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Sci. Signal., 7 January 2014
Vol. 7, Issue 307, p. ec7
[DOI: 10.1126/scisignal.2005047]

EDITORS' CHOICE

Physiology From Stimulating Regeneration to Provoking Fibrosis

Nancy R. Gough

Science Signaling, AAAS, Washington, DC 20005, USA

Chronic injury transforms the regenerative response of the liver into a fibrotic response. Understanding how hepatic vascular endothelial cells switch from signaling regeneration to promoting fibrosis should enable the development of therapeutic strategies to promote liver repair without exacerbating injury. Ding et al. used conditional endothelial cell–specific knockout of the chemokine receptors CXCR4 and CXCR7 and the fibroblast growth factor receptor FGFR1 with either acute or chronic liver injury models in mice to investigate how the liver vascular endothelial cells undergo this profibrotic transition. The proregenerative signal involves activation of CXCR4 and CXCR7, which can form heterodimers, by the chemokine SDF-1 to stimulate the activity of the transcription factor Id. Knockdown of either CXCR4 or CXCR7 in cultured liver sinusoidal endothelial cells (LSECs) prevented the SDF-1–induced increase in Id abundance. In response to acute liver injury, mice with conditional endothelial cell-specific knockout of CXCR7 showed exacerbated damage and a reduction in the Id-dependent increase in the expression of genes encoding regeneration-promoting factors in LSECs. In two chronic liver injury models, the abundance of CXCR4-encoding transcripts increased and that of CXCR7-encoding transcripts decreased, which was reflected in a decrease in the abundance of CXCR7. In the chronic injury mouse model, endothelial cell-specific CXCR7 knockout increased the abundance of the fibrotic indicators smooth muscle actin and collagen and increased liver damage. Experiments with cultured human LSECs suggested that FGF-2 mediated the switch in receptor balance from CXCR7 predominating to CXCR4 predominating. LSECs isolated from mice exposed to the chronic liver injury paradigm exhibited an increase in FGFR1 signaling, represented by increased phosphorylation of extracellular-regulated signaling kinases 1 and 2 (ERK1/2) and of the adaptor FRS2, and the increase peaked midway through the injury-inducing treatment. Endothelial cell-specific knockout of FGFR1 prevented (i) the switch in the abundance of CXCR4 and CXCR7, (ii) stimulation of phosphorylation of ERK1/2, (iii) reduction in the abundance of proregenerative factors, (iv) deposition of fibrotic markers, and (v) liver damage in the chronic liver injury model. Similarly, profibrotic events and liver injury were reduced in mice with the endothelial cell–specific knockout of CXCR4. Thus, chronic injury appears to induce excessive FGFR1 signaling, leading to a switch in chemokine receptor abundance that shifts the vascular niche from sending out a proregeneration signal to sending out a profibrosis signal.

B.-S. Ding, Z. Cao, R. Lis, D. J. Nolan, P. Guo, M. Simons, M. E. Penfold, K. Shido, S. Y. Rabbany, S. Raffi, Divergent angiocrine signals from vascular niche balance liver regeneration and fibrosis. Nature 505, 97–102 (2014). [PubMed]

Citation: N. R. Gough, From Stimulating Regeneration to Provoking Fibrosis. Sci. Signal. 7, ec7 (2014).



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