Gene defects plague stem-cell lines
Cancerous mutations threaten therapeutic future for cells.
Embryonic stem cells that are cultured in the lab accumulate an alarming array of genetic changes, including mutations known to be linked to cancer. The finding throws into question whether such cells could eventually be used for therapy, unless they can be kept fresh and checked for mutations before use.
Researchers think that stem cells, which can be programmed to grow into any kind of cell, could one day be used to regenerate or replace cells and organs damaged by disease. But growing these cells has proven problematic.
In January, researchers announced that most human embryonic stem-cell lines, including ones approved by the US government for use in federally funded studies, have been contaminated by animal cells used as a growth medium in lab dishes. Any cell containing such foreign proteins would presumably trigger a damaging immune response if transplanted into a human patient. Researchers realized they would have to grow their cells differently in order to use them for therapy.
Now another difficulty has come to light. The longer the cells are kept, and the more they divide, the more errors they build up in their genetic code. "These mutations we are finding are a much bigger problem," says Aravinda Chakravarti of the Johns Hopkins University in Baltimore, Maryland.
All DNA tends to accumulate mutations as it divides, because each step in the copying process can introduce errors. But previous, smaller studies of stem cells had not found problematic levels of mutations.
Chakravarti and his colleagues decided to take a closer look, examining nine of the human embryonic stem-cell lines that have federal approval. They compared frozen, archived cells with 'daughter' generations that had been created from these.
Many of the archived cells seemed normal, although some had already divided tens of times to build up cell numbers into the billions. But errors began to appear after further divisions. Out of nine cell lines, eight developed one or more genetic changes commonly observed in human cancers, the team reports in Nature Genetics1.
Changing state of play
The finding undermines a general assumption that stem cells remain unblemished until they are programmed to become a certain type of cell. "This is not good news. It suggests that the biological properties of the cells before and after replicating could be different," says Chakravarti.
It remains unclear what would happen if these stem cells were transplanted into a patient. But Chakravarti thinks the results should encourage the use of fresher stem cells or, preferably, genetic screens of stem-cell lines before they are used for therapy.
Stem-cell expert Roger Pedersen of the University of Cambridge, UK, says he takes a "glass half full" view of the findings, because the billions of archived cells seemed normal. This shows that the replications needed to boost stem-cell numbers to usable levels do not necessarily cause problems.
Pedersen adds that the study supports the idea that more, fresh stem-cell lines would be useful for the scientific community: US federal research currently relies on a very limited number of lines.
- Maitra A., et al. Nature Genet.Published onlie, doi: 10.1038/ng1631(2005).
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