We’ve been told by biology textbooks that the identity of an adult cell always remains fixed during differentiation. That is to say, when it has been decided by DNA as to what type of cell it’s going to create, the role of this cell generally does not change in the rest of its life. However, in a new study, researchers from the University of Geneva, Switzerland (UNIGE), for the first time, induced the production of insulin in human pancreatic cells that does normally produce non-insulin (namely, hormones other than insulin) after changing their function. The insulin is produced in a sustained manner, confirming that human cells is much more adaptable than previously thought. Moreover, this potential of changing cell function is not unique to human pancreatic cells. Relevant findings of the study were published online February 13, 2019 in Nature, titled "Diabetes relief in mice by glucose-sensing insulin-secreting human alpha-cells".

The human pancreas contains several types of endocrine cells (α, β, δ, ε, and Υ) that produce different hormones to regulate blood sugar levels. These cells clump together to form smaller clusters of cells called islets. When blood glucose levels are no longer controlled in the absence of functional beta cells, diabetes is produced. Professor Pedro Herrera of the University of Geneva School of Medicine and his team have confirmed in mice that the pancreas can regenerate new insulin-producing cells through a mechanism that spontaneously alters the identity of other pancreatic cells. But does this work the same in human body? Is it possible to artificially promote this transformation?

From one hormone to another, it’s usually a long-term change. To explore whether human cells have this ability to adapt, the Herrera team uses islets from diabetic donors and non-diabetic donors. They first classified different cell types, focusing on two of them: alpha cells (cells that produce glucagon) and sputum cells (cells that produce pancreatic polypeptide). Herrera explains, “We divided the cells we obtained into two groups: in one group of cells, we introduced only one fluorescent cell tracer, and in another group, we added a gene of β-cell-specific insulin transcription factor."

These researchers then reconstructed "pseudo-islets" with a cell type to accurately study their behavior. Kenichiro Furuyama, the lead author and a researcher in the Department of Genetics at the University of Geneva School of Medicine, have observed for the first time that cells clump together and even form single-type pseudoislets, promoting the expression of certain genes associated with insulin production, just like these non-β cells have naturally detected that other types of cells in islets does not exist. However, in order for these cells to start producing insulin, they have to artificially promote one or two key beta cell gene expressions. One week after the start of the experiment, 30 % of alpha cells produce and secrete insulin under glucose stimulation. Under the same treatment, sputum cells produce and secrete insulin more efficiently.

In the next experiment, these researchers transplanted the pseudotyped islets produced by these genetically modified human alpha cells into diabetic mice. Pleasant facts have been observed that these mice have recovered! As expected, when these human cell transplants are removed, these mice are again suffering from diabetes. Cells from diabetes donors and non-diabetic donors achieved the same results, indicating that the ability to change cell function is not impaired by the disease. In addition, it can work for a long time: these genetically modified pseudoislets persist after 6 months of transplantation.

A detailed analysis of these genetically modified cells that become insulin-producing cells indicates that they remain close to the cellular identity of alpha cells. Autoimmune diabetes (i.e., type 1 diabetes) is characterized by the destruction of insulin-producing beta cells by the patient's immune system. Given that these genetically modified alpha cells are different from beta cells, these researchers then wondered if these alpha cells would also be damaged by autoimmune responses. To test their resistance, they co-cultured these alpha cells with T cells from patients with type 1 diabetes. They found that these genetically modified alpha cells trigger a weaker immune response, so they are less susceptible to damage than native beta cells.

Today, pancreas transplantation (by transplanting the entire pancreas or preferably only islets) is performed in very severe diabetic patients. This technique is very effective, but it has its limitations: as with any transplant, it is combined with immunosuppressive therapy. Even so, these transplanted cells disappeared after a few years.

Herrera emphasizes that the idea of using the intrinsic regenerative capacity of the human body is meaningful in this study. However, there are many obstacles before appropriate treatment are developed based on these findings. This path will be long and arduous, for sure.

Reference:
Kenichiro Furuyama et al. Diabetes relief in mice by glucosesensing insulin-secreting human α-cells. Nature, 2019, doi:10.1038/s41586-019-0942-8.

Author's Bio: 

This article is written by scientists at Creative Peptides, a company that offers various peptides for diabetes research, including: Amylins Fragments (IAPP), Chromogranin A/ Pancreastatin, Exendins Fragments, Insulin C-Peptides, Insulin-Like Growth Factors Fragments (IGF), Glucagons and Glucagon-Like Peptides (GLP-1 / GLP-2), Gastric Inhibitory Polypeptide and Fragments, Ghrelin Peptides, γ Secretase Inhibitors, β Secretase Inhibitors, etc.