Tissue derived from stem cells grew a renewable population-study.
The liver has a unique ability to quickly regenerate and regain its original size if partially removed by surgery. Scientists have long know that stem cells that have the potential to create more liver cells must exist in the liver. But until now, no one had found a way to detect and cultivate liver stem cells.
An international team of researchers, led by Dr. Hans Clevers at the Hubrecht Institute in The Netherlands, sought to identify and grow mouse liver cells. Their work was funded in part by the European Union and the National Institutes of Health (NIH) National Institute of Diabetes and Digestive Diseases (NIDDK). The results of their study were described in the journal Nature on Feb. 14.
In earlier studies, Dr. Clevers and colleagues discovered that a protein called Lgr5 is found on the surface of rapidly dividing stem cells in the intestine, stomach and hair follicles. In all of these tissues, growth is prompted by signaling molecules known as Wnt proteins, which regulate expression of Lgr5 and many other genes. Wnt signaling is known to play a role in tissue regeneration, embryo development and cancer.
To see if Lgr5 might also be a marker for liver stem cells, the scientists studied genetically engineered mice in which the Lgr5 genes were tagged by "reporter" genes. The researchers reported they found that the gene was not activated in healthy mouse livers. However, in injured livers, small Lgr5-positive cells appeared near the bile ducts--a location where resting liver stem cells were thought to reside.
To grow Lgr5-positive liver cells, the researchers said they used a 3-D culture system they'd previously developed for growing stem cells into tiny clumps, or "organoids." Some of the cultures were propagated from a single Lgr5-positive cell.
The team was able to grow and propagate the resulting liver organoids for several months. In culture, the organoids could be coaxed into generating functional liver and bile duct cells. When the organoids were injected into mutant mice with a deadly liver enzyme deficiency, patches of enzyme producing liver cells appeared in the livers of 5 of the 15 treated mice. Mice with successful organoid transplants survived significantly longer than untreated enzyme-efficiency mice.
"This study raises hope that the human equivalent of these mouse liver stem cells can be grown in a similar way and efficiently converted into functional liver cells, said study co-author Dr. Markus Grompe of the Oregon Health Sciences University School of Medicine. The researchers said they plan to go forward to test other growth factors and conditions to improve the efficiency of the procedure.