Regeneration instead of transplantation
Gene switching scheme will help regenerate liver cells
Alexander Malianov, Informnauka based on the materials of Medicalexpress: Scientists shed light on how liver repairs itselfScientists from the Centre for Regenerative Medicine at the University of Edinburgh, led by Professor Stewart Forbes, have uncovered the genetic mechanism of differentiation of hepatocytes – the main liver cells – and learned how to artificially produce these cells from progenitor cells.
The results of the study are published in the latest issue of Nature Medicine (Macrophage-derived Wnt opposes Notch signaling to specify hepatic progenitor cell fate in chronic liver disease).
The main functions of the liver – protein synthesis, regulation of carbohydrate metabolism, detoxification, synthesis of bile for digestion, etc. – are performed by special cells called hepatocytes. Inside each of the hepatic lobules that make up the liver, hepatocytes are collected in thin plates separated by blood and bile capillaries.
In normal operation, the body regenerates liver progenitor stem cells, which, depending on the expression of certain genes (synthesis of proteins on mRNA matrices copied from the genes of the hereditary DNA molecule), can be transformed into both hepatocytes and cholangiocytes - connective tissue cells from which the walls of bile capillaries are formed. In case of liver damage (for example, in chronic hepatitis or cirrhosis), hepatocyte regeneration is extremely weak, and the destroyed fragments of the liver become overgrown with connective tissue. Useful liver cells are replaced by slag.
Researchers from the University of Edinburgh, first for mice and then for humans, found out the scheme of switching key genes that determine which way the differentiation of the hepatic progenitor cell will go, and developed a technology for controlling the mechanism of gene expression that allows increasing hepatocyte regeneration. It has been shown that when the Jagged1 protein acts on a stem cell, the Notch gene is activated in the cell DNA through the signal amplification cascade of the Hes/Hey membrane protein, and through it the Hnf1b and Hnf6 genes are activated, after which the stem cell acquires the properties of a bile duct connective tissue cell. In the case of differentiation of a stem cell into a hepatocyte, the Notch gene is repressed by the Numb ubiquitin ligase. As it turned out, the gene of this protein is activated by the Wnt3a protein, which triggers a cascade of signal amplification of the Wnt type. In addition to suppressing the activity of Notch, the Hnf4a and Hnf1a genes are activated, which are involved in the acquisition by the cell of a phenotype characteristic of a hepatocyte. Scientists have found out that in natural conditions such differentiation occurs with the participation of one of the types of cells of the immune system – macrophages.
This discovery is another (and extremely important) in a series of deciphering gene switching schemes that lead to one or another differentiation of progenitor cells. These studies make it possible to grow whole organs from several stem cells taken from the patient himself (that is, they do not require donors and are not rejected by the body's immune system), and in some cases, to start the process of regeneration of the corresponding cells in vivo. Before that, scientists learned how to grow bladder epithelial cells, smooth muscles, heart muscle, nervous tissue and some others from stem progenitor cells. The issue of growing hepatocytes is on the agenda of modern medicine.
The importance of the discovery of British biologists becomes clear if we recall the role of the liver in the body, the frequency of damage to this organ and the extreme complexity of its transplantation. The head of the study, Professor Stewart Forbes, noted that liver diseases occupy the fifth place among the causes of death in the UK. According to him, the study will help the liver.
Another member of the research team, Dr. Luke Boulter, stated: "This study will help us understand the mechanism of formation of cells necessary for the liver to function, and find a drug that will help in the restoration of a damaged liver."
Dr. Rob Buckle, head of the Center for Regenerative Medicine, described the prospects of the research conducted at his center as follows: "Liver transplantation has saved many lives, but demand will always outstrip supply. Therefore, in the long term, we must go beyond the simple replacement of damaged tissues and use the huge regenerative potential of the human body. This research opens up an opportunity for us to apply our knowledge of stem cell biology to stimulate dormant processes in our body as the basis of future medicine."
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06.03.2012