Model Organisms : Human Stem cells and Disease Modelling by Terri Holmes

Stem cells have been used as a tool to model disease for decades. The principle of reprogramming an adult cell into an induced pluripotent stem cell (iPSC) involves the use of the essential “Yamanaka factors”: Oct4, Sox2, Nanog and c-Myc. Pluripotency in this case, is the potential to become more than one cell; for example an iPSC can become a fibroblast (connective cell) or a cardiomyocyte (heart cell). These are transcription factors which induce pluripotency and turn differentiated “specialized” cells back into an ‘embryonic-like’ state. Once reprogrammed, iPSCs are cultured in vitro (in a dish) and can be differentiated into any cell type.

There are various strategies for using stem cells to model disease, and choosing the best strategy depends on the type of disease being studied. For example, for a disease caused by a genetic mutation, cells can be extracted from a patient with the disease and reprogrammed into iPSCs. There are various genome editing tools such as CRISPR/Cas9 which can be used to correct the mutation to generate an “isogenic control” – a line of iPSCs that are genetically identical to the disease line, except the mutation has been corrected. Both lines can be differentiated into whatever tissue type is involved in the disease. For example, if modelling a genetic heart condition, the iPSCs can be differentiated into cardiac muscle cells. This allows the generation of an in vitro model of diseased heart tissue, as well as healthy heart tissue that can be used for comparison. From there, various drugs and stimuli can be tested to see how diseased tissue responds compared to healthy tissue, which could lead to the discovery of novel treatment options.

Using human iPSCs in comparison

 to animal models is far more 

affordable, less labour intensive and less ethically controversial. The argument can also be made that human iPSCs are more biologically relevant to human conditions, as animals have different physiologies and are known to express different forms of many proteins. For example, mice express several different cardiac genes than humans, and have much smaller hearts and much higher heart rates. Therefore, using human heart tissue would be more biologically relevant to heart disease that using mouse tissue. Additionally, using iPSCs allows the use of an isogenic control which is far more difficult to achieve in an animal model. When comparing a diseased animal to a healthy relative, any variable genetic factor outside of the disease mutation could contribute to their different responses. When using an isogenic control, the lack of genetic variability between the diseased and healthy lines mitigates this issue, making for a much stronger control.

There are of course limitations to using iPSCs to model disease. Firstly, many cell types derived from iPSCs are difficult to fully differentiate. For example, heart muscle cells derived from iPSCs more closely resemble foetal heart tissue than adult heart tissue. Also, the cells are cultured in monolayer, which is not how they exist in the body. However, there are advancements being made to generate 3D tissue cultures that more closely resemble real human tissue. Ultimately with how fast progress is being made in the field of stem cell technology, iPSCs are one of the strongest tools for modelling human disease.

To find out more about how Terri and her colleagues in the Smith lab at UEA use stem cells you can see what they have been up to by clicking here! Or to contact Terri you can email her: terri.holmes@uea.ac.uk