Modeling Diabetes with Stem Cells

Reprogrammed adult cells could be used to reconstruct diabetes in the laboratory.

A technique that allows the insulin-producing cells that are destroyed by type 1 diabetes to be re-created in the lab could help researchers understand how the disease develops and perhaps lead to more effective treatments for the condition.

Insulin assistance: The cells on the left are derived from diabetic iPS cells, and those on the right are the derived from embryonic stem cells. Both populations contain insulin (yellow stain) and glucagon (green stain)–hormones normally secreted by the pancreas.

A study published today 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.”

Melton and his colleagues show that the reprogrammed iPS cells–so called for their ability to give rise to many cell types–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.

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 1diabetes 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.

By creating all these cell types from a single diabetic patient, it’s essentially possible to reconstruct the disease in a laboratory, says Jeanne Loring, founding director of the Center for Regenerative Medicine at the Scripps Research Institute in La Jolla, CA. “It’s completely mind boggling that you can actually study human disease in a dish,” says Loring, who was not involved in the new work.

This kind of model is especially important in type 1 diabetes, Loring adds, because while the disease is known to run in families, its genetic cause remain obscure. “By capturing the flawed cells and probing their dysfunction, researchers could begin to forge such an understanding.

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.

With such a model, Melton says, researchers could begin to address specific questions about how type 1 diabetes develops and progresses. For example, if it were possible to “reboot” a diabetic patient’s immune system, would he necessarily redevelop the disease? Is the disease process the same in all affected patients? And which of the three cell types is the first to go awry? “It’s quite amazing that we don’t know the answer to that,” Melton says.

It would also be possible to use this model to test potential treatments, says Melton. 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.

One potential roadblock is that different samples from the same patient don’t yield identical cell lines. The adult cells are reprogrammed using viruses that incorporate themselves into the genome and encode proteins known to sometimes revert cells to an earlier developmental state. These viruses don’t insert themselves in a predictable way, meaning the proteins they specify aren’t manufactured uniformly among different infected cells. “There’s no certainty that you can just make one iPS clone from an individual and assume it’s going to be representative of that individual,” says Loring.

Although the main goal of the project was to create a model of type 1 diabetes, the diabetic iPS cells may have therapeutic potential as well. In theory, iPS cells derived from a particular patient could be turned into betalike cells that could then be implanted to replace the cells that her immune system has destroyed. But there would be nothing to stop the patient’s immune system from attacking the implanted cells just as it attacks new beta cells naturally manufactured by the body. “That’s the catch-22 with this particular disease, and autoimmune diseases in general,” says Loring.

However, Loring says, it may be possible to cloak the implanted cells in order to hide them from the immune system. If so, it would be preferable to use cells derived from the patient to be treated. If the cloaking were to fail, the implanted cells would at least be recognized as “self,” avoiding a catastrophic rejection response. This would obviate the need for dangerous antirejection immunosuppressant therapy.

Melton suspects, however, that modifying beta cells enough to hide them from the immune system would so thoroughly alter them that they would no longer serve their normal function. And in any case, he says, the current methods for generating betalike cells from iPS cells are too inefficient to be therapeutically useful.

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