A Possibility For Humans To Regenerate Damaged Liver Tissue Faster Than Ever

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If you remember watching Spongebob Squarepants as a kid, you are probably familiar with his ability to quickly regenerate parts of his body that are injured or removed. This process is known as regeneration which refers to the process by which some organisms replace or rebuild lost or dismembered body parts, which is going on here.

Being mammals, humans have a limited ability to regenerate, in contrast to some animals, including fish and salamanders, which can effectively repair their organs. Currently, researchers at the Sulk Institute have discovered a method to partially restore liver cells to more youthful stages, enabling them to mend damaged tissue more quickly than previously noticed. The findings show that reprogramming molecules can enhance cell growth, resulting in more effective regeneration of liver tissue in mice.

This is a step forward in repairing cells of damaged livers which could eventually lead to replacing the whole organ itself. The study findings are crucial, with a significant number of people suffering from liver diseases that often lead to a need for liver transplants, which are limited in supply. 

The Possibility of Regrowing A Human Liver

Oct-3/4, Sox2, Klf4, and c-Myc, collectively known as “Yamanaka factors,” are four cellular reprogramming molecules the authors have previously demonstrated can both slow down aging and enhance the ability of mice to regenerate muscle tissue. In their most recent investigation, the researchers used Yamanaka factors to determine if they might lengthen the mice’s lives by improving liver function and liver size. The procedure encourages cell proliferation by partially reverting mature liver cells to “younger” stages.

According to the study, the liver is more adept at healing damaged tissue than most of our other organs. 

They examined the effectiveness of Yamanaka factors in a mouse liver model to see whether or not mammalian tissue regeneration could be improved.

How to regulate the production of components required for enhancing cell function and rejuvenation is a challenge faced by many researchers because some of these molecules can lead to unchecked cell development, as seen in cancer. Izpisua Belmonte’s group used a short-term Yamanaka factor regimen to get around this problem, giving the mice their medication for just one day. The team then closely observed cell division over several generations while taking periodic samples to track the activity of the partially reprogrammed liver cells. None of the mice had tumors even after nine months, or about a third of the animal’s lifespan.

However, according to the researchers, Yamanaka variables can have a double-edged effect. On the plus side, they might improve the regeneration of the liver in injured tissue, but on the negative side, they might result in tumors. The discovery that our short-term induction protocol has improved regeneration and no cancer was exciting to the researchers.

While investigating this reprogramming mechanism in a lab dish, the researchers made a second discovery: Top2a, a gene implicated in liver cell reprogramming, becomes highly active one day after short-term Yamanaka factor therapy. Topoisomerase 2a, an enzyme that aids in severing and reuniting DNA strands, is encoded by Top2a. The number of young cells decreased 40-fold when the researchers inhibited the gene, which decreased Topoisomerase 2a levels and caused cellular reprogramming. Future studies should focus on the precise role that Top2a plays in this process.

In conclusion, the researchers have created a mouse model that permits hepatocyte-specific 4F induction and subsequent lineage tracking of 4F-expressing cells. They show that rapid and transient partial reprogramming was quickly and temporarily produced by liver-specific 4F expression and that this improved liver regeneration. This research, which is the first to perform in vivo lineage tracing and single-cell transcriptome analysis for 4F-expressing cells, demonstrates that 4F-mediated cellular partial reprogramming is a possible method for triggering a proliferative, plastic progenitor state.

The scientists underlined that much more research is necessary before we completely comprehend the molecular mechanisms driving cellular rejuvenation programming approaches. The study’s findings represent a step toward creating new treatments for metabolic illnesses like nonalcoholic steatohepatitis, cancer, and infectious diseases of the liver (NASH).

Journal Reference

Hishida, T., Yamamoto, M., Hishida-Nozaki, Y., Shao, C., Huang, L., Wang, C., Shojima, K., Xue, Y., Hang, Y., Shokhirev, M., Memczak, S., Sahu, S. K., Hatanaka, F., Ros, R. R., Maxwell, M. B., Chavez, J., Shao, Y., Liao, H.-K., Martinez-Redondo, P., … Izpisua Belmonte, J. C. (2022). In-vivo partial cellular reprogramming enhances liver plasticity and regeneration. Cell Reports, 39(4), 110730. https://doi.org/10.1016/j.celrep.2022.110730 

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