Cellular secrets: how stem cells can help us model diseases and discover novel treatments
By: Sienna Schaeffer
Edited by: Namrata Damle
Discovering the underlying mechanisms of a disease can be difficult. Disease manifests at a cellular and systemic level, and depending on the outcome it can be very difficult to see through the fog of symptoms and complications to the root cause of the issue — if there even is one root cause. Often times, we come up with treatments for the condition before we even understand what is actually going wrong in the body. However, there is a new method on the scene for modeling diseases that may help alleviate some of these issues: stem cells.
You are probably familiar with the term stem cells, and you may have heard that they are capable of medically revolutionary feats and the answer to all of our problems. Stem cell research is indeed an exciting field with lots of potential, but many of the ‘revolutionary’ claims are overblown, or at least premature. One claim which is not overblown, however, is their excellent capacity for disease modeling has actually been proven. In 2017, researchers in Japan used stem cells to discover the underlying cellular cause of Pendred syndrome, a hereditary form of gradual hearing loss.
Now, when most people hear about stem cells they automatically think of embryonic stem cells. These cells are originally derived from human embryos and they are capable of producing any cell type in the body: bone cells, skin cells, neurons, you name it!. This ability to produce all other cell types is referred to as pluripotency. These cells are fascinating and have a lot of potential to provide new treatments for a variety of diseases, but their embryonic origin has made them controversial, so many scientists are trying to make alternatives. The goal of a lot of stem cell research in the past two decades has focused on taking older cells and giving them back the pluripotency that we see in embryonic stem cells, so that we can take cells from people instead of embryos. There’s been a lot of success on this front: today scientists can a differentiated cell, such as a skin cell, and treat it with proteins and and other substances that turn on certain genes that then tell the cell to revert to a pluripotent state. The cells that result from these treatments are called induced pluripotent cells (iPSCs). Once scientists have created iPSCs, they can then be re-differentiated by scientists to make whatever kind of cell they want.
iPSCs have many potential applications, and they are relatively free from many of the ethical issues surrounding the creation and use of embryonic stem cells. One of these potential applications is this new kind of disease modeling. Often times it can be hard for researchers to get their hands on the cells affected by a particular disease. They can and do use animal models, but not all diseases can be accurately modeled in animals and of course there can be key differences between humans and animal models. If they are able to obtain human cells relevant to the disease, they would need cells that carry the mutation (or edit the cells themselves), and even then, certain cell types do not like to grow in the lab. iPSCs offer solutions to these challenges. Scientists can get cells with the mutated gene directly from patients, from an easily accessible source like the blood. They can then turn those cells into iPSCs, which can grow indefinitely in the lab, and then differentiate the iPSCs to the cell type they are interested in. This allows them to use the patient’s own cells to find out what is going wrong with the disease at the cellular level. This also allows them to test drugs on the patient’s cells, quickly and easily showing if the drug would be beneficial for humans — a ‘clinical trial in a tube,’ if you will.
The possibility of such ‘clinical trials’* has been on scientists minds since iPSCs were first produced in 2006, but the work on Pendred syndrome was the first time researchers were able to realize this possibility. In the case of Pendred syndrome, it was known that mutations in the pendrin gene caused this form of hearing loss, but the mechanism by which the mutation could lead to the disease was unknown. However, they were pretty sure that whatever was going wrong, it was happening in a group of cells called ‘cochlear outer sulcus cells,’ or OSC. The cochlea is part of your inner ear, and it is where vibrations from sound waves get turned into information that your brain interprets as sound. OSCs play an important role in this vibration to information transformation.
Previous research on Pendred syndrome indicated that OSCs are somehow involved in the progressive hearing loss associated with Pendred syndrome, so these were the cells that the researchers wanted to obtain from Pendred patients in order to suss out the cause. However, they couldn’t just take OSCs from patients’ ears: they need those cells! Also, they would not be able to grow the cells in culture. Instead, they took cells from people with Pendred syndrome, treated them to create iPSCs, and then differentiated them into OSCs.
Once they had their OSCs, they began to investigate possible cellular mechanisms. Previous research had shown that pendrin, the protein that is mutated in people with Pendred syndrome, helps control the flow of charged substances in and out of cells, so they originally hypothesized that Pendred syndrome was caused by progressive damage from dysregulation of substances entering the cell. However, when they compared OSCs from patients with Pendred syndrome to OSCs from people without Pendred syndrome, there was not a significant difference between the two groups. They concluded that other proteins in the OSCs must be compensating for a lack of pendrin function. That is to say, their initial idea that the hearing loss was due to the cells’ inability to properly regulate substances flowing in and out was incorrect. The mutations in the pendrin gene must be causing problems some other way.
Next they tagged pendrin with a fluorescent tag, so that it could be easily visualized under a fluorescent microscope. When they looked at OSCs from patients with Pendred syndrome, they realized that there was an odd pattern appearing. In cells that carried the pendrin mutation, pendrin would aggregate in little clusters, forming bright clumps under the microscope. They also found that these clumps tended to form near two other proteins called ubiquitin and LC3b. These proteins are known to be part of a group of proteins that breaks down old proteins — a cellular clean-up crew, if you will. When mutated pendrin gathered around the clean-up crew proteins, the clean-up crew proteins stopped working. The researchers found that without the clean-up crew, OSCs exposed to stress died very easily. They concluded that the real cause of Pendred syndrome was the increased risk of death for OSCs because accumulation of mutant pendrin prevented normal clean-up function and made them much more susceptible to stress.
Once they knew the cellular cause of Pendred syndrome, the researchers were able to test drugs that had been previously shown to help with other conditions caused by inappropriate protein aggregation. Sure enough, these drugs decreased the accumulation of pendrin and made OSCs more resistant to stress, dramatically decreasing OSC death.
Pendred syndrome may be the first of many diseases to be successfully modeled using iPSCs. As the process of creating iPSCs and differentiating new cell types becomes more streamlined, we will likely see more and more drugs being tested on iPSCs before moving to human trials. This method of modeling could be enormously beneficial — but it also has its limits. Patient-derived iPSC modeling works best with diseases that manifest in a singular cell type. Many diseases have effects in numerous cell types, or involve different types of cells interacting with one another. For these diseases, such a straightforward model would not capture the whole picture. Of course, there’s a potential stem cell remedy for modeling more complex diseases — lab grown organoids, anyone? — but that’s another article for a different day.
Bibliography
Hosoya, M., Fujioka, M., Sone, T., Okamoto, S., Akamatsu, W., Ukai, H., . . . Okano, H. (2017). Cochlear Cell Modeling Using Disease-Specific iPSCs Unveils a Degenerative Phenotype and Suggests Treatments for Congenital Progressive Hearing Loss. Cell Reports,18(1), 68–81. doi:10.1016/j.celrep.2016.12.020
