that they are distinguishable and express markers related to their cell of origin. Importantly, these differences cor-relate with different levels of histone methylation, which may account for the gene expression differences.

Interestingly, the groups found that iPS cells gradually lose their DNA methylation marks and specific expression patterns and equalize their differentiation potentials over the course of successive cultures. This also occurs when secondary and tertiary iPS cells are generated by successive differentiation and reprogramming steps.

Together, these studies show that iPS cells retain an epigenetic memory of their cell of origin that restricts their differentiation potential, and that these epigenetic marks can be modulated. However, the mechanisms that affect this epigenetic memory remain to be determined.

Kim Baumann, Associate Editor,

Nature Reviews Molecular Cell Biology

ORIGINAL RESEARCH PAPERS Kim, K. et al. Epigenetic memory in induced pluripotent stem cells. Nature 19 Jul 2010 (doi:10.1038/nature09342) Polo, J. M. et al. Cell type of origin influences the molecular and functional properties of mouse induced pluripotent stem cells. Nature Biotech. 19 Jul 2010 (doi:10.1038/nbt.1667)

S T E M C E L L S

Holding onto the memories

GETTY

R e s e a R c h h i g h l i g h t s

NATuRE REvIEWS | Genetics voluME 11 | SEPTEMBER 2010

© 20 Macmillan Publishers Limited. All rights reserved10