Switch causes mature liver cells to revert back to stem cell-like state

Harvard Stem Cell Institute scientists at Boston Children's Hospital have new evidence in mice that it may be possible to repair a chronically diseased liver by forcing mature liver cells to revert back to a stem cell-like state.

The researchers, led by Fernando Camargo, PhD, happened upon this discovery while investigating whether a biochemical cascade called Hippo, which controls how big the liver grows, also affects cell fate. The unexpected answer, published in the journal Cell, is that switching off the Hippo-signaling pathway in mature liver cells generates very high rates of dedifferentiation. This means the cells turn back the clock to become stem-cell like again, thus allowing them to give rise to functional progenitor cells that can regenerate a diseased liver.

The liver has been a model of regeneration for decades, and it's well known that mature liver cells can duplicate in response to injury. Even if three-quarters of a liver is surgically removed, duplication alone could return the organ to its normal functioning mass. This new research indicates that there is a second mode of regeneration that may be repairing less radical, but more constant liver damage, and chips away at a long-held theory that there's a pool of stem cells in the liver waiting to be activated.

"I think this study highlights the tremendous plasticity of mature liver cells," said Camargo, who is an associate professor in the Harvard Department of Stem Cell and Regenerative Biology, and based in the Stem Cell Program at Boston Children's Hospital. "It's not that you have a very small population of cells that can be recruited to an injury; almost 80 percent of hepatocytes [liver cells] can undergo this cell fate change."