Age is just a number: Using iPSCs to model neurodegenerative diseases
Author: Samantha Payne
This year we celebrate the 10th anniversary of the seminal discovery of induced pluripotent stem cells (iPSCs). The excitement that this breakthrough has caused in the stem cell community cannot be overstated, and the imagination of researchers has been captured by the potential applications. To be able to obtain cells via a simple skin or blood biopsy and revert them to a state of self-renewal where they can become any cell of the body offers seemingly limitless possibilities.
In the time since we were first introduced to iPSCs we’ve learned that while they do live up to their promise, the road to their clinical use is more complicated than previously thought. Generally, iPSCs are produced and then differentiated into a desired precursor cell type for two purposes: to transplant cells or organoids into a patient to replace damaged or defective tissue, or to culture them from an individual with a genetic condition to study the mechanism of a disease or test therapeutic agents.
For transplantation, we have seen tremendous progress with iPSC-derived cells pre-clinically, and have even seen the recent re-launch of a clinical trial in Japan to transplant iPSC-derived cells for macular degeneration. However, it is worth noting that this trial was previously placed on hold in 2015 due to concerns over a mutation in the cells of a patient, as well as regulatory changes in Japan, emphasizing some of the issues delaying clinical use. A major hurdle is the reproducibility at several levels of the iPSC generation and testing processes; methods of iPSC differentiation vary widely, cell identity and age are often undefined or do not represent the source, and it can be difficult to meet clinical safety standards for culture and handling conditions. Efforts are underway in numerous facilities around the world to increase method standardization and develop iPSC banks and databases, which will help them to enter further clinical use for transplantation.
Although cell transplantation therapies are often given more attention, iPSC-derived cells are useful in disease modeling and drug screening (so called ‘clinical trials in a dish’). One such avenue of research gaining traction is the generation of neural cells for the study of neurodegenerative diseases, for which there are now a number of robust protocols for many of the subtypes of neurons associated with these diseases, such as motor neurons of the spinal cord or dopaminergic neurons of the brain. For example, we can de-differentiate cells from an amyotrophic lateral sclerosis (ALS) patient and then re-differentiate them into the affected motor neurons to study the pathology of the disease, including any mutations or markers of it.
One intriguing problem with modeling neurodegenerative conditions with iPSCs is the developmental age of a reprogrammed cell. How do we decide what age a cell taken from adult tissue is after reprogramming? When a cell is reprogrammed into an iPSC, it actually undergoes rejuvenation, reverting to a younger cell phenotype than those of the adult patient it was derived from. This phenomenon raises concerns about how well iPSC-derived cells can truly mimic neurodegenerative phenotypes. Do the reprogrammed cells really represent the cells we want to model, especially in aging diseases like Parkinson’s and Alzheimer’s?
Responding to this challenge, researchers have come up with some innovative ways to accelerate the aging of iPSC-derived neurons. Cells can be chemically aged using environmental stressors such as agents that cause oxidative stress or DNA degradation. Intriguingly, cells can also be artificially aged by altering genetic pathways and genes involved in aging. Lorenz Studer’s group in New York has harnessed the use of a gene that is mutated in people who suffer from premature aging diseases such as progeria. They found that by altering this gene in dopaminergic neurons derived from iPSCs they could get a cell that seemed to better represent aged neurons in Parkinson patients’ brains. However, the authors suggested that further research is needed to investigate the complex interplay of intrinsic and extrinsic factors to truly obtain an accurately aged cell.
When we look at the work that is still needed to make iPSC therapy a reality, it is tempting to be pessimistic about their future use. However, when we consider that in only the first 10 years since their discovery, we have established a multitude of methods to generate them, differentiate them, and are now starting to ask more sophisticated questions about their identity, in the next 10 years we may well be on our way to making their clinical use a routine practice. Continued support to researchers from organizations such as the Stem Cell Network ensures that we can advance this field and that Canada will remain at the forefront of stem cell research.
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