One step closer to an artificial liver
MIT bioengineers have found compounds that allow growing hepatocytes outside the body
LifeSciencesToday based on MIT materials: A step closer to artificial liversThe mythological hero Prometheus, who stole fire from the gods, was punished by them – chained to a rock.
Every day an eagle flew to him and pecked out the liver, which was restored overnight to be eaten the next day. Today, scientists know that there is a grain of truth in this myth, says an engineer at the Massachusetts Institute of Technology (MIT) Sangeeta Bhatia, MD, PhD. The liver can indeed repair itself if part of it is removed. However, researchers who tried to use this ability of the organ in the hope of obtaining artificial liver tissue for transplantation inevitably came to a dead end: mature liver cells taken from the body – hepatocytes – quickly lose the ability to perform their function normally.
This is a paradox, because we know that liver cells are able to grow, but for some reason we cannot force them to do it outside the body, says Professor Bhatia. Recently, her group has taken a big step towards this goal. In a study published in the journal Nature Chemical Biology (Shan et al., Identification of small molecules for human hepatocyte expansion and iPS differentiation), researchers have identified a dozen chemical compounds that can help hepatocytes not only maintain their normal function when grown in the laboratory, but also multiply, forming new tissue.
According to scientists, the cells grown in this way will help to obtain engineered tissue for the treatment of many of the 500 million people suffering from chronic liver diseases, such as hepatitis C.
Professor Bhatia has previously developed a way to temporarily maintain the normal function of hepatocytes after their removal from the body. She achieved this by mixing them with mouse fibroblasts with exact observance of a certain proportion between the two types of cells. For this study, funded by the National Institutes of Health and the Howard Hughes Medical Institute, scientists adapted the system so that liver cells, layered with fibroblasts, could grow in small depressions in Petri dishes. This made it possible to conduct a rapid large-scale screening of the effect of 12,500 different chemical compounds on the growth and function of hepatocytes.
The liver performs about 500 functions, conditionally divided into four main categories: neutralization of toxic substances, energy metabolism, protein synthesis and bile production. In collaboration with Todd Golub, associate researcher David Thomas from the Broad Institute measured the expression levels of 83 liver enzymes mediating some of the most difficult functions to maintain.
As a result of screening thousands of liver cells from eight different donors, scientists identified 12 compounds that helped cells maintain these functions, contributed to the division of hepatocytes, or both.
Two of these compounds were particularly active in cells obtained from younger donors. Therefore, researchers – including Robert Schwartz, a postdoctoral fellow at the Institute for Medical Engineering and Science, and Robert Schwartz, a professor of human genetics and molecular genetics at the University of Wisconsin Stephen Duncan, – they were also tested on liver cells derived from induced pluripotent stem cells.
Scientists have obtained hepatocytes from induced pluripotent stem cells before, but such cells usually do not reach full maturity. Treatment with the two most active compounds allowed hepatocytes to reach a greater degree of maturity.
To test whether hepatocytes treated with these compounds can be used to replace liver tissues, Professor Bhatia and her colleagues plan to place them on polymer tissue substrates and implant them in mice. In addition, in collaboration with Trista North and Wolfram Goessling from Harvard Medical School, they want to explore the possibility of developing compounds that can help regenerate patients' own liver tissues.
Eric Lagasse, associate Professor of Pathology at the University of Pittsburgh, considers the results of this study to be a promising approach to overcoming the difficulties that scientists have encountered in growing liver cells outside the body. "Developing a method for growing functional hepatocytes in culture would be a big breakthrough," says a scientist who was not involved in this study.
In the picture, the cell nuclei are colored blue.
Hepatocytes are colored green, actively dividing cells are red
(photo: Nature Chemical Biology).
Recently, Professor Bhatia and her group have made significant progress in solving another problem related to the engineering of liver tissue, concerning the growth in the recipient's body of blood vessels necessary to supply new tissues with oxygen and nutrients. In an article published in the Proceedings of the National Academy of Sciences, Bhatia and a professor at the University of Pennsylvania Christopher Chen has shown that if endothelial cells are pre-implanted into the tissue, then after implantation they quickly develop into a network of blood vessels.
To do this, Kelly Stevens (Kelly Stevens) from Bhatia's laboratory and Peter Zandstra (Peter Zandstra) from the University of Toronto (University of Toronto) have developed a new system that allows you to create 3D-engineered tissue and accurately control the localization of various types of cells in the tissue. This approach, described in the journal Nature Communications, allows the engineered tissue to function better in the recipient's body.
"Taken together, these works pave the way to solving two long–standing problems in the engineering of liver tissue – how to grow a large supply of liver cells outside the body and how to graft graft tissue to the recipient," concludes Professor Bhatia.
Portal "Eternal youth" http://vechnayamolodost.ru13.06.2013