Champaign, Illinois. The liver has a rare breakthrough power in the body – the ability to regenerate, even if 70% of its mass has been removed. A new study in mice found that they also maintain their metabolism and detoxification function during the regeneration process, thanks to a subset of cells that expand their workload while the rest focuses on multiplication.
Moreover, liver cells communicate with each other to coordinate regenerative activity, which progresses from the center to the periphery of the lost liver lobes, researchers at the University of Illinois Urbana-Champaign said.
“It’s wonderful that we still don’t understand many aspects of liver regeneration,” said Illinois professor of biochemistry Uenach Kalsutra, who led the study published in the journal. Genome research. “After a portion is surgically removed, the remaining portion begins to regenerate rapidly. Within weeks, the liver returns to its original size and mass – no more, no less.”
Previous work from the Calcutra Group found that during regeneration, mature liver cells – usually stable and slow to divide – revert to a more flexible newborn state. This allows them to divide rapidly but causes them to lose their metabolic function. Questions remained about how the liver maintained a mature metabolic function while its cells returned to an immature state, and how do cells know when to stop proliferating.
“Whether regeneration follows a surgical removal of the liver, or due to an underlying liver disease or chronic liver injury due to alcohol or toxins, the liver must continue to function. This study revealed a division of labor within the liver that allowed it to meet the body’s metabolic needs during regeneration,” Said Kalsutra, a member of the Carl R Woese Institute for Genomic Biology in Illinois.
The researchers used a technique that allows them to individually sequence the RNA for each cell in regenerating mouse livers, revealing their activity. They studied mouse liver at various points during the regeneration process to map how regeneration progressed, as well as where metabolic function was maintained.
They have identified a specific class of cells that does not reproduce, but which instead intensifies its metabolic function, and has a greater workload. Graduate students Ullas Chembazhi and Sushant Bangru, co-authors of the paper, said these were localized near blood vessels.
Meanwhile, the regenerative cells multiplied in a coordinated manner, starting in the central regions and progressing outwards towards the periphery of the liver – in contrast to the prevailing field theories which say that diffusion begins near the veins.
“We actually found that the middle cells are the most productive, and that made perfect sense to us because we just discovered that there are certain cells that maintain their metabolic profiles and actually develop them. These metabolic cells live near blood vessels, so it makes sense for these cells to stay in place, And the inner cells are what divide.
The researchers found that regeneration and metabolism activities were coordinated by intense cell-to-cell communication. Contact increased dramatically after a portion of the liver was removed, but by the time regeneration slowed and stopped, the signal had returned to baseline levels.
In the study of intercellular coordination, they also found a possible explanation for how the regeneration process itself is organized so that the liver stops growing when it reaches its original size. Mature hepatocytes have an abundance of receptors on their surfaces that are activated by molecules, and adjacent cells to them are released after surgery, causing the cells to become neonate and divide. However, during the process of reproduction, cells stopped expressing the receptors, allowing them to return to a state of maturity when division is complete.
Normally, cells are ready to receive these signals. But once they regenerate, they do not need to continue receiving these signals as they will go into an endless chain of propagation. So they stop expressing these receptors. “Once the stimuli disappear and the regeneration is complete, the cells begin to produce more receptors until they are ready in the event that an infection occurs again,” says Calcutra.
The National Institutes of Health, Muscular Dystrophy Association and the Cancer Center of Illinois and the Center for Advanced Study in Illinois supported this work.
Editor’s Notes: To reach Auinash Kalsotra, call 217-300-7654; E-mail [email protected] The paper “Cellular plasticity as a balance between metabolic and reproductive dynamics of a regenerated liver” is available online.
Doi: 10.1101 / g.267013.120
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