The mechanical effects of blood flow drive hepatic growth and regeneration, according to new research published in Nature.

Electron micrograph showing hepatic blood vessels. Image courtesy of D. Eberhard, Heinrich-Heine-University Düsseldorf, Germany and S. Köhler, Heinrich-Heine-University Düsseldorf, Germany.

Over the past decade, increasing attention has been paid to the role of angiocrine signals, derived from endothelial cells, in regulating the growth and repair of many organs. This aspect is particularly true for the liver, an organ with an extensive blood supply that can regenerate more than two-thirds of its volume.

To explore how blood perfusion regulates liver growth, Eckhard Lammert and colleagues studied liver development in mice. “We used ex vivo cultivation of mouse embryos in which we either stopped the heart beat and thus the blood flow or increased it using epinephrine and atropine,” explains Lammert. These experiments indicated that blood perfusion promotes liver growth. Notably, increased blood flow was associated with increased activation of the mechanosensory molecules β1 integrin and VEGFR3. Levels of hepatocyte growth factor (HGF), a key regulator of liver growth, were also upregulated by increased blood flow.

Liver growth was markedly impaired and HGF levels were decreased when β1 integrin or VEGFR3 were knocked out specifically in endothelial cells, despite no substantial change in the number of blood vessels. “We then showed that ex vivo perfusion of adult mouse liver also turns on HGF production and c-Met signalling as flow increases and sinusoids are dilated,” continues Lammert. To confirm the specific role of mechanical forces in this effect, the investigators stretched human liver sinusoidal endothelial cells in culture; these cells released HGF and the pro-regenerative factors MMP9, TNF and IL-6.

In addition to shedding light on the fundamental mechanisms regulating liver growth and regeneration, Lammert points out that these findings could improve hepatocyte culture in vitro. A better appreciation of the pathways involved in liver regeneration might also aid understanding of diseases in which this process is impaired, such as cirrhosis.