In contrast to most adult mammalian tissues, the liver can regenerate itself to an impressive degree. That regeneration is critical to survival – as a key digestive organ, the liver deals with all sorts of toxins, from rotten-ish food in the wild to alcohol in more cultured settings.

Nevertheless, Fatima Rizvi told her audience at Monday's plenary meeting of the The Liver Meeting - Digital Experience (TLMDX) 2021, first-line regenerative capacity can be overwhelmed through both chronic and acute settings.

In such circumstances, however, the liver has second-line defenses.

That first-line regeneration is driven by hepatocytes, which are the main functional cells of the liver and make up 80% of its bulk.

Rizvi, a postdoctoral scholar in the laboratory of Valerie Gouon-Evans at Boston University, described new insights into how another cell type, the cholangiocyte, could contribute to regeneration in response to either acute or chronic injuries.

Cholangiocytes are the epithelial cells lining the bile duct, and at 2%, make up a much smaller proportion of cells in the liver than hepatocytes.

When the bile duct is injured, cholangiocytes proliferate in a ductular reaction. This ductular reaction could also set off transition to a progenitor-like cell state, followed by differentiation into hepatocytes.

Previous work had suggested that VEGF2/KDR receptor expression on cholangiocytes was critical to the ductular reaction and hepatocyte conversion. In the studies presented at the meeting, which won an AASLD Foundation Abstract Award, Rizvi and her team induced either acute liver injury through an acetaminophen overdose, or chronic liver injury via diet.

Because cholangiocyte-derived liver repair is a backup mechanism when hepatocytes are exhausted, the team also induced senescence in hepatocytes through the transgenic delivery of the senescence protein p21.

Finally, they used mRNA complexed to lipid nanoparticles (mRNA-LNP) to induce the expression of VEGFA, which binds to the KDR receptor.

In both acute and chronic liver toxicity models, they showed that "transient VEGFA expression in the liver via mRNA-LNP delivery robustly and significantly increased the numbers of cholangiocyte-derived... hepatocytes, as well as fully reverted steatosis and fibrosis in chronically injured livers."

Rizvi said that in regeneration experiments, "a gold standard question [is] whether these cells that you are functional or not." In her team's experiments, the researchers showed that the induced cells were able to store glycogen, which is a key functional characteristic of hepatocytes.

The work suggests that in principle, VEGFA could be used to boost liver regeneration after injuries. The authors noted in their abstract that their project "introduces the non-integrative mRNA-LNP, currently used for COVID-19 vaccines, as a clinically safe tool for VEGFA delivery to potentially treat human liver diseases."

Rizvi's team plans to further study the molecular characteristics of the hepatocytes that result from cholangiocyte reprogramming, including checking whether they have additional functional abilities besides glycogen storage, for example, the ability to transport bile. Though the KDR/VEGFA signaling axis is "much studied with respect to angiogenesis and vasculogenesis," she said, "we don't know much yet" about how it works in liver cell regeneration.