Gene Silencing may be the Cause of Induced Pluripotent Stem Cells' Limitations

Scientists have discovered that a crucial cluster of genes is inactivated in induced pluripotent stem cells.

Scientists have discovered that a crucial cluster of genes is inactivated in induced pluripotent stem cells which do not have the complete development capabilities of embryonic stem cells.

"We found that a segment of chromosome 12 containing genes important for fetal development was abnormally shut off in most iPSCs. These findings indicate we need to keep improving the way we produce iPSCs and suggest the need for new reprogramming strategies," Nature quoted Dr. Konrad Hochedlinger, of the Massachusetts General Hospital Center for Regenerative Medicine (MGH-CRM) and the Harvard Stem Cell Institute (HSCI), who led the study.

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Although iPSCs appear quite similar to embryonic stem cells and give rise to many different types of cells, they have important limitations.

Several molecular differences have been observed, particularly in the epigenetic processes that control which genes are expressed, and procedures that are able to generate live animals from the embryonic stem cells of mice are much less successful with iPSCs.

Previous studies have compared iPSCs generated with the help of viruses, which can alter cellular DNA, to embryonic stem cells from unrelated animals.

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To reduce the chance that the different sources of the cells were responsible for observed molecular differences, the MGH/HSCI research team prepared two genetically matched cell lines.

After generating mice from embryonic stem cells, they used a technique that does not use viruses to prepare lines of iPSCs from several types of cells taken from those animals.

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They then compared the iPSCs with the original, genetically identical embryonic stem cells.

The most stringent assay of cells' developmental potential showed that two tested lines of embryonic stem cells were able to generate live mice as successfully as in previous studies, but no animals could be generated from genetically matched iPSCs.

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Closely comparing RNA transcription profiles of several matched cell lines revealed significantly reduced transcription of two genes in the iPSCs.

Both genes are part of a gene cluster on chromosome 12 that normally is maternally imprinted - meaning that only the gene copies inherited from the mother are expressed.

Examination of more than 60 iPSCs lines developed from several types of cells revealed that this gene cluster was silenced in the vast majority of cell lines.

While the gene-silenced iPSCs could generate many types of mouse tissues, their overall developmental potential was limited.

In an assay that produces chimeric animals that incorporate cells from two different stem cells, mice produced from gene-silenced cells had very few tissues that originated from the iPSCs.

However, in a few iPSC lines the gene cluster was normally activated, and in the most rigorous developmental assay, those iPSCs were as successful in producing live animals as embryonic stem cells have been.

According to the authors, this is the first report of animals being produced entirely from adult-derived iPSCs.

The study will appear in the journal Nature.

Source-ANI