Stem cell therapy for type 2 diabetes shows promise in mice

Treatment conducted at a Brazilian university reduces apoptosis in pancreatic islets, where insulin-producing cells are located.

By Karina Toledo

Agência FAPESP – After inducing the development of type 2 diabetes in mice that were fed a high-fat diet, researchers at the Federal University of São Carlos (UFSCar) in São Paulo State, Brazil, treated the animals with injections of mesenchymal stem cells.

This therapy led to a decrease in insulin-producing pancreatic cell death, an increase in insulin sensitivity, and a lasting reduction in blood sugar levels.

The experiment was conducted during Patricia de Godoy Bueno’s PhD research as part of a project supported by FAPESP and coordinated by Ângela Merice de Oliveira Leal, a professor in UFSCar’s Department of Medicine.

The results were published in the journal PLoS One in late April 2015.

“Mesenchymal cells are very interesting from the therapeutic standpoint because they have anti-inflammatory and immunomodulatory properties, besides being anti-apoptotic, meaning that they prevent cell death. They tend to migrate to inflamed tissues or joints. Another advantage is that the organism doesn’t react to them as if they are foreign bodies, so they don’t induce rejection,” Leal said.

Mesenchymal cells, which are present in multiple organs in both humans and rodents, support tissue survival and produce trophic factors that assure adequate nutrition for growth. They can be easily obtained from bone marrow or adipose tissue and can be grown in laboratory culture dishes.

“Mesenchymal cells are able to differentiate into other cell types, such as bone or cartilage cells. However, the studies performed so far suggest that in our case they probably don’t differentiate into pancreatic beta cells, which produce insulin. However, we believe that these cells instead secrete anti-inflammatory factors and reduce insulin resistance in peripheral tissues,” Leal said.

Study model

In type 2 diabetes, which is frequently associated with obesity, the pancreas produces even more insulin than is produced in healthy individuals, but the cells of peripheral tissues such as the liver, muscles and fat become insulin resistant, partly owing to inflammation induced by the molecules that are secreted by adipose tissue.

Pancreatic beta cells are also affected by inflammation and the overwork caused by insulin resistance. Their function is altered and over time they tend to progress toward apoptosis (programmed cell death), leading to a decrease in cellular mass.

“Many studies simulate type 2 diabetes by using genetically modified rodents or by administering a drug called streptozotocin, which destroys beta cells. However, that’s not how diabetes works in obese humans, so we induced the disease in mice simply by feeding them a high-fat diet,” Leal said.

The 60% fat diet was begun when the mice were four-weeks old. About eight weeks later, the mice had already presented with weight gain, insulin resistance, and hyperglycemia. They were then divided into two groups, one of which was treated with a placebo, while the other received four injections of mesenchymal cells at one-week intervals.

The researchers opted to use mesenchymal cells from rats rather than from mice because rat cells are easier to grow in the laboratory.

“We injected the cells into the peritoneal space, which is a relatively non-invasive form of administration,” Leal said. “Some studies infuse the cells intravenously, but this risks allowing the cells to migrate to the lungs and to cause a pulmonary embolism.” The peritoneum is a dual-layer membrane that lines the abdominal cavity and covers the viscera. The peritoneal space is the cavity between the layers.

The animals were evaluated weekly for a period of four months. By the end of the experiment, insulin sensitivity was approximately 30% higher and fasting glycemia had fallen 70% in the mice that were treated with stem cell therapy.

“We also evaluated the presence of a protein called caspase-3 in the pancreas, as this protein is involved in the cascade of chemical reactions that lead to apoptosis. We observed lower caspase-3 expression, suggesting less programmed cell death, in the animals treated with mesenchymal cells,” Leal said.

However, fasting serum insulin secretion was not altered in the treated group compared with the control group. According to Leal, the results suggest that glucose levels fell because of improved insulin action on peripheral tissues. The mechanisms underlying this effect are still being studied by her group.

“We’re investigating what happened in each tissue with regard to the action of insulin. We’re also testing the therapy in mice using human mesenchymal cells,” she said.

In another project, also supported by FAPESP and coordinated by Leal, the UFSCar research group is evaluating the effectiveness of mesenchymal stem cells for the treatment of diabetic neuropathy, a common complication of diabetes that causes nerve damage, pain, paresthesia (formication or burning, among other sensations) and the loss of sensitivity, especially in the feet and legs.

At least three clinical trials to evaluate the effectiveness of stem cell therapy for type 2 diabetes are in progress abroad. The UFSCar group, jointly with a team at the University of São Paulo’s Ribeirão Preto School of Medicine (FMRP-USP), submitted a human subject protocol for research on type 2 diabetes to CONEP, the national research ethics committee of Brazil, in 2012. The group is still awaiting a verdict.

“For the treatment of humans, it wouldn’t be ideal to use the diabetic patient’s own stem cells because there is evidence that hyperglycemia may affect the properties of these cells. We would have to resort to a different strategy,” Leal said.

The article “Metabolic and Pancreatic Effects of Bone Marrow Mesenchymal Stem Cells Transplantation in Mice Fed High-Fat Diet” (doi: 10.1371/journal.pone.0124369) by Ângela Leal et al. can be read at http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0124369.