An important step towards the cure of type 1 diabetes

Another success of Dr. Dean: fibroblasts are reprogrammed
in insulin-producing cells of the pancreas

LifeSciencesToday based on Gladstone Institutes: Scientists Reprogram Skin Cells into Insulin-Producing Pancreas CellsScientists do not yet know how to cure type 1 diabetes.

Not because they don't know what to do, but because they don't have the necessary tools in their hands yet. However, recently, scientists at the Gladstone Institute have developed a method that potentially makes it possible to replenish the mass of pancreatic cells that die in type 1 diabetes. The results achieved by American researchers, published in the journal Cell Stem Cell (Ke Li et al., Small Molecules Facilitate the Reprogramming of Mouse Fibroblasts into Pancreatic Lines), is an important step towards ridding millions of patients of insulin injections, vital for this disease.

The cause of type 1 diabetes, which usually develops in childhood, is the death of beta cells of the pancreas that produce the hormone insulin. Without insulin, tissues cannot absorb sugars in the blood, such as glucose. With a disease that used to be equivalent to a death sentence, you can now live by monitoring blood glucose levels and regularly receiving insulin injections. However, a more reliable solution to the problem would be to replace the dead beta cells. But these cells are difficult to obtain, and scientists are hopeful about cell technology as a method of creating them.

"The power of regenerative medicine is that it can provide an unlimited source of functional insulin-producing beta cells that can be transplanted to a patient," says Sheng Ding, professor at the University of California, San Francisco, UCSF. "But previous attempts to obtain large amounts of healthy beta cells - and to develop a technological delivery system – have so far failed. Therefore, we used a slightly different approach."

Dr. Dean's work is based on the methods of cellular reprogramming Shinya Yamanaka, MD, PhD. The development of a method for transforming adult skin cells into so-called induced pluripotent stem cells with the properties of embryonic stem cells, which earned Dr. Yamanaka the Nobel Prize, radically expands the field of cell biology and stem cell research. In the new study, Dr. Dean focused his attention on reprogramming skin cells into beta cells of the pancreas using the existing iPSCs technology, but brought his own "highlight" to this method. Using a unique chemical cocktail of small molecules and other reprogramming factors, Dr. Dean does not "allow" cells to go into a state of pluripotence. This avoids the potential danger that when used to replace or repair damaged organs or tissues, some pluripotent cells – genetic "evaders" – will develop into a tumor. In addition, this method makes it possible to create a much larger number of cells for scientific research or regenerative medicine.

One of the main problems in obtaining large quantities of beta cells is that cells of this type have a limited ability to regenerate. If they have reached maturity, their number is difficult to increase. Therefore, Professor Dean and his colleagues decided to return beta cells to a state corresponding to the previous stage of their life cycle.

Taking the skin cells of laboratory mice (fibroblasts), the scientists treated them with a unique "cocktail" of molecules and reprogramming factors and transformed them into cells close to endodermal – DELCs (definitive endoderm-like cells). Endodermal cells are a type of early embryo cells from which most organs eventually develop, including the pancreas.

"Then, using another chemical cocktail, we transformed these endoderm-like cells into cells that mimic cells of the early stage of pancreatic development, which we called PPLCs (pancreatic progenitor–like cells)," says postdoctoral researcher Ke Li, PhD, lead author of the article.

"Our initial goal was to find out if we could direct the development of PPLCs into mature cells that, like beta cells, respond to the right chemical signals, and, most importantly, secrete insulin. And our first experiments in a Petri dish showed that they can do it."

Then the scientists had to make sure that the same thing happens in live animal models. So they transplanted their PPLCs into mice with a model of hyperglycemia (high blood sugar) – a key sign of diabetes.

"It is important to note that just a week after transplantation, the glucose level in the animals began to decrease, gradually approaching normal," Dr. Lee continues. "After removing the transplanted cells, we saw an instantaneous release of glucose, which indicated a direct link between PPLCs transplantation and a decrease in hyperglycemia."

Diagram from an article in Cell Stem Cell

But the scientists saw the most significant changes eight weeks after transplantation: PPLCs gave rise to fully functional insulin-producing beta cells.

"These results not only demonstrate the possibilities of low-molecular compounds in cellular reprogramming, but also confirm the validity of the concept, which one day can be used as a personalized therapeutic approach to the treatment of patients," explains Professor Dean.

"I am particularly concerned about the prospects of translating these results into a human model," says Matthias Hebrok, director of the UCSF Diabetes Center, PhD, one of the authors of the article. "Now this method will significantly deepen the understanding of how hereditary defects of beta cells can lead to diabetes, significantly bringing us closer to the much-needed methods of curing this disease."

Portal "Eternal youth" http://vechnayamolodost.ru10.02.2014