A new method for deriving fully functional neurons from skin cells could provide essential model systems for studying neurodegenerative diseases, and testing new drugs and stem cell-based treatments.
Genetic engineering experiments with skin cells can produce cells with distinct neuron-like characteristics. By using viruses to introduce three neuron-specific genes (achaete-scute complex-like 1 (Ascl1), brain-2 (Brn2a), and myelin transcription factor-like 1 (Myt1l)) skin cells can be effectively and directly converted into induced neurons or iN cells. Unfortunately, iN cells are not fully functional neurons and are also produced in very low numbers (see O. Torpor, et al., Proc Natl Acad Sci U S A. 2013 Apr 23;110(17):7038-43).
This new technique, however, can produce neurons that are fully functional, which makes them better models for the study of age-related diseases such as Parkinson’s disease and Alzheimer’s disease.
Cambridge University researchers devised this new technique by carefully observing the way neurons developed on the nervous systems of tadpoles. In particular, the Cambridge group was interested in the maturation of neurons after their formation.
According to Anna Philpott, who is a member of the Department of Oncology, “When you reprogram cells, you’re essentially converting them from one form to another but often the cells you end up with look life they come from embryos rather than looking and acting like more mature cells. In order to increase our understanding of diseases like Alzheimer’s, we need to be able to work with cells that look and behave like those you would see in older individuals who have developed the disease, so producing more ‘adult’ cells after reprogramming is really important.”
Instead of simply adding transcription factors to skin cells, Philpott and her colleagues paid close attention to the activities of those transcription factors once they are expressed inside the cell. Dividing cells, for example, modify their transcription factors with attacking phosphate groups to them. This process of phosphate attachment helps with cell growth but prevents cells from maturing to fully adult neurons.
However, Philpott and her group engineered transcription factors that could were unable to receive phosphate group attachments. Such modified transcription factors produced neurons that were more mature and more useful as model systems for neurodegenerative diseases.
Such controls are also at work in other tissues such as the pancreatic islet cells, and Philpott and her co-workers are already attempting to use her strategy to make mature pancreatic beta cells that secrete insulin in response to increased glucose concentrations.
“We’ve found that not only do you have to think about how you start the process of cell differentiation in stem fells, but you also have to think about what you need to do to make differentiation complete – we can learn a lot from how cells in developing embryos manage this,” said Philpott.