Editors' ChoiceFibrosis

A Fine Line Between Healing and Fibrosis

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Science Translational Medicine  19 Feb 2014:
Vol. 6, Issue 224, pp. 224ec33
DOI: 10.1126/scitranslmed.3008648

The mammalian liver is an endless source of inspiration for developmental biologists because of its ability to regenerate in response to traumatic injury. Harnessing this innate capacity could do wonders to reverse the progression toward chronic liver disease such as cirrhosis. However, why the liver regenerates in response to acute injury but scars in response to chronic injury remains a long-standing puzzle whose solution is just out of reach.

Recent work from Rafii and colleagues sheds light on this mystery, and their work indicates strongly that sinusoidal endothelial cells, which compose the liver’s extensive microvasculature, dictate the regenerative fate of the organ. Stromal-derived factor-1 (SDF-1) is among the factors released in response to liver injury. Induction of acute injury by administration of a single dose of carbon tetrachloride resulted in enhanced expression of the SDF-1 receptor CXCR7 specifically, without affecting levels of the other SDF-1 receptor, CXCR4. Indeed, the livers of mice lacking Cxcr7 in endothelial cells specifically failed to regenerate robustly in response to acute injury. The authors demonstrated that hepatocyte growth factor and Wnt2 expression lie downstream of CXCR7 and that these factors mediate hepatocyte proliferation to regenerate the tissue in response to CXCR7-mediated angiocrine cues. In the context of chronic wounding, however, CXCR7 expression subsided after an initial spike, whereas CXCR4 levels steadily increased. Functionally, CXCR4 catalyzed a fibrotic response by altering the angiocrine profile of liver sinusoidal endothelial cells to one that promotes myofibroblast differentiation. Importantly, strategies that either blocked CXCR4 expression or induced CXCR7 levels substantially attenuated liver fibrosis and deactivated myofibroblast-like hepatic stellate cells

This provocative study provides a roadmap that should guide the development of therapies aimed at exploiting the natural regenerative capacity of the liver by either blocking upstream inducers of a profibrotic angiocrine profile or by manipulating the fate of the sinusoidal endothelium itself in order to subvert fibrosis and heal chronically wounded tissue. It remains to be seen whether sinusoidal endothelial cells also act earlier during liver disease progression by recruiting, polarizing, and/or maintaining specific immune cell populations that create a proinflammatory milieu and prevent proper regenerative healing. In either case, the work by Ding et al. illustrates that liver endothelium walks a fine line to regulate response to wounding.

B.-S. Ding et al., Divergent angiocrine signals from vascular niche balance liver regeneration and fibrosis. Nature, published online 20 November 2013 (10.1038/nature12681). [PubMed]

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