This scientific breakthrough could lead to new treatments to cure diseases that affect the liver
The team of scientists led by Dr. Juan Carlos Izpisua Belmonte, Extraordinary Professor of Developmental Biology at UCAM, has managed to improve and accelerate the regeneration of damaged livers in mice, which could lead to new treatments to cure liver diseases.
Mammals do not regenerate their organs as efficiently as other vertebrates, such as fish or salamanders. Izpisua’s team, also a professor at the Salk Institute’s Gene Expression Laboratory, where he holds the Roger Guillemin Chair, and director of the Institute at Altos Labs, Inc., has managed to partially rejuvenate liver cells, allowing them to rapidly regenerate damaged tissue. The results, published in the journal Cell Reports, derive from a project promoted and financed by the UCAM, and reveal that the use of reprogramming molecules improves cell growth and liver tissue regeneration in mice.
“We are excited about the advances made in repairing damaged liver cells because approaches like this could one day be used to regenerate whole livers,” says Dr. Izpisua Belmonte. “Our findings could lead to the development of new therapies to cure infections, cancers, genetic liver diseases, or metabolic diseases such as hepatic steatosis.”
The authors of this work have previously demonstrated, in studies also promoted and financed by the UCAM, 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 regeneration capacity 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 that many researchers in this field face 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 Belmonte we managed to solve this problem 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 really a double-edged sword,” says the paper’s first author, Tomohaki Hishida. “On the one hand, they have the potential to improve the regeneration of damaged liver tissue, and on the other hand, they have the drawback that they can generate tumors. Finding 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 collected in this work show a second discovery when studying this mechanism of reprogramming in cell cultures in the laboratory: A gene called Top2a, which is involved in the reprogramming of liver cells, is very active one day after short-term treatment. with the Yamanaka factors. Top2a encodes topoisomerase 2a, an 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 underlying 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 diseases. human«.
This work has funding from the Catholic University of Murcia (UCAM), the Dr. Pedro Guillén Foundation and a research grant from the Uehara Memorial Foundation.
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