Could stem cell-derived beta-cell transplantation reverse diabetes?
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I would not be surprised if there are clinical trials that occur with some form of a stem cell-derived beta cell in the next 2 years.
We have made a great deal of progress when it comes to taking pluripotent stem cells and transforming them into insulin-secreting beta cells. The two-part problem scientifically is this: How do you specify fate choice of these cells to a beta cell? Then, how do you take these beta cells and functionally mature them so they actually secrete enough insulin and are glucose-responsive enough to be able to actually reverse diabetes in an animal or in people?
There is still some work to be done on the second question in terms of maximizing the maturation, but the level of maturation we are able to achieve right now from these cells — the amount of insulin, how glucose-responsive they are — is quite good, to the point that we can rapidly reverse pre-existing diabetes within rodent models right now.
Even just a few years ago, we were able to make only progenitor cells that had the potential to become beta cells, but also had the potential to become all of the endocrine and exocrine cells in the pancreas. We relied on transplanting these cells into rodents and waiting several months for a fraction of them to spontaneously differentiate into insulin-producing cells. We have been able to make any cell type that resembles a beta cell for less than 5 years. We have gone from essentially nothing to cells that can cure diabetes in a week in mice within a very short time.
Still, hurdles remain, the biggest being getting these beta cells into patients and protecting them from an attack by the body’s own immune system. There are some really good ideas out there on how to do this; it remains to be seen which of these ideas make the most sense in a clinical context.
This is brand new technology, and brand new technologies are always going to take a large amount of time. This would be a cell-replacement product, for which there are no FDA-approved treatments with anything derived from a pluripotent stem cell. There is a lot of new ground that we would be breaking, and it is happening at an amazingly fast rate. It is going to take easily at least 10 years to validate the therapy in a rigorous and safe function, but I think we will get there.
Jeffrey R. Millman, PhD, is an assistant professor in the division of endocrinology, metabolism and lipid research at Washington University School of Medicine. Disclosure: Millman reports no relevant financial disclosures.
Although it is exciting to imagine that diabetes would be disrupted by some dramatic leap forward like stem cell-derived beta-cell transplantation, I remain grounded in the here and now.
The big question with respect to stem cell-derived beta-cell transplantation has been how to faithfully recapitulate the dynamic insulin secretion observed in cadaveric human islets in vitro. The field has made some progress. It is now possible to generate what looks like a bona fide endocrine progenitor according to a multistep protocol. The problem is that everyone has fallen short when it comes to the last few steps to create what looks like a pure beta cell that is truly equivalent to the best examples of insulin secretion within cadaveric human islets.
The quest to generate a stem cell-derived beta cell is probably going to be long and arduous, and we have not reached the finish line. Whereas we have things that look like a beta cell, my guess is that as we study human beta cells and then we study whatever these cells are, we will see differences. It will be important to understand exactly what has been generated.
A bigger question is, where do you put these cells? The ideal spot would be a location protected from immune system destruction that is fully oxygenated and vascularized, so the cells have complete access to all the nutrients required, and is, ideally, in the portal circulation, so that the insulin secretion is under the regulation of nutrients from the gut. That closed loop is very difficult to recapitulate by some other method. We are going to have to find a way to protect the islets from immune system destruction and oxygenate them. Sadly, nothing has worked thus far.
I also worry about the possibility of a lupus-like syndrome, where these cells could provoke additional autoimmunity at an accelerated rate. In the doomsday scenario, that endocrine autoimmunity could extend to organs that broadly secrete other hormones or peptides, including the liver and cells in the GI epithelium.
I am not saying that we can’t solve these problems, but we are going to need good science to understand the risks. It is possible to achieve stellar outcomes for people with type 1 diabetes with currently available technology. A combination of automated insulin, low-carb nutrition, exercise and high-quality health care can contribute to a high quality of life. We have to compare those outcomes with whatever outcomes you would imagine with a stem cell transplant-based approach. If it requires, for instance, broad immunosuppression, that would create another complex condition with significant implications for health. There are a few experimental papers with hypotheses that might work in rodents; however, it is going to take a sophisticated leap in science — in material science and immunology — to get to the point where you can imagine perfectly protecting these new insulin-secreting cells from immune destruction in human patients.
Jake Kushner, MD, is medical director of the private investment and management company McNair Interests and former chief of pediatric diabetes and endocrinology at Baylor College of Medicine and Texas Children’s Hospital in Houston. Disclosure: Kushner reports McNair Interests has ongoing investments in a range of type 1 diabetes-related companies.