EU-funded study sheds light on DNA changes in human embryonic stem cells
Scientists in Europe have discovered that the prolonged culture of human embryonic stem cells (hESCs) can trigger changes resulting in chromosomal abnormalities. Published in the journal Nature Biotechnology, the findings are an outcome of the ESTOOLS ('Platforms for biomedical discovery with human ES cells') project, which received EUR 12 million under the 'Life sciences, genomics and biotechnology for health' Thematic area of the EU's Sixth Framework Programme (FP6). ESTOOLS set out to develop the skills, tools and techniques needed for medical, pharmaceutical and bioindustrial applications of human ES and induced pluripotent stem (IPS) cell research. Scientists seeking to determine how to best prevent harmful changes in cultured hESCs will benefit from the results of this latest study, as the findings will help them to secure more reliable applications of stem cell-based regenerative treatments. The research team said the findings will also support further examination of the so-called culture adaptation process, in which hESCs in culture mimic the accumulation of genetic changes typical of malignant transformation; this has the potential to offer clues to some genetic mechanisms responsible for cancer development. 'Prolonged culture of hESCs can lead to adaptation and the acquisition of chromosomal abnormalities, underscoring the need for rigorous genetic analysis of these cells,' the authors wrote in their paper. Researchers are currently investigating embryonic stem cells for their potential use in regenerative cell replacement therapies because they have the capacity to self-renew and develop into a variety of cell and tissue types such as blood cells, neurons, bone and muscle. Scientists, however, recognise that genetic changes occur in a number of hESC lines as they multiply in the laboratory, and these changes can resemble the DNA (deoxyribonucleic acid) abnormalities often found in cancer cells. In addition, hESCs may also experience other genetic changes that traditional methods fail to detect. As a result, serious concerns remain over their use in the medical world. The team used high-resolution DNA analysis to map genetic changes in 17 hESC lines cultured over many generations and maintained in different laboratories. Their analysis identified 843 copy number variations (CNVs), and 'on average, 24% of the loss of heterozygosity (LOH) sites and 66% of the CNVs changed in culture between early and late passages of the same lines', the authors wrote. CNV and LOH are genetic variations that could be linked to tumour transformation. They discovered that 30% of the genes with CNV sites had 'altered expression versus samples with normal copy number states, of which more than 44% were functionally linked to cancer'. 'When we know which genes are involved, it will be easier to reject those hESC lines in which those genes are more likely to mutate,' explained co-author Peter Andrews, a professor from the Centre for Stem Cell Biology at the University of Sheffield in the UK, and leader of the ESTOOLS consortium. The ESTOOLS team is made up of 21 partners (18 academic research institutes and 3 companies) from the Czech Republic, Finland, Germany, Italy, Israel, the Netherlands, Spain, Sweden, Switzerland and the UK. The project partners say training and dissemination activities will help maximise the impact of their research, and develop a strong, competitive European base for human ES cell research.