Promising Embryonic Stem Cell News

This new paper from Stem Cells is a wonderful example of the potential of human embryonic stem cells (hESC) to treat diseases like Type I diabetes.

The reason type I diabetes is such an obvious target for hESC therapy get a little complicated, but I'll walk you guys through this paper, and recent results in islet cell transplantation to give you an idea why this result is very promising.

Type I diabetes results from the destruction of the pancreatic islet cells, or specifically the beta cells in the islets which are responsible for insulin production in response to rising blood sugar. As a result, without proper insulin secretion by the pancreas, blood sugar levels continue to rise after eating and the glucose in the blood is not absorbed by tissues like muscle and fat that respond to insulin. A type I diabetic must inject insulin before or after meals or throughout the day to ensure the sugar is absorbed into their tissues, and if insulin is not administered a condition known as diabetic ketoacidosis occurs as a response from the body's inability to absorb the sugar for energy. This is a potentially life-threatening condition.

Recently, the Edmonton Protocol of islet-cell transplantation has shown promise as a way to treat type I diabetes by replacing the destroyed islet cells with new ones from organ donors. The islet cells are harvested from the pancreas by digestion with enzymes, and then a slurry of these cells is usually injected into the liver. There are two major limitations to this treatment. First, cadaverous transplants are always in short supply, there simply are not enough donors. Second, the recipient's body will attack the foreign cells, even if genetically-matched, and therefore they must take a mild immunosuppressive regimen to prevent rejection. In a way, you're just trading one problem for another.

Ideally, an autologous transplant of pancreatic stem cells would be a cure for type I diabetes, that would be the use of one's own stem cells to regenerate the damaged tissue. There are two problems with such a strategy however. First, the body would likely then attack the new islet cells. Second, no known population of pancreatic stem cells has been discovered. It's not clear why the pancreas doesn't have a stem cell population, but it's really kind of a crappy organ. As I've discussed previously, adult stem cells do not transdifferentiate, or make cell-types that they aren't programmed to, very well. So far, no one has figured out a way to make something like a blood stem cell turn into an islet cell with high efficiency.

Hence the importance of this new paper in the journal Stem Cells. The authors, Jiang et al., used hESC cultured without xenobiotics to generate islet cells as high enough frequencies that one could ideally purify out the insulin-secreting cells. To do this, they took undifferentiated hESC, which you can culture and expand almost indefinitely, and then began to differentiate them using two chemicals (Activin A and Sodium Butyrate) which had previously been shown to direct mouse and human ESC towards endodermal/pancreatic lineages. Their expanded 35 day protocol is sumarized in this figure from the paper.

The result of this protocol was a relatively large population of cells that secreted all the right factors in response to all the right cues. And by relatively large population I mean 2-8% of the cells, which is despite seeming low is pretty huge in terms of making pancreatic islet cells (which, after all, are only about 1% of an adult pancreas).

Here are some immunfluorescence images from their 4th figure:

What you see here are little buds that are positive for all the appropriate proteins that one would expect to find in an islet, like c-peptide (marker for insulin), glucagon and somatostatin all localized to a single area. They could further purify these cells by just selecting by size, so you end up with a pure population of the little insulin secreting buds.

What does this mean for type I diabetes treatments? This is a very promising advance in the creation of islet cells from scratch. Such preparations could be scaled up, purified similar to the Edmonton protocol and used as a supply of islets to supplement or replace cadaverous donations. Further, the future holds the possibility of cells that could be engineered or selected to match to specific donor-HLA types (if we can expand the number of lines available to scientists), decreasing the risk of rejection and allowing more patients to receive transplants if they desire. Alternatively, tissue engineering technology could be pursued with the goal of creating "immunologically privileged" containers for these cells which could then be implanted into the body that allow small molecules like sugar and insulin through, but prevent attacks from the body's antibodies and immune cells, thus preventing rejection without continuous immunosuppression.

Whatever the future holds this is a significant advance towards the use of hESC in cell therapies.

References:
Shapiro, A.M. James, Lakey, Jonathan R.T., Ryan, Edmond A., Korbutt, Gregory S., Toth, Ellen, Warnock, Garth L., Kneteman, Norman M., Rajotte, Ray V. Islet Transplantation in Seven Patients with Type 1 Diabetes Mellitus Using a Glucocorticoid-Free Immunosuppressive Regimen. N Engl J Med 2000 343: 230-238

Cale N. Street, Jonathan R.T. Lakey, A.M. James Shapiro, Sharleen Imes, Ray V. Rajotte, Edmond A. Ryan, James G. Lyon, Tatsuya Kin, Jose Avila, Toshiaki Tsujimura, and Gregory S. Korbutt. Islet Graft Assessment in the Edmonton Protocol: Implications for Predicting Long-Term Clinical Outcome. Diabetes 53: 3107-3114.

Jiang, Jianjie , Au, Melinda , Lu, Kuanghui , Eshpeter, Alana , Korbutt, Gregory , Fisk, Greg , Majumdar, Anish S. Generation of Insulin-producing Islet-like Clusters from Human Embryonic Stem Cells. Stem Cells. First published online May 17, 2007.