Researchers discover stem cells that can generate insulin-secreting cells

Researchers at Massachusetts General Hospital (MGH) have discovered stem cells within the pancreatic islets of Langerhans that can generate insulin-secreting cells (beta cells). In Type 1 diabetes, which affects one percent of Americans, the body's immune system attacks the islet beta cells, resulting in insufficient insulin. This discovery reported in the March issue of Diabetes may eventually help to make islet transplantation become a standard treatment of diabetes.

Prior to this study, scientists believed that precursors of islet cells existed only in pancreatic ducts and, when exposed to growth factor stimuli, would differentiate into new islet cells that would then migrate and form islets. Additionally, scientists thought that all the types of cells in the pancreatic islets had been identified, says study co-author Joel F. Habener, MD, of the MGH Laboratory of Molecular Endocrinology and a Howard Hughes Medical Institute Investigator

The research team had several clues to the existence of islet stem cells. In previous experiments, they had given rats growth factors, such as glucose or a glucagon-like peptide, which are known to induce differentiation. Within 72 hours, cell mass in the islets doubled, suggesting that stem cells were present in the islets and had been stimulated to differentiate. Now they needed to look for stem cells � or at least their paper trail.

During the early embryonic development of mammalian embryos, developing islet cells share features with developing neural cells. A special characteristic of neural stem cells is their expression of the protein nestin. "Beta cells have very neuronal-like properties," Habener says. Perhaps, the researchers theorized, nestin occurs in the pancreatic islets, and, if so, stem cells might also be present. Henryk Zulewski, MD, who was a postdoctoral fellow with the lab at the time, jumped on the project and set up experiments to hunt for these stem cells. He and fellow researcher, Elizabeth J. Abraham, PhD, who took over the experiment when Zulewski finished his fellowship, contributed equally to this study. The researchers found the stem cell marker nestin within developing islet cells. Using additional tests, they established that these cells contained nestin and were a newly identified cell type within the pancreatic islets: nestin-positive islet-derived progenitor cells (NIPs). (Later, the investigators also detected nestin-positive in the pancreatic ducts of adult rats and, thus, confirmed that stem cells were in the ducts.)

"Zulewski got the idea of growing these cells out," Habener says. Their lucky break came when the cells did, in fact, grow out. In about four weeks, the investigators picked out the new cells and exposed them to a proliferative media. If they were indeed stem cells, the research team expected to see the cells proliferate greatly�which they did. They removed the cells from that media and exposed them to a differentiation media. The cells converted into islet cells and started expressing the master regulator of beta cells that turns on the insulin gene. These cells began producing insulin.

"Stem cells are very distinct from other cells. They have projections and move around a lot [within tissues]," Habener says. "Stem cells have an incredible capacity to migrate. The stem cells crawl around like bloodhounds with their receptors sniffing for a morphogen�or chemical cue�that they like." Sure enough, these NIPs showed a penchant for motility. Once stem cells find their niche, they differentiate when they sense the right amount of growth factors.

The MGH team wants to use time-lapse photography to see what the NIPs are doing. Eventually, they would like to know where these stem cells originate. Two possibilities are the nervous system and bone marrow. Islet cell transplantation techniques take advantage of pancreatic stem cells' dogged quality. Canadian researchers last year reported that seven patients who had Type 1 diabetes of long duration received larger than usual amounts of islets and were insulin-independent for up to 14 months. However, islet harvesting and transplantation techniques need more fine-tuning before becoming widely available. In addition, the supply of donor islets is greatly limited.

Down the road, NIPs taken from a patient's pancreas could possibly be grown in large quantities and returned to the patient. Genetic engineering of NIPs may eliminate the prospect of rejection and, in turn, the need for large doses of immunosuppresive drugs, given to prevent the immune system from destroying the islet cells but cause harmful side effects. This research may hold promise, Habener says, but a cure for diabetes is years away.

Other study co-authors from MGH are Melissa J. Gerlach, Philip B. Daniel, PhD, and Melissa K. Thomas, MD, PhD. The European co-authors are Wolfgang Moritz, PhD, of the University Hospital of Zurich; Beat Muller, MD, of University Hospitals in Basel, Switzerland; and Mario Vallejo, MD, PhD, of the Superior Council of Scientific Research in Madrid.

Established in 1811, Massachusetts General Hospital is the original and largest teaching hospital of Harvard Medical School. MGH conducts the largest hospital-based research program in the United States, with an annual research budget of almost $250 million and major research centers in AIDS, the neurosciences, cardiovascular research, cancer, cutaneous biology, transplantation biology and photomedicine. In 1994, MGH joined with Brigham and Women�s Hospital to form Partners HealthCare System, an integrated health care delivery system comprising the two academic medical centers, specialty and community hospitals, a network of physician groups, and nonacute and home health services.