Pregnancy helps liver?

Pregnancy boosts the regenerative capacity of the liver in mice, a finding that may shed light on a process entirely separate from pregnancy -- aging, researchers report in linkurl:a study;http://www.ncbi.nlm.nih.gov/pubmed/20231314 published this week in Genes and Development.

lithograph of liver, Gray's Anatomy
Image: Wikimedia Commons

The findings are "really unexpected," said linkurl:Nikolai Timchenko,;http://www.bcm.edu/pathology/labs/timchenko/index.htm who studies liver regeneration and aging at Baylor College of Medicine in Houston, Texas. He noted that the researchers identified a specific regeneration mechanism present only during pregnancy and harnessed the relevant pathway to boost liver regeneration in aging mice. "I think from a molecular point of view this is the major discovery of this work," he said. "The loss of regenerative capacity of tissues with age is one of the main characteristics of aging," Timchenko, who didn't participate in the work, wrote in an email. Scientists have known for many years that old mice lose the regenerative capacity in their livers, but little about the molecular mechanisms underlying this process, he added. "Impaired liver regeneration and high rate of mortality after surgical resections in old patients are [the] two most significant problems which are discussed on each meeting of liver biology." linkurl:Yehudit Bergman,;http://www.hunews.huji.ac.il/articles.asp?cat=28&artID=942 a molecular biologist studying epigenetics in embryonic stem cells at The Hebrew University of Jerusalem, and her colleagues were interested in studying tissue regenerative capacity. They began with an linkurl:observation published;http://www.nature.com/nature/journal/v433/n7027/full/nature03260.html five years ago that the regenerative capacity of muscle progenitor cells in an older animal can be boosted by parabiosis -- an experimental technique in which the older animal's circulatory system is surgically linked to a younger animal, allowing it to benefit from the younger animal's systemic environment. Musing that pregnancy might be called a kind of parabiosis, the researchers tested the ability of the liver to regenerate after removing two thirds of it in older (10-12 month old) pregnant and nonpregnant mice. They observed a striking difference -- the liver regenerated to only about half its original volume in nonpregnant animals, but it grew back to 96 percent its normal size in pregnant ones. Nine out of 19 older nonpregnant mice died after the surgery, compared to just two out of 22 of the pregnant group. In contrast, younger animals (3 months old) showed robust regeneration whether they were pregnant or not. The researchers assumed this bounce-back was caused by liver cells proliferating during pregnancy, but a marker for dividing cells showed almost no proliferation in the liver between the second and third day after the surgery -- when proliferation is highest in nonpregnant animals. Rather than dividing, the cells that were present seemed to be growing larger. The results revealed that "in pregnancy the mechanism by which liver regeneration occurs is very different than the mechanism in nonpregnant mice," Bergman said. They then linked this effect to a signaling pathway called Akt/mTORC1, which is known to play a role in cell growth. When they blocked the pathway, the cell growth they had observed was eliminated. Meanwhile, proliferation got a small boost, but not enough to spur significant regeneration. "Once we knew that in pregnancy the model of regeneration is different, and we also knew that in aged mice liver regeneration is suffering, we thought, ok, maybe we can persuade aged mice to behave like pregnant mice," Bergman said. They tested the effect of a compound that activated the Akt/mTORC1 signaling pathway in old mice, between 18 and 24 months of age, and again removed two-thirds of their livers. None of the nine treated mice died after partial hepatectomy while four out of nine untreated mice died. "I'm not sure how important this observation is, and whether it has clinical implications," said linkurl:Douglas Schmucker,;http://anatomy.ucsf.edu/schmuckerfaculty6.html an expert in the liver and aging at the University of California, San Francisco, who was not involved in the work. Although he agreed that the observed effects were "pretty startling," he noted that it's not clear whether cell growth is equivalent to cell proliferation in how well regenerated liver will function. "Basically...are fatter, old cells better than thinner new cells?" he asked. Also, he said, if the effects are partly maternal, as the study suggests, it's not clear that men would be benefited by an approach based in this signaling pathway. Bergman noted that in their experiments, the liver appeared to be working normally, but agreed that the findings are extremely preliminary. Her group is now working on pinning down the molecular mechanism of the effect. "There must be something in pregnancy that induces this pathway," she said. The researchers are also trying to determine whether pregnancy has a similar regenerative effect on other organs.
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[30th March 2006]