by Monya Baker
A single added gene prompts liver progenitor cells to make insulin and reverse diabetes
With the introduction of a single gene, cells in the liver can take on the function of pancreatic cells and go on to reverse symptoms of diabetes in a mouse model of the disease. Researchers led by Lawrence Chan at Baylor College of Medicine in Houston, Texas, had already shown that they could, in effect, cure diabetes in mice by infecting their livers with a virus containing the gene for neurogenin (Ngn3), a transcription factor that is expressed as cells begin differentiating into insulin-producing beta-cells, the type of cells lost in juvenile diabetes. Although the researchers knew that this process worked, they did not know why, so they began trying to figure out which cells in the liver began producing insulin.
Careful lineage-tracing studies implicated two types of cells1. The first were hepatocytes — mature cells that made insulin only for about six weeks after infection. The other, more stable source of insulin-producing cells were liver progenitor cells. These actually switched lineages and went on to form clusters of islet cells that resembled those that the pancreas would make normally after an injury. Further analysis showed that the liver cells were expressing a wealth of genes made in pancreatic lineages in general and in the insulin-producing beta-cells in particular.
"The phenomenon is certainly worth further investigation," says Kenneth Zaret, a cell biologist at the Fox Chase Cancer Center in Philadelphia. He says that Chan's work is similar to that of other researchers who showed that adding genes for transcription factors can change cell differentiation2, 3. "However, it differs in discovering that the more stable target in the target tissue is not the terminally differentiated cells, here the hepatocyte, but rather an apparent facultative progenitor cell."
Chan believes that fully developed hepatocytes are not capable of transdifferentiating, or switching from one mature cell type to another. However, the progenitor cells are at a "weak point" in their differentiation pathway, in which their default lineage can be transdetermined to another lineage. Liver and pancreas are both endoderm organs, and some molecules expressed early in their development are the same. "I believe that the more closely the cells are related to the endocrine pancreas lineage, the more likely they will be 'pushed' into the beta-cell lineage," Chan explains.
Several factors may be doing the pushing. "My sense is that the success of the experiments is due to the convergence of multiple stimuli," says Zaret. In addition to the Ngn3 transcription factor, he says, other conditions, particularly the viral infection could be necessary to stimulate the nascent beta-like cells to proliferate.
Chan believes that this approach of causing progenitor cells to switch lineages may have more general applications. "Induced transdetermination may be easier to accomplish than induced transdifferentiation, if one can identify the receptive cell lineage," he says. Thus, 'receptive' progenitor cells could be a viable target to regenerate organs in multiple diseases, including but not limited to diabetes.
Source: Nature