Direct mechanical exposure initiates hepatocyte proliferation.

Background & Aims: Liver paracrine signaling from liver sinusoid endothelial cells to hepatocytes in response to mechanical stimuli is crucial in highly coordinated liver regeneration. Interstitial flow through the fenestrated endothelium inside the space of Disse potentiates the role of direct exposure of hepatocytes to fluid flow in the immediate regenerative responses after partial hepatectomy, but the underlying mechanisms remain unclear.

Methods: Mouse liver perfusion was used to identify the effects of interstitial flow on hepatocyte proliferation . Isolated hepatocytes were further exposed to varied shear stresses directly . Knockdown and/or inhibition of mechanosensitive proteins were used to unravel the signaling pathways responsible for cell proliferation.

Results: An increased interstitial flow was visualized and hepatocytes' regenerative response was demonstrated experimentally by perfusion of mouse livers. measurements also showed that fluid flow initiated hepatocyte proliferation in a duration- and amplitude-dependent manner. Mechanistically, flow enhanced β1 integrin expression and nuclear translocation of YAP (yes-associated protein), via the Hippo pathway, to stimulate hepatocytes to re-enter the cell cycle.

Conclusions: Hepatocyte proliferation was initiated after direct exposure to interstitial flow or shear stress , which provides new insights into the contributions of mechanical forces to liver regeneration.

Impact And Implications: By using both liver perfusion and flow exposure tests, we identified the roles of interstitial flow in the space of Disse in stimulating hepatocytes to re-enter the cell cycle. We found an increase in shear flow-induced hepatocyte proliferation via β1 integrin-YAP mechanotransductive pathways. This serves as a useful model to potentiate hepatocyte expansion using mechanical forces.