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Human stem cells become unstable in the lab
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Stem cells cultured for long periods in the lab develop genetic changes in areas known to be involved in human cancers, researchers are warning. The potential therapeutic benefits of human embryonic stem cells, which so many researchers are pinning their hopes on, should perhaps come with a “best before date”, US-based researchers suggest. “It seems that there must be something in the cell culture that turns on some genetic pathways, which in the body would normally be modulated,” says Aravinda Chakravarti, who led the research at the Johns Hopkins University School of Medicine in Baltimore, US. “We don’t know why stem cells are so sensitive to mutations in vitro, or even if it is just stem cells that show such mutations over time, but certainly the medium in which they are cultured needs to be investigated,” he adds. Metabolic function The research is a setback for stem cell science and contradicts an earlier study which found no significant changes to the genomes of lab-cultured stem cells. Chakravarti and colleagues found serious genetic alterations in eight of the nine cell lines they cultured, including large DNA deletions and amplifications in certain regions of the genome over time. They also found mutations in the mitochondrial DNA, which could affect the metabolic functions of the cells, as well as changes in the patterns of DNA methylation – the process which chemically alters which genes are “switched on or off”. This sort of alteration in how genes are expressed, called epigenetic inheritance, had been seen in lab-cultured embryonic stem cells from mice, but a previous study in human cultured embryonic stem cells had concluded that the genome was very stable over time. Huge implications Chakravarti and colleagues followed the lines of stem cells as they were cultured, examining them twice – first at an average of 35 passages (after the cells had divided 35 times) and then 20 passages later. In the latter testing of cells, they found 90% showed changes in patterns of methylation, 22% had mutations in mitochondrial DNA and 50% had major deletions or amplifications in the DNA. “Perhaps if stem cells are transplanted therapeutically, they should be restricted to early passage stem cell lines,” Chakravarti suggests. But much of the current research into therapeutic uses for stem cell lines involves growing the lines until they differentiate into a tissue type – Chakravarti’s research could have huge implications for this emerging field of medical research. “The first thing it should lead to is a greater understanding of what happens when we culture cells – it may be that stem cells don’t turn out to be especially sensitive to mutations,” |
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