Secret to diabetes cure rests with liver stem cells
By Ruth SoRelle, M.P.H.
Lawrence C.B. Chan, M.D., D.Sc., and his colleagues in his Baylor College of Medicine laboratory cured mice with type 1 diabetes in 2003 by using a gene to induce liver cells to make insulin.
It turns out that the mechanism behind that cure was much more elegant than they realized at the time.
Stem cells
"The answer is adult stem cells," said Chan, director of the federally designed Diabetes and Endocrinology Research Center at BCM and chief of the division of endocrinology in BCM’s department of medicine.
They introduced a gene called neurogenin3 that proved critical to inducing liver cells to produce insulin on a continuing basis, said Chan and Vijay Yechoor, M.D., assistant professor of medicine-endocrinology and first author of the report that appears in the current issue of the journal Developmental Cell. The research team used a disarmed virus called a vector to deliver the gene to the livers of diabetic mice by a procedure commonly known as gene therapy.
Fast response
"The mice responded within a week," said Yechoor. The release of insulin pushed their levels of circulating glucose to normal. It stayed normal for the rest of their lives. However, said Yechoor, that quick response posed a question as did the permanence of the cure.
What was happening? He and Chan continued their work.
Two-step response
They found that the gene prompted two kinds of activity – one short-lived and the other permanent. First, the neurogenin3 gene prompted the mature cell of the liver to make small quantities of insulin – just enough to reduce glucose levels in the blood to normal.
"This is a transient effect," Yechoor said. "Liver cells lose the capacity to make insulin after about six weeks."
New insulin-producing cells
Before the glucose levels could rise again, new cells appeared that made larger quantities of the hormone. These cells clustered around the blood vessels that carry blood from the intestines and abdominal organs to the liver.
"They look similar to normal pancreatic islet cells (that make insulin normally)," said Yechoor.
These cells actually originate from a small population of adult stem cells usually found near the portal vein. The body needs only a few because they remain dormant unless the liver is injured. Then this safety net of stem cells goes into action to replace the damaged liver tissue.
Islet cells in the liver
In this case, the neurogenin3 changes their fates. Instead of becoming liver cells, they enter a pathway that results in their becoming insulin-producing islet cells located in the liver. The mature liver cell cannot make this change because its fate appears to be fixed before exposure to neurogenin3.
The islet cells in the liver look similar to those made by the pancreas after an injury, said Yechoor.
Neurogenin3 is the key
"If we didn’t use neurogenin3, none of this would happen," he said. "Neurogenin3 is necessary and sufficient to produce these changes."
Chan cautioned that much more work is needed before similar results could be seen in humans. The gene therapy they undertook in the animals used a disarmed viral vector that could still have substantial toxic effects in humans.
Proof of concept
"The concept is important because we can induce normal adult stem cells to acquire a new cell fate. It might even be applicable to regenerating other organs or tissues using a different gene from other types of adult stem cells," he said.
Finding a way to use the treatment in human sounds easier than it is, he said. The environment in which cells grow appears to be an important part of the cell fate determination.
However, he and Yechoor plan to continue their work with the eventual goal of providing a workable treatment for people with diabetes.
Others who took part in this research include Victoria Liu, Christie Espiritu, Antoni Paul, Kazuhiro Oka and Hideto Kojima. (Kojima is now with Shiga University of Medical Science in Otsu, Japan.)
Funding for this work came from the National Institutes of Health, the NIDDK-designated Diabetes and Endocrinology Research Center at BCM, the Betty Rutherford Chair in Diabetes Research (held by Chan), St. Luke’s Episcopal Hospital, the Iacocca Foundation and the T.T. & W.F. Chao Global Foundation.
