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The liver is an organ with a rare ability to self-regenerate after partial destruction. However, this ability is limited to a certain extent, especially in severe chronic pathologies, when the natural cycle of organ regeneration is deeply disturbed. At this stage, liver damage is irreversible and no specific therapy has yet been able to reverse the destruction of liver cells. A new study published in Cellular reports may finally find a solution to this problem, inspired by the incredible regenerative ability of lizards and salamanders. As in these vertebrates, partial cellular dedifferentiation (the transformation of a mature cell into a younger one) followed by the proliferation of healthy young cells was effective in very rapidly repairing damaged liver tissue in mice. This feat was made possible by a cluster of four reprogramming molecules called the Yamanaka Factors.
The liver is the organ in the human body with the greatest capacity for natural regeneration. In the event of damage or partial removal, it is able to restore its original weight in record time (from several months to several weeks). However, some chronic progressive diseases, such as non-alcoholic steatohepatitis (NAHS), can interfere with this natural healing ability.
This condition is due to steatosis, a natural defense mechanism that traps unhealthy fatty acids and stores them as lipid droplets. But sometimes this progressive phenomenon affects the liver, which can lead to local inflammation. Due to the accumulation of fatty acids, liver cells are so stressed that the immune system is activated and causes chronic inflammation. At this stage, steatosis turns into steatohepatitis, which progresses irreversibly.
The relatively limited natural regenerative capacity of the liver is characteristic of mammals, since other vertebrates, such as some fish, lizards, and salamanders, are known to be exceptionally efficient in natural regeneration. To regenerate severed limbs or other organs, these animals use the mechanisms of cellular “dedifferentiation” followed by the proliferation of healthy young cells that are formed.
So researchers at the prestigious Salk Institute of Biology in San Diego were inspired by these “supervertebrates.” They started by isolating molecules (called “Yamanaka factors”) that are supposedly capable of inducing the same healing abilities in humans. ” Similar approaches can be extended to whole organ replacement. “explains Juan Carlos Izpisua Belmonte, a professor at the Salk Gene Expression Laboratory and author of the study, in a press release. ” They could lead to the development of new treatments for infections, cancer, genetic liver disease, and metabolic diseases such as non-alcoholic steatohepatitis (NASH). “, he considers.
double edged weapon
According to the authors of the new study, four Yamanaka factors (Oct-3/4, Sox2, Klf4 and c-Myc) are able to reprogram cells at the molecular level to slow down their aging process and regenerate muscle tissue. in mice. They then applied these factors in an attempt to increase liver size (through cell proliferation), improve liver function, and increase lifespan in mice (with induced liver disease). Thus, molecular factors work by partially converting mature cells back into younger cells that differentiate again and proliferate into healthier cells.
However, the use of these factors carries a risk that researchers have not yet fully controlled. In particular, it is necessary to control the expression of factors, since some of them can induce the same excessive cell proliferation as in tumors. To avoid this risk, Salk’s team adopted a protocol for introducing known short-term molecular factors.
Thus, the mice only received treatment for one day, and the team monitored the activity of the partially reprogrammed liver cells by periodically taking tissue samples. By carefully tracking how cells divide over several generations, the results showed that the mice did not develop tumors even after nine months (about a third of their average lifespan).
In addition, the research team also found that a protein called TOP2A, which is involved in the reprogramming of liver cells, becomes very active one day after administration of Yamanaka factor. The gene encodes, in particular, the synthesis of topoisomerase 2a, the enzyme responsible for DNA cleavage and recombination. To confirm this mechanism, the scientists blocked the Top2a gene, which led to a drop in the level of topoisomerase 2a. Mice with a deactivated TOP2A gene had 40 times fewer cases of cell reprogramming to turn adult cells into younger ones.
These results provide promising insights into potential effective treatments for liver disease, but ” There is still a lot of work to be done before we can fully understand the molecular basis behind programmatic approaches to cellular rejuvenation. concludes Izpisua Belmonte.