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Researchers use skin cells from type 1 diabetes patients to produce cells that make insulin
09-08-2009
by David Hutton  |  Email the author
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WORCHESTER, Mass.A group of researchers have been able to use skin cells from people with type 1 diabetes to produce cells that made insulin in response to changing blood sugar levels, though not as efficiently as normal insulin-producing cells do. 
 
A study published recently in the Proceedings of the National Academy of Sciences describes a way to create induced pluripotent stem (iPS) cells from ordinary adult cells taken from patients with type 1 diabetes. These stem cells then can be reprogrammed to produce all of the cell types relevant to the disease.
 
"What you get is the ability to watch, for the first time, type 1 diabetes develop," says senior author Douglas Melton, a professor of natural sciences at Harvard University and co-director of the Harvard Stem Cell Institute. "Until you watch a disease develop, you will not understand the mechanism, and you therefore cannot devise any kind of sensible treatment or cure."  
 
The major immediate implication from this experiment is that scientists now have a preliminary lab model of human type 1 diabetes cells, and the hope is that an animal model of the disease could be developed from this research.
 
"These cells, which capture all the genes involved in T1 diabetes (because the cells come from a patient), are going to become a powerful model to study how T1 D develops," Melton says. "It is not our intention to use these cells for transplantation into patients, but rather to reconstruct or recapitulate the disease so that we can understand its cause."  
 
To test whether their lab-made cells could function like normal beta cells, Melton's group exposed them to glucose in a dish. When sugar levels were high, the cells produced more of a protein that beta cells release when they break down sugar; when glucose levels were low, the protein levels were low as well.  
 
As a result, by capturing flawed cells and studying their imperfections, Melton notes that it is possible to gain an understanding of the genetic cause of the disease. The science could also be applied to other diseases, he says.
 
"Work at the Harvard Stem Cell Institute on neurodegeneration (ALS and SMA) is another example," adds Melton.   Melton and his colleagues were able to show that the reprogrammed iPS cells can be spurred to differentiate into tissue resembling the insulin-producing pancreatic beta cells that are destroyed by the immune system in type 1 diabetes.
 
"Directing the differentiation of the pluripotent stem cells was accomplished in a multi-step process, adding signals such as growth factors and inducing molecules, at each stage," Melton says. "This has been done, albeit inefficiently, by many labs and the problem is how to make each step more efficient so that at the end one gets many beta or beta-like cells. With present methods, one gets less than 1 percent of the cells becoming beta-like cells."
 
Embryonic stem (ES) cells have long been the gold standard for deriving pluripotent cell lines. But ES cells can only be used to create disease models for disorders such as cystic fibrosis, where the genetic underpinnings are straightforward. Because the genetics underlying type 1 diabetes are complex and poorly understood, researchers have no way to identify diabetes-specific ES cells.  
 
Therefore, iPS cells derived from patients known to be diabetic offer the best hope for modeling the disease by allowing researchers to generate diabetes-specific versions of all the relevant cell types: The pancreatic beta cells, the immune cells that destroy them and the thymus cells that orchestrate their destruction.  
 
Ultimately, Melton plans to construct a "living test tube" for probing the interplay between the beta cells and the immune system in diabetes. He hopes to use the diabetic iPS cells to generate all three relevant cell types and then to put those cells into a so-called humanized mouse that can accept human cells to see how they interact.
 
"We have to make beta cells more efficiently, then make cells of the immune system (by making hematopoietic stem cells), then make thymic epithelium (to educate the immune cells) and then, finally, put all 3 components into a living test tube ( an immunodeficient mouse) to reconstruct the disease," he says. "It's an ambitious, some might say overly ambitious, experiment, but if it works, we will for the first time be able to watch human T1D develop."
 
Measuring continued success will start with the results of that experiment. If it works, Melton says "then we'll have a celebration."
 
According to Melton, researchers could use such a model to address specific questions about how type 1 diabetes develops and progresses. It would also be possible to use this model to test potential treatments. But he cautions that all these applications are still a long way off. A humanized mouse carrying differentiated diabetic iPS cells doesn't yet exist, and it could be years until it does.  
 
Moving forward, as these methods of making beta cells become more established, Dr. Rohit Kulkarni, a diabetes expert at Joslin Diabetes Center in Boston, told Time Magazine that the strategy could be expanded to help patients with either type 1 or 2 diabetes.
 
"It might even be more relevant for other types of diabetes where there is no immune-system attack," he says. In those cases, simply replacing nonfunctioning beta cells might go a long way toward treating or even curing the disease.  
 
The research also is good news to Susan Solomon, CEO of the New York Stem Cell Foundation, which provided some of the funding for the study.  
 
"This is a big deal," she says in a statement. "Tackling the basic biology of type 1 diabetes, which is a very complex disease, is a critical step. With these cells, we can see in a dish what's happening to the immune system, and if you don't understand the immune response, you get nowhere with type 1 diabetes."
 
Code: E09090903

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