Mammalian organs usually cannot regenerate as efficiently as in other vertebrates, such as fish or lizards. Regeneration in these species depends on dedifferentiation (loss of characteristics characteristic of a specialized cell and return to a simpler state) with subsequent proliferation. Earlier, the research group of Juan Carlos Ispisua Belmonte from the Salk Institute for Biological Research showed that Yamanaki transcription factors (a mixture of four Oct3/4, Sox2, Klf4 and cMYC proteins capable of turning somatic cells into pluripotent stem cells) can safely slow down the aging process in mice, as well as improve the ability of muscle tissue to regenerate. In their new study, they used Yamanaki factors to find out whether they could be used to repair damaged liver and improve its function, while increasing the lifespan of mice. The group created a mouse model that allows to enhance the expression of Yamanaki factors specifically in hepatocytes.
The problem faced by many researchers in this field is the difficulty of controlling the expression of Yamanaki factors, since some of these molecules can provoke unrestrained cell growth and cause cancer. To avoid this, the Ispisua Belmonte group used a short protocol: Yamanaka factors ceased activity a day after administration. The researchers then tracked the activity of partially reprogrammed liver cells, closely observing their division. Even after nine months–that's about a third of the animal's life–none of the mice had tumors.
Liver cells were partially reprogrammed into younger ones (red) using Yamanaki factors (white). Cell nuclei (blue) and cytoskeletal proteins (green) are also shown.
The expression of Yamanaki factors induced partial reprogramming of adult hepatocytes into the state of progenitor cells and simultaneously increased cell proliferation. This is indicated by a decrease in the expression of markers of differentiated hepatocytes and an increase in the expression of markers of proliferation and chromatin modifiers, large-scale changes in the availability of DNA and the appearance of markers of liver stem and progenitor cells.
A gene called Top2a has been found to be involved in the rejuvenation of liver cells. It is most active a day after a one-day induction of Yamanaki factors. Top2a encodes topoisomerase 2a– an enzyme that helps cleave and connect DNA strands. When the researchers knocked out the gene and lowered the level of topoisomerase 2a, they saw a 40-fold slowdown in the rate of cellular reprogramming, which led to a much smaller number of young cells. The exact role that Top2a plays in this process remains unknown.
Liver-specific expression of Yamanaki factors may one day become the basis for the treatment of liver failure by enhancing regeneration. Research in this direction will continue.
Article by T.Hishida et al. In vivo partial cellular reprogramming enhances liver plasticity and regeneration is published in the journal Cell Reports.
Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru based on the materials of the Salk Institute for Biological Studies: Cellular regeneration therapy restores damaged liver tissue faster than ever.