LA JOLLA, Calif. , February 19, 2006
Researchers collaborating at the Burnham Institute for Medical Research and the Rebecca and John Moores Cancer Center at the University of California at San Diego have shown that endocrine progenitor stem cells exist in the adult human pancreas, and they have demonstrated that these stem cells can be transformed into insulin-producing cells. These findings, to be published in the March 1 edition of Nature Medicine, advance a major, long-range goal in developing new therapies for the treatment of diabetes, based on transplantation of insulin-producing cells and suggest a new approach to treating diabetes by transforming adult progenitor cells residing within the pancreas into insulin-producing cells.
Both type 1 and type 2 diabetes are characterized by the loss and dysfunction of insulin-producing cells, also known as beta cells. Beta cells reside in the pancreatic islets, which comprise less than 2% of the pancreas. Although the success rate for islet transplantation has improved, it remains an experimental treatment for diabetes, due to the shortage of islet cells and other complications. The development of beta cell transplantation therapies is the focus of intensive study among medical scientists working on diabetes.
In the current study, researchers developed rigorous purification and cell culture techniques and used them to cull adult human pancreatic cells, incapable of producing insulin, which they termed "non-endocrine pancreatic epithelial cells", or NEPECS. To determine whether this cell population could be induced to produce insulin, they labeled the NEPECS with genetic markers and mixed them with developing pancreatic cells known to be a rich source of endocrine progenitor cells and growth factors that induce the progenitor cells' development into insulin-producing beta cells. The cells were then transplanted into mice, and after three months tissue from the mice was examined. It was found that the NEPECS labeled with the genetic marker did, in fact, include insulin-producing beta cells.
"We hypothesized that the inductive factors in developing pancreatic cells might work on cells in the adult pancreas and that turned out to be true," said Fred Levine, M.D., Ph.D., Adjunct Professor at the Burnham, project director and senior author on this paper. "We have shown, in as rigorous a manner as possible, proof-of-concept for the existence of progenitor stem insulin-producing cells within the adult human pancreas. Our proven ability to transform these progenitor stem cells into insulin-producing cells greatly expands the possibility that beta cell regeneration therapies can be developed for the treatment of diabetes. Prior to our study, it was thought that replication of beta cells arising from injury to the pancreas was the only regenerative source of beta cells in the adult pancreas. We now know that we have another, potentially more abundant, reservoir."
The team working on this project, led by Drs. Levine, Itkin-Ansari, and Mercola, indicate that the next phase of this project will focus on isolating and characterizing the growth factors that transformed NEPECS into insulin-producing, beta cells and determining whether all or a subset of the NEPECS are the progenitors of these insulin-producing beta cells.
Authors contributing to this publication:
Fred Levine, M.D., Ph.D., is Professor at the Rebecca and John Moores Cancer Center and Department of Pediatrics at the University of California San Diego where he is a clinical geneticist. Dr. Levine's laboratory is at the Burnham Institute for Medical Research ("the Burnham"), where he has an adjunct appointment.
Ergeng Hao, Ph.D. and Bjorn Tyrberg, Ph.D., who share first authorship on this paper, work in Dr. Levine's laboratory at the Burnham. Dr. Hao isolated islet cells, performed transplantations, and helped develop culture methods. Dr. Tyrberg performed histological analyses.
Pamela Itkin-Ansari, Ph.D., Assistant Professor, Department of Pediatrics, University of California San Diego, and Adjunct Assistant Professor at the Burnham. Dr. Itkin-Ansari has partnered with Dr. Levine for many years. On this project, she helped to supervise the project, helped to develop a method for cell fusion and helped carry out those and other experiments.
Maria Barcova, Ph.D., works with Mark Mercola Ph.D., Professor in the Stem Cells and Regeneration Program at Burnham Institute for Medical Research. Dr. Barcova developed genetic marking vectors for this study. Dr. Mercola was co-principal investigator on a grant that supported this project from the Juvenile Diabetes Research Foundation.
Jonathan R.T. Lakey, Ph.D., Director of Human Islet Isolation Laboratory at University of Edmonton, Canada. Dr. Lakey's laboratory provided the vast majority of the human pancreas cells used for the project.
Edward Monosov, Ph.D., Director, Cell Imaging and Histology at the Burnham. Dr. Monosov performed imaging and labeling experiments.
Ifat Geron, technician, is at the University of California San Diego.
This research was supported by grants from the National Institutes of Health, the Juvenile Diabetes Research Foundation, the Beta Cell Biology Consortium, and the Larry L. Hillblom Foundation.