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"The human liver has amazing regeneration capabilities: Even if up to 70 percent of it is removed, the remaining tissue can regrow a full-sized liver within months. ...
The new study, which appears this week in the Proceedings of the National Academy of Sciences, has identified one molecule that appears to play a key role, and also yielded several other candidates that the researchers plan to explore further. ...
Using this system, the researchers showed that increased fluid flow on its own did not stimulate hepatocytes to enter the cell division cycle. However, if they also delivered an inflammatory signal (the cytokine IL-1-beta), hepatocytes did enter the cell cycle. ..."
The new study, which appears this week in the Proceedings of the National Academy of Sciences, has identified one molecule that appears to play a key role, and also yielded several other candidates that the researchers plan to explore further. ...
One key factor is the reciprocal relationship between hepatocytes (the main type of cell found in the liver) and endothelial cells, which line the blood vessels. Hepatocytes produce factors that help blood vessels develop, and endothelial cells generate growth factors that help hepatocytes proliferate.
Another contributor that researchers have identified is fluid flow in the blood vessels. ...
To model all of these interactions ... designs microfluidic devices with channels that mimic blood vessels. To create these models of “regeneration on a chip,” the researchers grew blood vessels along one of these microfluidic channels and then added multicellular spheroid aggregates derived from liver cells from human organ donors. ...Using this system, the researchers showed that increased fluid flow on its own did not stimulate hepatocytes to enter the cell division cycle. However, if they also delivered an inflammatory signal (the cytokine IL-1-beta), hepatocytes did enter the cell cycle. ..."
"Liver disease causes ∼2 million annual deaths, yet medical treatments and transplantable organs are both lacking. The liver can regenerate when mature hepatocytes divide, and while this process is well studied in rodents, parallel study of human biology has been impossible. We developed a microfluidic device that allows us to manipulate fluid flow, circulating cytokines, and/or paracrine interactions between liver and vascular cells, in order to model multicellular aspects of human liver regeneration. We found that physiologically relevant shear stresses increased the secretion of angiogenesis- and regeneration-associated factors, including prostaglandin E2 from endothelial cells, and induced primary human hepatocytes to enter the cell cycle. ..."
From the abstract:
"... To this end, we developed a three-dimensional (3D) platform called structurally vascularized hepatic ensembles for analyzing regeneration (SHEAR) to model multiple aspects of human liver regeneration. SHEAR enables control over hemodynamic alterations to mimic those that occur during liver injury and regeneration and supports the administration of biochemical inputs such as cytokines and paracrine interactions with endothelial cells. We found that exposing the endothelium-lined channel to fluid flow led to increased secretion of regeneration-associated factors. Stimulation with relevant cytokines not only amplified the secretory response, but also induced cell-cycle entry of primary human hepatocytes (PHHs) embedded within the device. Further, we identified endothelial-derived mediators that are sufficient to initiate proliferation of PHHs in this context. ..."
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