medwireNews: Researchers have successfully grown liver stem cells in culture for the first time and transplanted them into a mouse model.
"This study raises the 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 author Markus Grompe (Oregon Health and Science University, Portland, USA) in a press statement.
The researchers, led by Hans Clevers of the Hubrecht Institute in Utrecht, the Netherlands, modified a technique previously used to identify stem cells in the colon, stomach, and hair follicles. They found that by damaging the liver in adult mice using carbon tetrachloride, they could induce expression of the Lgr5 gene - a marker of actively dividing stem cells - in groups of cells near the bile ducts.
The researchers were able to grow liver progenitor cultures from biliary duct fragments which formed liver organoids. From these they successfully derived single-cell clonal cultures, as well as secondary cultures.
Initially, markers for hepatocyte maturation were weakly expressed but, using a differentiation medium for 8-14 days, the researchers observed several indicators for hepatocyte function, including low-density lipoprotein and glycogen uptake, albumin secretion, and cytochrome p450 function. Additionally, they detected binucleation, high granulation, and expression of the marker OC2-2F8, which all indicate hepatocyte maturation.
"We were able to massively expand the liver cells and subsequently convert them to hepatocytes at a modest percentage," said Grompe. "Going forward, we will enlist other growth factors and conditions to improve that percentage."
The researchers then transplanted organoids into mutant mice lacking the gene for fumarylacetoacetate hydrolase -a model of tyrosinemia Type I liver disease. They found that the cells developed into mature hepatocytes in vivo and they also observed a significant survival increase among mice that received the transplant compared with those that did not.
"Our observations may serve as the basis for the development of regenerative strategies using adult stem or progenitor cells obtained from solid organs," the authors write in Nature.
"Because these approaches can be based on the in vitro expansion of a single adult Lgr5 progenitor cell, specific and safe genetic modifications may become feasible."
Grompe asserts: "Liver stem cell therapy for chronic liver disease in humans is coming."
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