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A team of Spanish scientists has managed to improve and accelerate the regeneration of the damaged liver in mice, which could lead to new treatments to cure liver diseases.
Specifically, the team led by Juan Carlos Izpisua, from the Salk Institute (USA) and UCAM, has managed to partially rejuvenate liver cells, allowing them to rapidly regenerate damaged tissue.
The results, published in the journal Cell Reports, reveal that the use of reprogramming molecules improves cell growth and liver tissue regeneration in mice.
“Our findings could lead to the development of new therapies to cure infections, cancers, genetic liver diseases or metabolic diseases such as hepatic steatosis», says Izpisua, who adds that he believes that, one day, «approaches like this could be used to regenerate whole livers».
Mammals do not regenerate their organs as efficiently as other vertebrates, such as fish or salamanders.
The authors of this work have previously demonstrated how the use of four cell reprogramming molecules -Oct-3/4, Sox2, Klf4 and c-Myc, also called ‘Yamanaka factors’, can slow down the aging process and improve the ability regeneration of muscle tissue in mice.
In the current study, the researchers used Yamanaka factors to increase liver size and improve liver function, while prolonging the health of mice over time. The reprogramming process used consists of partially converting mature liver cells into ‘younger’ cells, which favors cell growth and function.
The problem faced by many researchers in this field is how to control the expression of Yamanaka factors to rejuvenate cells and improve their function, since some of these molecules can cause uncontrolled cell growth, as in the case of cancer. With the help of Izpisua, this problem has been solved by applying the Yamanaka factors for short periods of time.
The treatment was administered to the mice for only one day” – explains Estrella Núñez, co-author of the article and vice-rector for Research at UCAM – “then, the team monitored the activity of the partially reprogrammed liver cells by taking periodic samples and keeping a close eye on how cells divided over time. Even after nine months, about a third of the mice’s life, none of them had tumors.”
Yamanaka factors are truly a double-edged sword, says the paper’s first author, Tomohaki Hishida. “On the one hand, they have the potential to improve regeneration of damaged tissue of the liver, and on the other they have the inconvenience that they can generate tumors. Finding out that our short-term induction protocol has the good effects, but not the bad, is important: it improves liver regeneration and does not cause cancer.”
The results show a second discovery when studying this reprogramming mechanism in cell cultures in the laboratory: A gene called Top2a, which is involved in liver cell reprogramming, is highly active one day after short-term treatment with Yamanaka factors. top2a encode la topoisomerasa 2aan enzyme that helps unwind the two strands of DNA so that genes can be expressed.
“When we blocked this gene, the levels of topoisomerase 2a decreased and the rate of cell reprogramming was reduced 40 times, which gave rise to many fewer young cells,” says Rubén Rabadán, co-author of the work and postdoctoral researcher at UCAM. The exact role that the Top2a gene plays in this process is still under study.”
“There is still a lot of work to be done before we can fully understand the molecular bases that underlie the reprogramming processes of cellular rejuvenation,” says Izpisua Belmonte, which is essential to be able to develop effective medical treatments to reverse the effects of human diseases. ».
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