Neutralization of CXCL10 accelerates liver regeneration in carbon tetrachloride-induced acute liver injury.
Remodeling of hepatic tissue structure following injury requires the coordinated action of hepatocytes, hepatic stellate cells (HSCs), and endothelial cells. However, their in vivo properties are not fully understood. We report here that the chemokine CXCL10 regulates hepatic tissue remodeling in a carbon tetrachloride (CCl(4))-induced acute liver injury in mice. The production of CXCL10 was enhanced by hepatocytes after CCl(4) exposure. Neutralization of CXCL10 protected mice from acute liver dysfunction and diminished hepatocellular loss. The hepatoprotective effect was associated with increased numbers of 5'-bromo-2' deoxyuridine (BrdU)+ hepatocytes from day 1 and with accumulation of HSCs and endothelial cells within the injured zones from day 3. In vitro, recombinant CXCL10 directly inhibited the proliferation of hepatocytic cells, establishing a novel role of CXCL10 in modulating hepatocyte proliferation, in addition to a previously reported angiostatic role. In summary, neutralization of CXCL10 initially stimulates hepatocyte proliferation and, subsequently, HSC migration and angiogenesis to facilitate remodeling of hepatic cords. Thus, CXCL10 can be a novel therapeutic target for acute hepatocellular damage by regulating liver tissue remodeling.
Yoneyama
Hiroyuki
H
Laboratory of Stem Cell Dynamism, Stelic Institute of Regenerative Medicine, Stelic Institute & Co., 1-9-15 Higashi-azabu, Mihato-ku, Tokyo, Japan. yoneyama@stelic.co.jp
Kai
Yoshiro
Y
Koyama
Jun
J
Suzuki
Kenji
K
Kawachi
Hiroshi
H
Narumi
Shosaku
S
Ichida
Takafumi
T
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D002251:Carbon Tetrachloride; D049109:Cell Proliferation / Q000187:drug effects; D054357:Chemokine CXCL10 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D022781:Hepatocytes / Q000187:drug effects / Q000473:pathology; D017114:Liver Failure, Acute / Q000139:chemically induced / Q000378:metabolism*; D008115:Liver Regeneration / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009500:Neutralization Tests; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
D054357:Chemokine CXCL10; D012333:RNA, Messenger; D011994:Recombinant Proteins; D002251:Carbon Tetrachloride; D000410:Alanine Transaminase