Islet and Stem Cells – By Dr Alex Ryan
Last week I attended a seminar by Professor Maike Sander, titled ‘Deconstructing development to construct islet cells from stem cells’. It’s a bit of mouthful, but sounds interesting right? And it really was. I know stem cells are a hot topic, and in theory they hold so much potential. But unfortunately, a lot more research has to be done, and Professor Sander’s talk highlighted a few of the problems facing researchers.
Pancreatic islets contain beta cells, which are the insulin producing cells. Type 1 diabetes arises from the destruction of these cells by the immune system and, in Type 2 diabetes, the increased demand for insulin can lead to beta cell death. Islet transplants are currently an experimental treatment for Type 1 diabetes , so you can imagine how useful it would be to be able to generate an everlasting supply.
Unfortunately it’s not that simple. To generate islet cells from stem cells is a multi-step process . First cells have to develop into gut tube cells. These can then differentiate into pancreatic cells, as well as lung and liver cells. Therefore, it is important that these cells are treated with the correct chemical signals. When the cells have been differentiated into a group of cells called the pancreatic endoderm, they must be matured. This is done by transplanting the cells into the subcutaneous tissue of rats. The cells are transplanted in a cool little capsule, that allows nutrients in and out, but not the cells. This means that they can be removed simply, which is perfect for studying the cells. After 150 days in the rats, markers of pancreatic function can be seen, including increased insulin levels .
Once these cells have been removed, experiments show that pancreatic genes are expressed, meaning that the stem cells have successfully differentiated into pancreatic cells . In the pancreas, approximately 90% of the cells are endocrine, meaning that they secrete something, with 20% being alpha cells (which secrete glucagon, which increases blood glucose levels) and 40% being beta cells. Importantly these percentages are also seen in the cells produced in the lab. These results basically mean that the stem cells have, for all intents and purposes, become pancreatic islet cells.
So, in theory, these cells can then be transplanted into patients with diabetes. Viacyte, the company which perfected this process, are beginning clinical trials soon. They plan to implant immature pancreatic cells into people and see if the cells differentiate into islet cells, as they do in rats. However, when Professor Sander was questioned about the timeline, she was very conservative.
Firstly, islet transplantation for Type 1 diabetes is still at the experimental stage at the moment, despite showing lots of potential. A key factor with islet transplants is the cell number, and transplanting immature cells means the final cell number is not known. Furthermore, the transplant required in rats is quite large, and scaling up for humans may prove to be problematic. Secondly, it is not known how humans will react to the capsules, and what the lifespan of the capsules will be. If repeat transplants are required, then standard insulin therapy may actually be preferable. Thirdly, it is not known if the premature cells will differentiate into functional islet cells.
However, this is assuming the worst. Being able to generate islet cells could be hugely beneficial to those with Type 1 and Type 2 diabetes, and could potentially end insulin therapy. A huge benefit is that successful islet transplants release insulin in response to glucose levels in the blood, offering tighter control over glucose levels. Either way it’s exciting, and I’m eagerly awaiting the results from the preliminary trials.
It’s also worth noting that islet cells traditionally do not do well outside of the body. Experiments have to be carried out rapidly, as the beta cells stop functioning properly within a couple of days. A steady supply of islet cells would allow scientists to investigate the root cause of islet loss in Type 1 and Type 2 diabetes, and hopefully find ways to prevent it in the first place.
I’ve attached some papers for further reading, and I can definitely recommend checking out the Viacyte webpage for a list of even more stuff to read. Again, if anyone has any questions feel free to leave a comment, and I’ll try my best to address them.
2 D’Amour, K. A., Bang, A. G., Eliazer, S., Kelly, O. G., Agulnick, A. D., Smart, N. G., Moorman, M. A., Kroon, E., Carpenter, M. K. and Baetge, E. E. (2006) Production of pancreatic hormone-expressing endocrine cells from human embryonic stem cells. Nat. Biotechnol. 24, 1392–401.
3 Kroon, E., Martinson, L. A., Kadoya, K., Bang, A. G., Kelly, O. G., Eliazer, S., Young, H., Richardson, M., Smart, N. G., Cunningham, J., et al. (2008) Pancreatic endoderm derived from human embryonic stem cells generates glucose-responsive insulin-secreting cells in vivo. Nat. Biotechnol. 26, 443–52.
4 Xie, R., Everett, L. J., Lim, H.-W., Patel, N. A., Schug, J., Kroon, E., Kelly, O. G., Wang, A., D’Amour, K. A., Robins, A. J., et al. (2013) Dynamic chromatin remodeling mediated by polycomb proteins orchestrates pancreatic differentiation of human embryonic stem cells. Cell Stem Cell 12, 224–37.