Scientists improve liver regeneration in mice, which could lead to new treatments for liver disease

Mammals generally cannot regenerate organs as efficiently as other vertebrates such as fish and lizards. Now, Salk scientists have found a way to partially return liver cells to a younger state, allowing them to repair damaged tissue faster than previously seen. Results published in Cellular reports April 26, 2022 showed that the use of reprogramming molecules can enhance cell growth, leading to better liver tissue regeneration in mice.

“We are excited to make progress in repairing cells from damaged livers, because one day these approaches could be extended to whole organ replacement,” says author Juan Carlos Izpisua Belmonte, Salk Gene Expression Laboratory Professor and chairperson Roger Guillemin. “Our results may lead to the development of new treatments for infections, cancers and genetic diseases of the liver, as well as metabolic diseases such as non-alcoholic steatohepatitis (NASH). »

Previously, the authors showed how four cellular reprogramming molecules – Oct-3/4, Sox2, Klf4 and c-Myc, also known as “Yamanaka factors” – can slow down the aging process and improve the ability of muscle tissue to regenerate in women. mouse. In their latest study, the authors used Yamanaka factors to see if they could increase liver size and function while extending lifespan in mice. This process involves the partial transformation of mature liver cells back into “younger” states, which promotes cell growth.

“Unlike most of our other organs, the liver is more efficient at repairing damaged tissue,” says co-author Mako Yamamoto, a researcher at Izpisua Belmonte’s lab. “To find out if mammalian tissue regeneration can be improved, we tested the effectiveness of Yamanaka factors in a mouse liver model. »

The problem that many researchers face is how to control the expression of factors needed to improve cell function and rejuvenation, since some of these molecules can cause uncontrolled cell growth, as occurs in cancer. To get around this, Izpisua Belmonte’s team used a short-term Yamanaka factor protocol in which the mice were treated for one day. The team then monitored the activity of the partially reprogrammed liver cells, periodically taking samples and closely monitoring how the cells divided over several generations. Even after nine months – about a third of an animal’s life – none of the mice had tumors.

“Yamanaka factors are a double-edged sword,” says co-author Tomoaki Hishida, a former researcher in the Izpisua Belmonte lab and current assistant professor at Wakayama Medical University in Japan. “On the one hand, they can enhance liver regeneration in damaged tissues, but the downside is that they can cause tumors. We were delighted to find that our short-term induction protocol produced good effects without the bad ones – improved regeneration and no cancer. »

Scientists made a second discovery by studying this reprogramming mechanism in a lab dish: a gene called Top2a participates in the reprogramming of liver cells and is highly active one day after short-term treatment with Yamanaka factor. Top2a encodes topoisomerase 2a, an enzyme that helps break and rejoin DNA strands. When the researchers blocked the topoisomerase 2a-reducing gene, they saw a 40-fold decrease in the rate of cell reprogramming, resulting in a significant reduction in the number of young cells. Exact Role Top2a plays in this process remains an area for future research.

“There is still a lot of work to be done before we can fully understand the molecular basis behind programming approaches to cellular rejuvenation,” says Izpisua Belmonte. “This is a necessary condition for the development of effective and universal methods of treatment and elimination of the consequences of human diseases. »

Izpisua Belmonte is currently the director of Altos Labs Inc. and a professor at the Salk Institute.

This work was supported by the UCAM Uehara Memorial Foundation and the research grant Fundacion Dr. Pedro Guillen.

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