Reprogramming of liver cells to pancreas progenitor cells based on a single factor

Reprogramming of liver cells to pancreas progenitor cells based on a single factor


It is now possible to reprogram cells from the liver into the precursor cells that give rise to the pancreas by altering the activity of a single gene. A team of researchers have now accomplished this feat in mice. Their results should make it feasible to help diabetic patients through cell therapy.

In patients suffering from type I diabetes, their immune system turns against their own bodies and destroys a type of pancreatic cell called islet cells. Without these cells, the pancreas is unable to produce the hormone insulin and blood glucose rises, which leads to diabetic disease. At that point, such patients need to inject insulin for the rest of their lives.

A way to provide a lasting help to the afflicted may be to grow new pancreatic cells outside of the body. The team has now succeeded in thrusting liver cells into an "identity crisis" -- in other words, to reprogram them to take on a less specialized state -- and then stimulate their development into cells with pancreatic properties.

A gene called TGIF2 plays a crucial role in the process. TGIF2 is active in the tissue of the pancreas but not in the liver. For the current study a graduate student tested how cells from mouse liver behave when they are given additional copies of the TGIF2 gene.

Hepatocytes expressing Tgif2 undergo extensive transcriptional remodelling, which represses the original hepatic identity and, over time, induces a pancreatic progenitor-like phenotype. Consistently, in vivo forced expression of Tgif2 activates pancreatic progenitor genes in adult mouse hepatocytes.

The researchers transplanted the modified cells into diabetic mice. Soon after this intervention, the animals' blood glucose levels improved, indicating that the cells indeed were replacing the functions of the lost islet cells. The results bring cell therapies for human diabetic patients one step closer to reality.

This study uncovers the reprogramming activity of TGIF2 and suggests a stepwise reprogramming paradigm, whereby a ‘lineage-restricted’ dedifferentiation step precedes the identity switch.

The obvious next step is to translate the findings from the mouse to humans. The lab is currently testing the strategy on human liver cells in a project funded in 2015 by the European Research Council. "There are differences between mice and humans, which we still have to overcome," senior author says. "But we are well on the path to developing a 'proof of concept' for future therapies."

Edited

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