The largest study to date on the genetic stability of cultured human embryonic stem cells (hESCs) has shed light on whether genetic mutations in the cells are related to the nature of the cells themselves or to the techniques used to grow them in culture.
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LONDON: The largest international clinical study ever performed on human embryonic stem (ES) cell differentiation has resulted in the identification of DNA that drives growth in cultured human ES cells.
Headed by the International Stem Cell Initiative (ISCI), the scale and design of the ethnically diverse sample screen provide the most accurate representation to date of the world population, surveying 125 independent human embryonic stem (ES) cell lines from 38 laboratories in 19 different countries.
Although the exact number of human ES cells derived worldwide is unknown, the 125 ES cell lines analysed in this study, published in Nature: Biotechnology today, represent those that are commonly available, and also include ES cell lines representative of most major ethnic groups. In addition to the human ES cells, 11 induced pluripotent stem (iPS) cell lines were analysed in order to act as comparative study controls.
Observing the candidates
iPS cells are artificially derived pluripotent stem cells, which are stem cells which have the potential to give rise to both foetal and adult cell types. They are key to understanding the roles genes play in controlling cell programming, and could be major players in the process of epigenetic change - the heritable changes in gene expression - observed in cancer cells.
Previous research has hypothesised that by observing certain 'candidate' genes that likely play a role in controlling the development or hindrance of ES cell differentiation, it would be possible to identify the targets of epigenetic change.
Stem cells are sure to adopt one of three fates: self-renewal, differentiation or death, and by studying the mutations, or amplifications that occur in cells that neither die nor replicate. So the isolation point of a mutation can be identified as a source of selective advantage for variant stem cells.
The fate of pluripotent cells
The ES cell cultures were examined at early and late passage in order to gain insight into the type and frequency of genetic changes that affect human ES cells on prolonged passage.
The results showed that the variant genes on chromosome 20 had a growth advantage, but the nature of the selective advantage remains unclear. One particular gene, named BCL2L1, has been identified as being able to stop cell death, and in one manifestation of the mutation, promotes grow in a rare, malignant tumour of the cells that line the yolk sac of the embryo.
Understanding the drivers of change in cell replication is crucial for developing effective regenerative medicine, but it is also key to our understanding of the fate decisions of pluripotent cells.
"The interest in this case is that now we have knowledge of the decision making process the cells need to make," research associate at the University of Sheffield, Paul Gokhale, one of the co-authors of the paper with Andrew Laslett from the Materials Science and Engineering Department of national science agency, CSIRO. "If the extremely fine region that contains BCL2L1 is isolated, you've found exactly the gene you would look for for selective advantage, because these cells aren't dying in stressful conditions."
How cells proliferate
"A certain subset of mutation [studied here] was already known, but given the scale of the study and the fact that it was done by ISCI is probably the most credible thing," commented Philippa Brice, head of knowledge and communications at London's Foundation for Genomics and Public Health (PHG).
"They looked at a lot of different cell lines, which does make this study unlike any other, and the best yet from a knowledge position. While they have found one gene variant that is very common, which while it isn't new, does provide more information into how embryonic cells and cancer cells proliferate."
"The idea of this study is that it has a large cohort of samples, and if you can see, and therefore eliminate the chromosomes being replicated or lost, you can hone down on what is being amplified," Gokhale said.
