New Insights into Liver Regeneration

The liver is the most regenerative of organs in mammals, capable of regrowing large amounts of lost tissue following injury. Its strategy for regrowth is somewhat different from that of other tissues, and somewhat different again from the mechanisms employed by species capable of proficient regeneration, such as salamanders. Evolution has produced many approaches to growth and regrowth, it seems. It may or may not be the case that researchers can find ways to make other organs behave more like the liver. I think it is far too early to say just how challenging a proposition this might be; even were there compelling mechanisms in hand and being worked on, that would be a tough prediction to make.

Meanwhile, investigative research continues. In the work noted here, researchers uncover a role for shifts in alternative splicing in liver regeneration. Alternative splicing allows for the production of different proteins from the same genetic blueprint, and is a complex enough epicycle atop all of the other complexity of cellular biochemistry to remain comparatively poorly explored in most specific cases. The researchers tie their findings to the Hippo signaling pathway, something that has attracted attention of late in the context of rejuvenation. A number of research groups are eyeing the Hippo pathway as a target for therapies that might enhance regeneration in various internal organs. This is all largely very early stage work, and it will likely be years before something emerges into the development pipeline.

Study: Damaged liver cells undergo reprogramming to regenerate

The liver is a resilient organ. It can restore up to 70 percent of lost mass and function after just a few weeks. We know that in a healthy adult liver, the cells are dormant and rarely undergo cell division. However, if the liver is damaged, the liver cells re-enter the cell cycle to divide and produce more of themselves. Using a mouse model of a liver severely damaged by toxins, researchers compared injured adult liver cells with healthy cells present during a stage of development just after birth. They found that injured cells undergo a partial reprogramming that returns them to a neonatal state of gene expression.

The team discovered that fragments of messenger RNA, the molecular blueprints for proteins, are rearranged and processed in regenerating liver cells in a manner reminiscent of the neonatal period of development. This phenomenon is regulated through alternative splicing, a process wherein exons (expressed regions of genes) are cut from introns (intervening regions) and stitched together in various combinations to direct the synthesis of many different proteins from a single gene.

"We found that the liver cells after birth use a specific RNA-binding protein called ESRP2 to generate the right assortment of alternatively spliced RNAs that can produce the protein products necessary for meeting the functional demands of the adult liver. When damaged, the liver cells lower the quantity of ESRP2 protein. This reactivates fetal RNA splicing in what is called the Hippo signaling pathway, giving it instructions about how to restore and repopulate the liver with new and healthy cells."

Alternative splicing rewires Hippo signaling pathway in hepatocytes to promote liver regeneration

During liver regeneration, most new hepatocytes arise via self-duplication; yet, the underlying mechanisms that drive hepatocyte proliferation following injury remain poorly defined. By combining high-resolution transcriptome and polysome profiling of hepatocytes purified from quiescent and toxin-injured mouse livers, we uncover pervasive alterations in messenger RNA translation of metabolic and RNA-processing factors, which modulate the protein levels of a set of splicing regulators.

Specifically, downregulation of the splicing regulator ESRP2 activates a neonatal alternative splicing program that rewires the Hippo signaling pathway in regenerating hepatocytes. We show that production of neonatal splice isoforms attenuates Hippo signaling, enables greater transcriptional activation of downstream target genes, and facilitates liver regeneration. We further demonstrate that ESRP2 deletion in mice causes excessive hepatocyte proliferation upon injury, whereas forced expression of ESRP2 inhibits proliferation by suppressing the expression of neonatal Hippo pathway isoforms. Thus, our findings reveal an alternative splicing axis that supports regeneration following chronic liver injury.

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