Setback in non-embryonic stem cell use

Stem cells created from a patients' own tissue are subtly different from those derived from embryos in ways that may affect their therapeutic potential, two independent research groups have found. Both studies found iPS (induced pluripotent stem) cells retain an 'epigenetic memory' of their tissue of origin. The findings are a setback for those hoping to use iPS cells to regenerate a patients' damaged tissue, circumventing the ethical dilemma of using embryos as a source of stem cells.

A study published in Nature found differences in DNA methylation - 'stop signs' in DNA that turn genes off - in mouse and embryonic stem cells (ES cells). These epigenetic differences were 'detectible to the point where we could literally use the methylation signatures to tell the lineage…where the iPS cells had come from', said Professor George Daley from Harvard Medical School and the Children's Hospital Boston.

Moreover, iPS cells behaved differently when they were prompted to differentiate into mature blood or bone cells. Bone-derived iPS cells were more efficient at differentiating into mature bone cells and less efficient at differentiating into blood cells, whereas the opposite was observed in blood-derived iPS cells.

'When we select for pluripotency, we haven't necessarily erased all of the epigenetic memory', said Professor Daley. This residual epigenetic memory in iPS cells 'favours their differentiation along lineages related to the donor cell'.

A parallel study published in Nature Biotechnology also found iPS cells vary in gene expression - how much a gene is turned on and producing proteins - and methylation patterns depending on the tissue they originated from, which affects how easily they turn into different mature cell types. Professor Konrad Hochedlinger and colleagues at the Massachusetts General Hospital Center for Regenerative Medicine used iPS cells created from mouse skin, muscle and immune system cells.

Both studies included methods of erasing the epigenetic memory imprinted on the iPS cells. When Professor Daley's team used a different, more challenging technique to reprogramme adult cells - by SCNT  (somatic cell nuclear transfer) - they found that the stem cells generated did not retain an epigenetic signature from their tissue of origin and behaved similar to ES cells.

Professor Daley and colleagues could also remove the DNA methylation patterns by serially reprogramming the iPS cells, or by treating them with chromatin-modifying drugs. Similarly, Professor Hochedlinger observed that iPS cells lose their epigenetic memory and became more similar to ES cells if they underwent multiple cycles of cell division.

These aren't the first studies to find subtle differences between iPS cells. In a Nature paper earlier this year, Professor Hochedlinger found certain developmental genes weren't activated in reprogrammed mouse iPS cells.  Researchers from Stanford School of Medicine also reported in PLoS ONE that iPS cells derived from fat or skin retain some gene activity from their tissue of origin.

These studies suggest the results of earlier disease-modelling research using iPS cells could be misleading because the findings 'may in part not be due to patient-specific abnormalities, as you hope, but rather that there was memory of the cell of origin in our iPS cell', Professor Hochedlinger explains.

Professor Daley cautions: 'everyone working with these cells has to think about the tissues of origin and how that affects reprogramming… These findings cut across all clinical applications people are pursuing and whatever disease they are modelling.'