A team of scientists has succeeded in coaxing mature human cells to be reprogrammed into a type of liver cell that can repopulate the organ after liver failure in a mouse model. Researchers have been searching for cell‑based alternatives to liver transplantation because of the limited supply of donor organs. It would be ideal to use cells from an individual’s other healthy tissues to repopulate the diseased liver, but mature cells are usually terminally committed in their specific roles and cannot switch to performing the part of a liver cell. On the other hand, so-called induced pluripotent stem cells, created by reprogramming mature cells all the way back to a stem-cell-like state, have shown promise. These cells, however, have been unable to proliferate adequately in vivo and can also carry a risk of producing tumors.
Now researchers seem to have hit on a unique solution using cells that are not too stem‑cell‑like and also not too mature. Starting with mature cells called fibroblasts taken from humans, they induced the cells to regress somewhat by inserting genes for three factors produced by embryonic stem cells. They then added growth factors and other molecules to encourage the cells to take on a more liver-like persona. The cells then produced several proteins such as albumin that are distinctive for liver cells, took on a liver-cell-like shape, and displayed liver-associated functions such as storage of glycogen (a reserve form of glucose [sugar]), storage and uptake of fats, and production of urea. But the real test came when the scientists transplanted these liver‑like cells into a mouse model of liver injury and failure. Over the ensuing months, the cells expanded to repopulate the liver and underwent further maturation, improving the survival of the mice. The transplanted cells also showed a lasting effect, synthesizing human albumin that was still detectable in the mouse’s blood 9 months after transplant. Though further experiments are needed before this cell technology can be applied to humans, these experiments represent a major step towards using cells from a person’s own body to heal their diseased liver. This technology could overcome the current challenges confronted by patients of long wait times for donor organs and life‑long immunosuppressive drugs to prevent organ rejection.
Zhu S, Rezvani M, Harbell J, Mattis AN, Wolfe AR, Benet LZ, Willenbring H, Ding S. Mouse liver repopulation with hepatocytes generated from human fibroblasts. Nature 508: 93-97, 2014.