The human liver has an impressive ability to regenerate in response to acute injury. However, in the case of chronic injury, liver damage leads to fibrosis, or scarring, rather than regeneration. Endothelial cells of the liver vasculature, liver sinusoidal endothelial cells (LSECs), produce angiocrine factors that induce either regeneration or fibrosis, dependent on the injury. New research from the lab of Shahin Rafii, M.D., at Weill Cornell Medical College, sheds light on how the LSECs modulate the liver’s response to damage. In a new paper published in Nature, Dr. Rafii’s research team identified two receptors in the LSECs, CXCR4 and CXCR7, that are induced following injury. Acute injury upregulates CXCR7 in the LSECs, where in conjunction with CXCR4, it activates Id2, turning on the pro-regenerative angiocrine factors. In contrast, chronic injury results in increased expression of CXCR4 and another receptor, FGFR1, that opposes CXCR7 activity, leading to fibrosis. Using several lines of knockout mice, the group showed that inactivation of CXCR7 impairs liver regeneration in the acute injury model, while inactivation of either FGFR1 or CXCR4 restored regeneration. Further, treatment of mice with a drug that activates CXCR7 prevented fibrogenesis. Identifying drug candidates or other means of modulating these angiocrine pathways could provide potential therapeutic strategies to spur liver regeneration even in the case of chronic injury.
This research was supported by NYSTEM awards C024180 (Shared Facilities) and C026438 and C028117 (IIRP to Dr. Rafii), as well as NYSTEM Institutional Training award C026878 to Weill Cornell.
Ding BS, Cao Z, Lis R, Nolan DJ, Guo P, Simons M, Penfold ME, Shido K, Rabbany SY, Rafii S. Divergent angiocrine signals from vascular niche balance liver regeneration and fibrosis. Nature. 2014 Jan 2; 505(7481):97-102. [Epub ahead of print].