Source of liver stem cells identified

Scientists have identified stem cells in the liver that give rise to functional liver cells.
The study, by Howard Hughes Medical Institute (HHMI) scientists, solves a long-standing mystery about the origin of new cells in the liver, which must constantly be replenished as cells die off, even in a healthy organ.
"We've shown that like other tissues that need to replace lost cells, the liver has stem cells that both proliferate and give rise to mature cells, even in the absence of injury or disease," said Roel Nusse, an HHMI investigator at Stanford University in US, who led the study.

The liver is made up mostly of hepatocytes, highly specialised cells that carry out the organ's many tasks, including storing vitamins and minerals and removing toxins.
As these cells die off, they are replaced by healthy new hepatocytes. The source of those new cells had never been identified, Nusse said.
Stem cells replenish their own populations and maintain the ability to develop into more specialised cells. However, no stem cells had been found in the liver.

Some scientists speculated that mature hepatocytes might maintain their populations by dividing.
But Nusse said the mature cells have become so specialised to carry out the work of the liver, they have likely lost the ability to divide.

"Differentiated hepatocytes have amplified their chromosomes. That is, the cells have more than the usual two copies of every chromosome. This enables the cells to make more proteins, but it really compromises their ability to divide," Nusse said.
Nusse's lab at Stanford focuses on a family of proteins of called Wnts, which are key regulators of stem cell fate. To find and follow stem cells in a variety of tissues, researchers developed mice in which cells that respond to the Wnt signal are labelled with a fluorescent protein.
The researchers began by searching for fluorescently labelled, Wnt-responsive cells in the livers of the engineered mice, and ultimately found them clustered around the liver's central vein.

Once they knew which cells to focus on, the scientists tracked the fluorescently labelled cells' behaviour.
Over time, they noticed that the cells they were tracking divided rapidly, steadily replenishing their own population. This was possible because unlike mature hepatocytes, the labelled cells had only two copies of each chromosome.
By following the descendents of the stem cells for up to a year, the scientists discovered that these had changed, taking on the specialised features and amplified genomes of mature hepatocytes.
As expected, the liver stem cells required Wnt signals to maintain their stem cell identity.
Nusse's team discovered that endothelial cells lining the central vein, the blood vessel around which the stem cells were clustered, released Wnt molecules into the tissue.

Stem cells that migrated out of reach of that signal quickly lost their ability to divide into new stem cells and began to develop into mature hepatocytes.