SAN DIEGO — Researchers at the University of California, San Diego, and the Burnham Institute for Medical Research claim to have engineered a cell line that very closely mimics a true beta cell, while additional work by the same group screened primary human pancreatic cells that contain a stem cell-like population.
Pamela Itkin-Ansari, an assistant professor of pediatrics at UCSD and the Burnham Institute led the project. She said that her team developed a cell line that mimics characteristics of endogenous beta cells closely enough that they are using it to screen for drugs that reverse beta cell toxicity or turn cells in vitro into beta cells.
Speaking at the annual Assays and Cellular Targets meeting, held here last week, Itkin-Ansari said that she and a colleague are currently performing high-content screens on these primary cells to find drugs that can differentiate those cells into beta cells.
“We have developed an assay, and we are looking for a drug that will induce pancreas duodenum homeobox-1 (PDX-1) transcription in non-endocrine pancreatic cells,” Itkin-Ansari said during her presentation at the conference, adding that the evaluation of promising leads is ongoing.
Itkin-Ansari and colleague Fred Levine, a professor of pediatrics at UCSD and the Burnham Institute, published their initial report on the existence of stem cells in the adult human pancreas in the March 1, 2006, issue of Nature Medicine.
According to Itkin-Ansari, the Nature Medicine study used pancreatic material normally discarded during the islet transplantation process. Islets comprise only about 1 percent of pancreatic tissue, she said.
Itkin-Ansari and her group have engineered a human islet cell line, called TRM-6, which very closely mimics a true beta cell in several ways. The investigators are able to induce a 100-fold increase in insulin gene expression in that cell line, Ansari said. So if they find drugs that increase insulin gene expression, then those drugs could potentially be given to patients with type 2 diabetes or even be used in the laboratory to induce embryonic stem cells to differentiate into beta cells.
“In addition, when we induce this 100-fold increase in insulin gene expression, the TRM-6 cell line stops growing,” said Itkin-Ansari, adding that normal beta cells do notgrow rapidly.
Endogenous beta cells also stop growing as they becomes more differentiated, which Itkin-Ansari said her group sees as a very good sign that the TRM-6 cell line closely mimics true beta cell biology.
“What this cell line allows us to do is also screen for small molecules that would induce this very beta cell-like cell line to grow again,” said Itkin-Ansari. “If we could find a drug that induced beta-cell replication, we could potentially grow beta cells in the lab.”
“Drugs that increase insulin gene expression could be given not only to type 1 diabetes patients, if they have remaining beta cells, but also to type 2 diabetes patients who often have toxicity to their beta cells.”
That drug could be given not only to type 1 diabetes patients, if they have remaining beta cells, but also to type 2 diabetes patients who often develop toxicity to their beta cells, said Itkin-Ansari.
“We are looking for drugs that induce replication, and we have actually identified one hit and are doing further screens to find more,” said Itkin-Ansari.
Type 2 diabetes manifests with a peripheral resistance to insulin, which eventually leads to high blood glucose and fat levels. This in turn causes gluco- and lipotoxicity to beta cells.
“We found that the TRM-6 cell line responds to lipotoxicity just like a primary beta cell,” Itkin-Ansari said. She said her team is now running screens to find drugs that reverse the lipotoxicity on this cell line with the hope that those drugs would be useful in type 2 diabetes patients.
Itkin-Ansari told CBA News this week that although her group has not yet screened for hits that reverse glucotoxicity, it may do so in the future.
Itkin-Ansari also mentioned during her presentation in San Diego that her group has developed a very robust RNAi screen using one of its TRM-6 cell lines. That work follows a completely different path because the cellular target is already identified.
She said her group is not currently participating in any collaborations with pharmaceutical or biotech companies, but would be interested in entering into such agreements in the future to move its hits toward clinical usefulness.