UF Stem Cell Researchers Successfully Treat Diabetes In Mice By Coaxing Cells To Change

March 22, 2004

GAINESVILLE, Fla. — University of Florida adult stem cell experts have restored normal blood sugar levels in diabetic mice for three months by chemically coaxing bone marrow cells to produce insulin, a hormone normally made in the pancreas.

The findings, reported today in the online edition of the journal Laboratory Investigation, demonstrate the continued importance of adult stem cell research and may one day help doctors combat a form of diabetes in people, said senior author Bryon Petersen, an assistant professor of pathology, immunology and laboratory medicine at UF’s College of Medicine. But crucial questions about the treatment’s potential may take another decade to answer.

“This is a preliminary study conducted in animals with diabetes,” Petersen said. “But I think it’s a very profound study, since it shows that adult stem cell plasticity still exists and that if we understand how we can get a cell to differentiate, we can actually teach an old dog some new tricks.”

The study was funded by grants from the National Institutes of Health and other sources totaling $2 million.

Stem cells change into other types of cells, a process called differentiation, Petersen said. Human embryos contain large quantities of embryonic stem cells needed for tissue development. After birth, another type called adult stem cells are produced that act to repair the body. Experts disagree about the potential medical value of adult stem cells.

“There are still a lot of questions that we need to answer in the different facets of stem cell research,” Petersen said. “Everybody tends to give the pat answer that clinical applications of stem cell technology are at least 10 years down the road. The way the field is moving, it may be 10 years, it may be sooner.”

UF researchers conducted the study on bone marrow stem cells obtained from adult rats, he said. Using a unique chemical process, the reseachers induced laboratory cultures of cells to form clusters that produced insulin and three other hormones usually made only in the pancreas by structures called the islets of Langerhans. When the clusters were implanted in nine diabetic mice, the animals’ blood sugar levels dropped from about 550 milligrams per deciliter to 200 milligrams per deciliter and remained stable for three months. The mice were fed the same diet throughout the study.

“Whether or not these (clusters) are full, mature islets remains to be seen,” said Petersen, who also is associated with the UF College of Medicine’s Program in Stem Cell Biology and Regenerative Medicine. “But they are (similar) enough that they will play by the same rules as a normal islet would in the pancreas.”

Petersen and lead investigator Seh-Hoon Oh, a UF research associate, hope to get similar results in a future study using laboratory cultures of human bone marrow stem cells or umbilical cord blood cells, Petersen said. Eventually, the treatment could be useful against type 1 diabetes, a disease in which the immune system attacks the islets of Langerhans and destroys them, reducing the body’s supply of insulin. The hormone is needed to convert sugar and starch into energy.

Type 1 diabetes accounts for 5 percent to 10 percent of America’s 12 million diagnosed diabetes cases, according to the American Diabetes Association. Its cause is unknown but both genetics and environmental factors may play a role. The disease, usually diagnosed in children and young adults, almost always must be controlled with daily shots of insulin. Complications can include heart disease, blindness, nerve damage and kidney damage.

The UF study suggests that eventually it may be possible to take bone marrow from a person, put it in culture, turn it into islet cells and then return it to the same person as an islet cell transplant, said Dr. Neil Theise, an attending physician in the departments of pathology and medicine at Beth Israel Hospital in New York who is considered an expert on adult stem cells.

Dr. James Crawford, chairman of the UF pathology department and editor-in-chief of Laboratory Investigation, said, “These promising results just add to the growing evidence that adult stem cells may be a critically important source of treatment options for patients with debilitating diseases in which normal tissues are destroyed.”

UF researchers hope that adult stem cells will lead to a diabetes treatment that does not involve the danger of tissue rejection, a major obstacle to current type 1 diabetes therapies using transplanted islets of Langerhans, Petersen said. Additional research is needed to explore whether the cell clusters mimic natural islets too effectively for their own good – the diabetic mice used in the current study were genetically altered and had no immune system, so their bodies could not mistake the cell clusters for islets and attack them.

“As much as I would like to be able to go to a clinical trial tomorrow, we’re not ready,” Petersen said.

The study began with removal of bone marrow cells from the long leg bones of about 30 rats. The stem cells were then separated from other cells using a chemical bath, collected and cultured in a solution containing either large or small amounts of glucose, a type of sugar.

When the cell clusters formed, researchers confirmed production of the hormones using seven tests. In the study’s second phase they implanted about 150 cell clusters each into nine diabetic mice, under a membrane that surrounds each kidney. Within two to three days blood glucose in the mice began to reach normal levels. After another two weeks, the clusters were removed from six of the mice and those animals’ blood glucose levels increased, suggesting the cell clusters were responsible for the normalizing effect, Petersen said.

Mice that retained the cell clusters maintained fairly normal blood glucose levels until the study ended after 90 days, and the animals appeared capable of producing the insulin indefinitely, Petersen said. Two control groups totaling 13 diabetic mice did not receive cell cluster implants and continued to have abnormally high blood glucose levels.

Oh designed the study, inspired by previous UF research showing that rat liver stem cells could be coaxed into producing insulin. Both Oh and Petersen are named in a patent application for the technology, filed in October.