A new method for generating hundreds of millions of insulin-producing pancreatic beta cells from human pluripotent stem cells is being hailed as a major step toward a diabetes cure, although there is still a long road ahead.
The paper was published in the October 9 issue of Cell by a group at the department of stem-cell and regenerative biology, Harvard Stem Cell Institute, Harvard University, in Cambridge, Massachusetts. The team is led by institute codirector and department cochair Dr Douglas A Melton, the Xander University Professor at Harvard.
Dr Melton has 2 children with type 1 diabetes, and he dedicated his career to finding a cure for the disease when his son was first diagnosed over 20 years ago.
The results, he and his colleagues write, "suggest that stem-cell–derived beta cells present an opportunity for cell therapy. Limited supplies of donated cadaveric islets and the very small amount of human beta-cell replication achieved in vitro have severely limited human beta-cell supplies to date. This limitation has restricted transplantation options for patients."
Now, "the generation of an unlimited supply of human beta cells could extend this therapy to millions of new patients and could be an important test case for translating stem-cell biology into the clinic."
Using a human embryonic stem-cell line and two human-induced pluripotent stem-cell lines, the team applied a novel 4- to 5-week scalable differentiation protocol to generate hundreds of millions of glucose-responsive beta cells in vitro that lowered glucose levels when transplanted into diabetic mice.
Some of the stem-cell–derived beta-cell batches secreted as much insulin as cadaveric islets.
Dr Melton told Medscape Medical News that his team is now "starting experiments on monkeys....I don't anticipate human trials for at least 3 years."
Asked to comment, Dr Julia L Greenstein, vice president of discovery research at the Juvenile Diabetes Research Foundation, New York, told Medscape Medical News: "It's really exciting work. It's where the community has been moving for a long time, to try to get more differentiated beta cells from a human source that would be available both for biological studies and potential therapy."
Dr Robert E Ratner, chief scientific and medical officer for the American Diabetes Association, told Medscape Medical News that the results are important because the team was able to use both human pluripotent stem cells and embryonic stem cells and because they were able to generate a large volume of beta cells that can be used for in vitro beta-cell testing.
He noted that the beta-cell volume generated per batch — about 300 million — still may not be quite enough for one human transplant, which requires about 500 million, but nonetheless, "it's logarithmically more than we've had before." (The paper says that "one or two flasks may be sufficient for treatment of a patient.")
Concern as to How Long Cells Will Survive, Autoimmunity Issues
But among the issues that need to be ironed out before this technology can be brought to the clinic is the concern that stimulating stem cells to grow and develop could turn them into tumors, said Dr Ratner.
"[The investigators] are pretty sure about keeping them beta cells, but the safety has to be guaranteed," he said.
Also, it's not clear how long the cells will last after transplantation. "Will they survive following injection for a week, a month, or a lifetime, or somewhere in between? We have no idea," he told Medscape Medical News.
And there's the remaining autoimmunity that caused the type 1 diabetes in the first place, he added. A method for protecting the cells from rejection will be necessary, either by immunosuppression, encapsulation, or masking the antigens on the cells in vitro prior to injection.
Dr Greenstein also mentioned the autoimmunity issue. "We'd have to find a way to protect the cells….I don't think immunosuppression is the way to go in the vast majority of individuals with type 1 diabetes."
Dr Greenstein says there is a lot of effort going on at JDRF into encapsulation technology that might address this problem.
Dr Melton told Medscape Medical News that his team is currently investigating two ways of protecting the beta cells from immune attack. They are collaborating with scientists at the Massachusetts Institute of Technology to develop microcapsules, formed by dropping a few clusters of cells into a drop of alginate. "The alginate has been chemically modified in such a way that it does not allow fibroblasts to attach," he explained. To treat one animal, or eventually patient, hundreds of thousands of these microcapsules will be required.
"The other 'device' involves a large membrane into which millions of cells are placed; these larger devices are currently available, and we are pursuing their utility with several other investigators," Dr Melton said.
Asked what doctors should tell their patients who have seen this story in the news with "breakthrough" and "cure" headlines, Dr Greenstein advised: "It's a very exciting step toward the cure, but there's still a lot of work that needs to be done to get it ready to be available for patients."
The work was supported by grants from the Harvard Stem Cell Institute, the National Institutes of Health, Helmsley Charitable Trust, the JPB Foundation, and the generosity of M and A Barry. Dr Melton is an investigator at the Howard Hughes Medical Institute. Disclosures for the coauthors are listed in the article. Dr Ratner and Dr Greenstein have reported no relevant financial relationships.
Cell. 2014;159:428-439. Abstract
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Cite this: Is New Stem-Cell Research Major Step Toward Diabetes Cure? - Medscape - Oct 13, 2014.