The well-known Spanish researcher Juan Carlos Izpisúa has led a research, recently published in Cell Reports, in which scientists have managed to regenerate liver tissue in mice by reprogramming liver cells to earlier stages of development.

Mammals have limited regenerative capacity, while other vertebrates, such as fish and salamanders, can efficiently regenerate their organs. Regeneration in these species depends on two successive events: cell dedifferentiation or reprogramming, a kind of rejuvenation of cells towards a form more similar to the embryonic than to the adult, and the subsequent proliferation of cells, whose multiplication regenerates the damaged tissue. Achieving this capacity in mammals could represent a way to improve the regeneration of damaged tissues in humans.

The new technique “makes the liver regenerate more efficiently and faster than control animals and prevents cirrhosis and death,” Izpisúa told Diario Médico, advancing that “our findings could lead to the development of new therapies to treat liver diseases such as viral infections, cancers, genetic liver diseases or metabolic diseases, such as hepatic steatosis. The latter is, by far, the most prevalent in the Western world. It is the most common cause of liver disease in Western populations and is fast becoming the number one reason for liver transplants.”

To achieve the reprogramming of liver cells in vivo, that is, in the mice’s own body, the researchers generated a genetically modified mouse model to produce, transiently and in the liver, four molecules typical of embryonic development, known as the four Yamanaka factors, in honor of the Japanese researcher who developed the cell reprogramming technique.

The transient in vivo expression of these four factors achieved the partial reprogramming of adult hepatocytes to a progenitor state and subsequent cell proliferation, improving the regenerative capacity of the liver. “Partial reprogramming rejuvenates liver cells, which therefore regenerates better and faster,” explains Izpisúa.

For the study, the mice were exposed to compounds that induce cirrhosis, that is, the global deformation of the internal structure of the liver due to the accumulation of non-functional scar tissue in the organ. In the research carried out, the cell reprogramming treatment was able to counteract liver failure in mice, regenerating liver tissue and preventing the death of the treated animals.

These advances are promising in the field of regenerative medicine. However, the technique is not ready to be applied to humans, as many questions remain to be resolved regarding the safety of long-term treatment and the biological mechanisms involved in tissue regeneration.

One of the problems associated with cell reprogramming is the formation of tumors caused by uncontrolled cell growth. In the study discussed here, the researchers avoided this unwanted effect by expressing Yamanaka factors for just one day. “Our protocol does not entail an aberrant cell division and does not produce tumors” Izpisúa points out. Despite this, in the article the scientists acknowledge that the health of the mice was monitored over a period of nine months, and that additional studies will be needed to verify long-term safety.

On the other hand, the mechanisms that produce successful tissue regeneration remain unclear. In their article, the researchers suggest that it may be due to the action of a gene called Top2a, since its activity was increased after the administration of Yamanaka factors.

Another question to be resolved is how the reprogrammed cells contribute to the improvement of liver regeneration. To do this, future studies will need to investigate the trajectory of these cells in vivo and perform in-depth cellular analyses.

Finally, the usefulness of the technique in other liver pathologies, such as hepatic fibrosis or non-alcoholic fatty liver disease, remains to be determined.

If all these questions are resolved, the regeneration of damaged liver tissue could be a reality in the future, probably accompanied by similar possibilities for the healing of other organs.

Lucía Gómez Tatay

Bioethics Observatory – Institute of Life Sciences

Catholic University of Valencia

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