As the prospect of using regenerative stem cell therapies draws ever closer, a consortium of biomedical scientists recently reported that, of the induced pluripotent stem cells from 10 research institutions they analyzed, around 30% were genetically unstable and could not be safely used in the clinic.
In a study published in the journal Stem Cell Reports on 9 June, supported by the U.S. National Heart, Lung, and Blood Institute, a multi-institutional research group provided a comprehensive characterization of a large set of induced pluripotent stem cells (iPSCs). These specialized iPSCs were reprogrammed from adult skin cells or infant umbilical cord blood cells and have the potential to become any cell type in the body – a property known as pluripotency – mimicking the function of human embryonic stem cells (hESCs).
As part of the Progenitor Cell Biology Consortium, the scientists are working to verify that this rapidly emerging field of medical research is built on safe and sound science. Although the technology to produce safe and effective iPSCs exists, the researchers reported that they encountered an unexpected number of unstable cell production runs. These included some cell lines contaminated with bacteria or carrying cancer-related genes and mutations.
Senior author Dr. Carolyn Lutzko, of the Cincinnati Children's Hospital Medical Center laboratory, noted: "We were surprised to find such a large number of unstable cell lines in this study, which highlights the importance of establishing environmental safety standards for stem cell therapies. Many of the cell lines we studied did meet quality standards, but an unexpected number that did not meet these standards cannot be used in clinical therapies."
The researchers also announced the establishment of an online portal and database: https://www.synapse.org/. It gives scientists open access to data from the study, supporting their own research into iPSC-based stem cell therapies. This allows researchers to compare the quality and stability of iPSCs currently being generated in their own laboratories.
Different tools, different results
The researchers compared 58 different cell lines submitted by different institutions. The cells were generated by various methods and have a range of genetic and tissue origins, such as adult skin or infant umbilical cord blood cells. The researchers assessed the iPSCs for genetic stability, pluripotency and other scientific criteria.
Genetic stability is critical to the safety of iPSCs, helping to avoid cancer or other medical problems triggered by experimental therapies. Before being directed to become a specific cell type, an iPSC line continually self-renews and expands in a "blank" state, and it is also crucial that this happens without introducing genetic errors. The researchers also compared the molecular and functional characteristics of iPSCs with human embryonic stem cells, which are seldom used as a benchmark gold standard for testing quality.
How well the 56 iPSC lines met quality standards depended on the origin of the reprogrammed cells (skin vs. blood, male vs. female) and the specific reprogramming method. These different methods included the use of various recombinant genes, vectors (engineered viruses that deliver genetic material to cells) or plasmids (small DNA molecules that can deliver recombinant genes).
Teratoma testing
Pluripotency means that iPSCs can give rise to the three fundamental germ-cell layers that make up the body – endoderm (gut region), ectoderm (epidermis, neural tissue, etc.) and mesoderm (muscle, blood cells, etc.). Pluripotency can be tested by determining whether an iPSC line is able to form a so-called teratoma – a benign tumor composed of various cell types (teeth, bone, brain, etc.).
Lutzko said it had been thought that low-quality iPSC lines were not pluripotent, but until the current study this theory had not been carefully tested due to cost. This prompted Lutzko and her colleagues to examine all iPSC lines – of both high and low quality – and explore whether they could give rise to teratomas.
To do this, the researchers studied different iPSC lines to investigate, first, whether tumors formed, and second, whether the tumors contained the three different germ-cell types. The tests showed that both genetically stable and unstable iPSC lines could form teratomas containing all three germ layers.
According to the study's authors, although genetically unstable iPSC lines exhibit pluripotency, the clinical context involved could also lead to cancer, again highlighting the need for safe reprogramming methods. (Original paper: Integrated Genomic Analysis of Diverse Induced Pluripotent Stem Cell from the Progenitor Cell Biology Consortium)
In January 2014, the research group of Professor Tian Jianhui of China Agricultural University and the laboratory of Researcher Gao Shaorong of the National Institute of Biological Sciences, Beijing, jointly identified a gene called Zrsr1, whose level of methylation affects the quality of induced pluripotent stem cells (iPS cells) and can be used to distinguish good iPS cells from poor ones. This research will have important value for the use of iPS cells in regenerative medicine and drug development.
Source: ebiotrade
