In Greek mythology, Zeus punishes the trickster Prometheus by chaining him to a rock and sending an eagle to eat a portion of his liver every day, in perpetuity. It was the right organ to target; the liver has the ability to regenerate itself—though not overnight nor for eternity. New research has determined how damaged liver cells repair and restore themselves through a signal to return to an early stage of postnatal organ development.
"The liver is a resilient organ. It can restore up to 70 percent of lost mass and function after just a few weeks,” says senior author Dr. Auinash Kalsotra of the University of Illinois. "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, the researchers compared injured adult liver cells with healthy cells present during a stage of development just after birth. The team discovered that fragments of messenger RNA 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. These proteins can have different cellular functions or properties.
"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," said first author Sushant Bangru. "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."
Kalsotra described the science in mythological terms: "When Zeus' eagle comes in for its daily snack, damaging the liver, the alternatively spliced form of Hippos come into play—repairing Prometheus's liver so the poor guy can go through this whole punishment again the next day."
Image: The Greek hero Prometheus was punished by being lashed to a rock and having his liver eaten each day by an eagle, a myth that hints at the extraordinary regenerative powers of the human liver. A new study offers insight into how RNA splicing generates alternate forms of the "Hippo signaling pathway" to promote liver regeneration. Image courtesy of Jose Luis Vasquez, Beckman Institute.