Recapturing the liver’s fountain of youth

fountain of youth stem cellsThis post is condensed from a report from the Harvard Stem Cell Institute.

The liver has been a model of tissue regeneration for decades, and it’s well known that a person’s liver cells can duplicate in response to injury. Even if three-quarters of the liver is surgically removed, duplication alone can return the organ to its normal functioning mass. It’s why people are able to donate part of their liver to someone in need—like this mother to her son who was born with biliary atresia.

But what about people with more chronic liver damage? Researchers led by Fernando Camargo, PhD, of the Harvard Stem Cell Institute and Boston Children’s Hospital’s Stem Cell Program, have new evidence in mice that it may be possible to repair such liver disease by forcing mature liver cells to turn back the clock and revert to a stem cell-like state, able to generate functional liver progenitor cells to replace damaged tissue.

Camargo and colleagues happened upon this discovery, reported last week in the journal Cell, while investigating a biochemical cascade called Hippo, which controls how big the liver grows. Unexpectedly, they found that switching off the Hippo-signaling pathway in mature liver cells made them lose their specialized, differentiated status and become more stem cell-like.

liver regeneration
These liver cells are transitioning from a mature cell type (green) to a stem cell type (red) as a result of inactivation of the Hippo pathway. (Dean Yimlamai/Boston Children's Hospital)
Previously, it was believed that there’s a pool of stem cells in the liver waiting to be activated, if only it could be found. “I think this study highlights the tremendous plasticity of mature liver cells,” says Camargo. “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.”

The next step, he adds, would be to figure out how Hippo’s activity changes in cells affected by chronic liver injury or diseases such as hepatitis. In the long term, this work could lead to drugs that manipulate the Hippo activity of mature liver cells inside of patients to recapture their youthful properties and hasten healing. Another option might be to get patients to donate healthy hepatocytes, manipulate their Hippo signaling and create progenitor cells in a laboratory dish for transplant. In the Cell paper, they report therapeutic success with this approach in mice.

The observation that mature liver cells dedifferentiate comes after a number of recent studies from Harvard researchers showing that mature cells in several different internal organs, including the kidneys, adrenal glands and lungs, are more plastic than we once assumed.

“I think this has been overlooked because the field has been so stem cell-centric,” says Camargo. “Understanding pathways that underlie [cell] plasticity could be another way of potentially manipulating regeneration or expanding some kind of cell type for regenerative medicine.”

Joseph Caputo is communications manager at the Harvard Stem Cell Institute.