Inducing an identity crisis in liver cells may help diabetics
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 at the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) has now accomplished this feat in mice. Their results should make it feasible to help diabetic patients through cell therapy.
A new, fully functional pancreas is probably something all diabetics dream of, especially those suffering from type I diabetes. In this form of the disease, the pancreas loses a type of cell called islet cells and ceases to produce the hormone insulin. The loss is due to an autoimmune reaction where the body turns against its own tissues. Without insulin, blood glucose rises to dangerous levels, which then leads to diabetes. Patients need to inject insulin for the rest of their lives to alleviate the life-threatening symptoms of the disease.
Searching for a suitable source of renewed pancreatic cells
How might one provide long-term help for diabetics? The key may be cell therapy, explains MDC group leader and researcher Dr. Francesca Spagnoli. “We may be able to grow new pancreatic cells outside of the body and then return them to the patient, where they would restore the lost function of the islet cells.”
This is a 3D map of liver and pancreatic buds in a mouse embryo. Cells of the pancreas are marked in red and green, while liver cells appear in blue.
The researcher has been pursuing the idea of reprogramming liver cells to become pancreatic cells by modulating the activity of certain genes. “The liver and pancreas are closely related organs,” Spagnoli says. “They develop from the same tissue in the embryo, and there is significant overlap in their genetic programs.”
Scientists have already been able to outfit hepatic (liver) cells with certain pancreatic functions. However, the performance of these hybrid cells is a far cry from how actual pancreatic cells work.
A single gene to turn liver cells into cells of the pancreas
Dr. Spagnoli’s team has now succeeded in thrusting liver cells into an “identity crisis” – in other words, reprogramming them to take on a less specialized precursor state – and then triggering their redevelopment into cells with pancreatic properties. Their results appear in the current issue of the journal Nature Communications.
A gene called TGIF2 has a crucial role in the reprogramming process. Years ago, Dr. Spagnoli discovered that TGIF2 is active in the tissue of the pancreas but not the liver. In the current study Dr. Nuria Cerda Esteban, then working as a PhD student in Dr. Spagnoli’s lab, tested how cells from mouse liver behave when they are given additional copies of the TGIF2 gene, causing them to produce TGIF2 protein.
TGIF2 distinguishes the identities of liver and pancreatic cells
In the experiment, the hepatic cells first lost their hepatic properties, then gained properties found in cells of the pancreas. They even clustered into small, pancreas-like “organoids”. Next the researchers implanted the modified cells into an intact pancreas. There, the cells not only began to produce insulin, but also digestive enzymes that are characteristic of natural pancreatic cells.
“These experiments give us insights into an interesting detail of the embryonic development of the two organs,” Spagnoli says. “TGIF2 alone seems to be sufficient to determine whether a precursor cell specializes to become a cell of the liver or the pancreas.”
This is an organoid that was generated with the pancreatic progenitor cells obtained through Tgif2-mediated lineage reprogramming.
In a final step, the researchers transplanted the modified cells into diabetic mice. Shortly after transplantation, the animals’ experienced an improvement in blood glucose levels – indicating that the cells were successfully fulfilling the functions of the lost islet cells. These results bring scientists one step closer to developing cell therapies for humans suffering from diabetes type I.
Using liver cells has significant advantages for application
Obtaining cells from the liver would have an important advantage in cell therapies: The organ regenerates itself quickly and easily, thus providing a virtually unlimited pool of cells that can be harvested.
There might be several other ways to achieve the same goal. The most explored avenue has been to grow pancreatic cells from stem cells, but the use of this strategy may be limited in humans because of the cells’ potential of developing into tumors. Researchers might also try to remove part of a patient’s pancreas, modify the tissue in the lab, and then return it. But the organ is delicate and highly sensitive to injuries, making it tricky to obtain the source material that would be needed.
The findings offer a way into therapy
The obvious next step is to translate the lab’s findings from mice to humans. The Spagnoli lab is currently testing the strategy on human liver cells in a project that received funding in 2015 from the European Research Council. “There are differences between mice and humans, which we still have to overcome,” Spagnoli says. “But we are well on the path to developing a ‘proof of concept’ for future therapies”.
“One day it may also be possible to specifically modulate the activity of TGIF2 with drugs,” the researcher says. “But this is still up in the air, since nobody knows exactly how TGIF2 works in the cell.” Clarifying that question is another current project of her lab.
Text: Martin Ballaschk
Nuria Cerdá-Esteban1, Heike Naumann1, Silvia Ruzittu1, Nancy Mah2,3, Igor M. Pongrac1, Corinna Cozzitorto1, Angela Hommel4, Miguel A. Andrade-Navarro2,5, Ezio Bonifacio4, Francesca M. Spagnoli1 (2017): “Stepwise reprogramming of liver cells to a pancreas progenitor state by the transcriptional regulator Tgif2.” Nature Communications. doi:10.1038/ncomms14127
1Laboratory of Molecular and Cellular Basis of Embryonic Development, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany. 2Computational Biology and Data Mining, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany. 3BCRT, Charité – Universitätsmedizin Berlin, Berlin, Germany. 4DFG-Center for Regenerative Therapies Dresden, Technische Universität Dresden, Dresden, Germany. 5Faculty of Biology, Johannes Gutenberg University Mainz and Institute of Molecular Biology, Mainz, Germany.
