`Artificial livers for transplantation` a step closer to reality
London: An Indian origin scientist and her team have made a breakthrough that could lead to development of artificial livers for transplantation.
The liver can indeed regenerate itself if part of it is removed. However, researchers trying to exploit that ability in hopes of producing artificial liver tissue for transplantation have repeatedly been stymied: Mature liver cells, known as hepatocytes, quickly lose their normal function when removed from the body.
"It`s a paradox because we know liver cells are capable of growing, but somehow we can`t get them to grow" outside the body, said Sangeeta Bhatia, the John and Dorothy Wilson Professor of Health Sciences and Technology and Electrical Engineering and Computer Science at MIT, a senior associate member of the Broad Institute and a member of MIT`s Koch Institute for Integrative Cancer Research and Institute for Medical Engineering and Science.
Now, Bhatia and colleagues have taken a step toward that goal. They have identified a dozen chemical compounds that can help liver cells not only maintain their normal function while grown in a lab dish, but also multiply to produce new tissue.
Cells grown this way could help researchers develop engineered tissue to treat many of the 500 million people suffering from chronic liver diseases such as hepatitis C, according to the researchers.
Lead author of the paper is Jing (Meghan) Shan, a graduate student in the Harvard-MIT Division of Health Sciences and Technology. Members of Bhatia`s lab collaborated with researchers from the Broad Institute, Harvard Medical School and the University of Wisconsin.
Bhatia has previously developed a way to temporarily maintain normal liver-cell function after those cells are removed from the body, by precisely intermingling them with mouse fibroblast cells. For this study, funded by the National Institutes of Health and Howard Hughes Medical Institute, the research team adapted the system so that the liver cells could grow, in layers with the fibroblast cells, in small depressions in a lab dish. This allowed the researchers to perform large-scale, rapid studies of how 12,500 different chemicals affect liver-cell growth and function.
The liver has about 500 functions, divided into four general categories: drug detoxification, energy metabolism, protein synthesis and bile production.
David Thomas, an associate researcher working with Todd Golub at the Broad Institute, measured expression levels of 83 liver enzymes representing some of the most finicky functions to maintain.
After screening thousands of liver cells from eight different tissue donors, the researchers identified 12 compounds that helped the cells maintain those functions, promoted liver cell division, or both.
Two of those compounds seemed to work especially well in cells from younger donors, so the researchers - including Robert Schwartz, an IMES postdoc, and Stephen Duncan, a professor of human and molecular genetics at the University of Wisconsin - also tested them in liver cells generated from induced pluripotent stem cells (iPSCs). Scientists have tried to create hepatocytes from iPSCs before, but such cells don`t usually reach a fully mature state. However, when treated with those two compounds, the cells matured more completely.
Bhatia and her team wonder whether these compounds might launch a universal maturation program that could influence other types of cells as well. Other researchers are now testing them in a variety of cell types generated from iPSCs.
In future studies, the MIT team plans to embed the treated liver cells on polymer tissue scaffolds and implant them in mice, to test whether they could be used as replacement liver tissues. They are also pursuing the possibility of developing the compounds as drugs to help regenerate patients` own liver tissues, working with Trista North and Wolfram Goessling of Harvard Medical School.
Their work is detailed in a paper appearing in the latest issue of Nature Chemical Biology.
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