Source of liver stem cells identified

August 05, 2015

Howard Hughes Medical Institute (HHMI) scientists have identified stem cells in the liver that give rise to functional liver cells. The work 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 solved a very old problem," says Roel Nusse, an HHMI investigator at Stanford University who led the research. "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." Nusse and his colleagues reported their findings August 5, 2015, in the journal Nature.

The liver is made up mostly of hepatocytes, highly specialized cells that carry out the organ's many tasks, including storing vitamins and minerals, removing toxins, and helping regulate fats and sugars in the bloodstream. As these cells die off, they are replaced by healthy new hepatocytes. The source of those new cells had never been identified, Nusse says.

Stem cells, which replenish their own populations and maintain the ability to develop into more specialized cells, provide new cells in the skin, blood, and other tissues where cells are naturally lost over time. But no stem cells had been found in the liver. Some scientists speculated that mature hepatocytes might maintain their populations by dividing. But Nusse says the mature cells have become so specialized to carry out the work of the liver, they have likely lost the ability to divide.

"Differentiated hepatocytes have amplified their chromosomes," he explains. 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'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, they have developed mice in which cells that respond to the Wnt signal are labeled with a fluorescent protein. Several years ago, they decided to use the mice to search for stem cells in the liver.

Bruce Wang, a gastroenterologist at the Liver Center at the University of California, San Francisco, led the experiments as a visiting scholar in Nusse's lab. Wang began by searching for fluorescently labeled, Wnt-responsive cells in the livers of the engineered mice, and he ultimately found them clustered around the liver's central vein.

Once they knew which cells to focus on, the scientists tracked the fluorescently labeled cells' behavior. 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 labeled 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 specialized features and amplified genomes of mature hepatocytes. "This fits the definition of stem cells," Nusse says.

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. Nusse says this is consistent with how stem cells are known to behave in other tissues.

The lab is now investigating how the newly identified stem cells might contribute to regeneration of liver tissue after injury. It will also be important to explore whether liver cancers tend to originate in these replicating cells, as opposed to more mature hepatocytes, Nusse says.
-end-


Howard Hughes Medical Institute

Related Stem Cells Articles from Brightsurf:

SUTD researchers create heart cells from stem cells using 3D printing
SUTD researchers 3D printed a micro-scaled physical device to demonstrate a new level of control in the directed differentiation of stem cells, enhancing the production of cardiomyocytes.

More selective elimination of leukemia stem cells and blood stem cells
Hematopoietic stem cells from a healthy donor can help patients suffering from acute leukemia.

Computer simulations visualize how DNA is recognized to convert cells into stem cells
Researchers of the Hubrecht Institute (KNAW - The Netherlands) and the Max Planck Institute in Münster (Germany) have revealed how an essential protein helps to activate genomic DNA during the conversion of regular adult human cells into stem cells.

First events in stem cells becoming specialized cells needed for organ development
Cell biologists at the University of Toronto shed light on the very first step stem cells go through to turn into the specialized cells that make up organs.

Surprising research result: All immature cells can develop into stem cells
New sensational study conducted at the University of Copenhagen disproves traditional knowledge of stem cell development.

The development of brain stem cells into new nerve cells and why this can lead to cancer
Stem cells are true Jacks-of-all-trades of our bodies, as they can turn into the many different cell types of all organs.

Healthy blood stem cells have as many DNA mutations as leukemic cells
Researchers from the Princess Máxima Center for Pediatric Oncology have shown that the number of mutations in healthy and leukemic blood stem cells does not differ.

New method grows brain cells from stem cells quickly and efficiently
Researchers at Lund University in Sweden have developed a faster method to generate functional brain cells, called astrocytes, from embryonic stem cells.

NUS researchers confine mature cells to turn them into stem cells
Recent research led by Professor G.V. Shivashankar of the Mechanobiology Institute at the National University of Singapore and the FIRC Institute of Molecular Oncology in Italy, has revealed that mature cells can be reprogrammed into re-deployable stem cells without direct genetic modification -- by confining them to a defined geometric space for an extended period of time.

Researchers develop a new method for turning skin cells into pluripotent stem cells
Researchers at the University of Helsinki, Finland, and Karolinska Institutet, Sweden, have for the first time succeeded in converting human skin cells into pluripotent stem cells by activating the cell's own genes.

Read More: Stem Cells News and Stem Cells Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.