Scientists at the Gladstone Institutes and the University of California, San Francisco, have managed to convert human skin cells into fully functioning, insulin-producing pancreatic cells. The new study in Nature Communications reveals that this novel approach to cellular reprogramming not only works, but has the potential to be scaled up in order to produce trillions of these cells in a careful, controlled manner, helping to treat those who suffer from diabetes.
A key area of what is known as “translational” research – taking findings in medical research and making them practical and meaningful to patients – is the generation of insulin-producing pancreatic cells. In order to achieve this, previous researchers have used stem cells, undifferentiated cells that can potentially be forced to become more specialized cells. Heart, brain, and liver cells have all been created in this way.
In this case, the researchers hoped to try a new technique in order to make the conversion process more efficient. First off, human skin cells – an abundant, easily accessible source of human tissue – were chosen. By using carefully chosen pharmaceutical chemicals, among others, the skin cells were immatured into what are known as endoderm progenitor cells.
The endoderm is one of the primary layers on a very young human embryo; “progenitor” cells are those that can transform into other types of cell. Although similar to a “pluripotent” stem cell, which can become any cell that can be found in the human body, these progenitor cells are already somewhat differentiated, meaning they are already programmed to become a specific target cell.
By not immaturing the skin cells all the way back to the most basic pluripotent stem cells, the scientists could then coax them into becoming pancreatic cells faster than ever before. Using additional initiating chemicals, the endoderm progenitor cells began to divide incredibly rapidly, eventually reaching a trillion-fold replication rate.
Although cancer is essentially the uncontrollable division of cells, these cells did not exhibit any evidence of malignant tumor formation, maintaining their identity as organ-specific progenitor cells. After a little more chemical coaxing, these cells were directed to become first pancreatic precursor cells and then fully functioning pancreatic beta cells – those that store and release insulin.
A mouse’s pancreatic islet containing beta cells (green). The unit used for the scale here is micrometers: one-millionth of a meter. Tryphon/Wikimedia Commons; CC BY-SA 3.0
“The final step was the most unique – and the most difficult,” said lead author Saiyong Zhu, a postdoctoral researcher at the Gladstone Institute of Cardiovascular Disease, in a statement. In this procedure, molecules included various inhibitors and encouragers of various biochemical signaling processes. “Molecules had not previously been identified that could take reprogrammed cells the final step to functional pancreatic cells in a dish,” Zhu added.
These cells are normally found in the islets of Langerhans, the regions of the pancreas that contain its hormone production cells. In order to test how compatible these laboratory-grown variants were, they were implanted into the pancreases of mice. The mice’s glucose levels were then altered by the researchers, who then observed how their body responded. Remarkably, these cells were perfectly effective, producing insulin in response to rising glucose levels.
Sheng Ding, a senior investigator in the Roddenberry Stem Cell Center at Gladstone and co-senior author on the study, added: “This development ensures much greater regulation in the manufacturing process of new cells. Now we can generate virtually unlimited numbers of patient-matched insulin-producing pancreatic cells.”
Future experimentation will be required to assess their applicability for use in human patients suffering from diabetes, but for now, this is an incredible medical accomplishment.