Time-lapse imaging and tracking of single human embryonic stem cells has allowed researchers to zoom in and take a closer look at the behaviour of these special cells. Researchers from the University of Sheffield have identified multiple bottlenecks that restrict the growth of these cells in the laboratory, and observed complex and diverse behaviour as the cells move around the culture dish and interact with their neighbours. These findings will help researchers design the best conditions to safely and efficiently grow human embryonic stem cells in the laboratory.
What is the idea behind this study?
Human embryonic stem cells can form all the different types of cell in the body. This means that they are very useful in research. They can help us to understand development and disease, search for and test new drugs, and potentially be used in new cell-based therapies for currently untreatable diseases.
There are, however, limitations on their use in this way. When they are cultured in the laboratory, lots of cells die, while others develop disadvantageous genetic changes, or mutations.
By tracking single human embryonic stem cells in the culture dish, combined with mathematical modelling, the researchers hoped to better understand the subtle influences and processes that cause stem cells to behave in very different ways – in some cases resulting in cell death or mutation. This knowledge could then be the foundation for safer and more efficient ways of growing these cells in the lab.
What did this study show?
Researchers at Sheffield developed new methods for analyzing images, and measured many parameters from time-lapse videos, tracking individual human embryonic stem cells to help them identify factors that restrict growth as well as factors that enable cells to grow more efficiently.
They discovered that cells have individual traits. Some develop genetic mutations known to provide stem cells with superior growth capabilities, enabling them to overtake the culture. This phenomenon, termed ‘culture adaptation’, mimics the behaviour of cancer cells.
Commenting on the research, Professor Peter Andrews said: The researchers compared normal human embryonic stem cells with these adapted cells (see videos above). They identified three major bottlenecks affecting colony formation: survival after plating, failure to start division and continued cell death after division. In the same culture conditions, they found adapted cells performed better in all of these points leading to more colonies. Bottlenecks were also alleviated through cell-to-cell contact and pro-survival compounds.
In a sense we appear to be seeing cells make ‘vocational choices’ depending on their immediate environment. These choices appear to be influenced by near neighbours, leading us to believe that there is something akin to ‘teaching’ that can occur between neighbouring cells as they develop. The focus of our research now will be to examine the molecular mechanisms that control these choices. Instead of taking a herd view in our research, we are focusing our efforts on what happens at individual cellular level.
What does this mean for patients?
The research team plans to further develop the methods from this study into an image processing and analysis software solution to monitor cell behaviour. This could be used to ensure safer, more efficient and more consistent culture conditions. The direct monitoring of cells by time-lapse can also help minimize the occurrence of genetic abnormalities – an important consideration when using the cells in medical research and the development of new treatments.
Further information and links
This summary was written by Kate Doherty, based on information about the research provided by Ivana Barbaric.
The full reference for the paper described in this summary is:
Barbaric et al. Time-Lapse Analysis of Human Embryonic Stem Cells Reveals Multiple Bottlenecks Restricting Colony Formation and Their Relief upon Culture Adaptation, Stem Cell Reports 3(1):142-55. doi: 10.1016/j.stemcr.2014.05.006