Attenuated response to liver injury in moesin-deficient mice: impaired stellate cell migration and decreased fibrosis.
Hepatic stellate cells (HSCs) respond to injury with a coordinated set of events (termed activation), which includes migration and upregulation of matrix protein production. Cell migration requires an intact actin cytoskeleton that is linked to the plasma membrane by ezrin-radixin-moesin (ERM) proteins. We have previously found that the linker protein in HSCs is exclusively moesin. Here, we describe HSC migration and fibrogenesis in moesin-deficient mice. We developed an acute liver injury model that involved focal thermal denaturation and common bile duct ligation. HSC migration and collagen deposition were assessed by immunohistology and quantitative real-time PCR. Activated HSCs were isolated from wild-type or moesin-deficient mice for direct examination of migration. Activated HSCs from wild-type mice were positive for moesin. Migration of moesin-deficient HSCs was significantly reduced. In a culture assay, 22.1% of normal HSCs migrated across a filter in 36 h. In contrast, only 1.3% of activated moesin-deficient HSCs migrated. Collagen deposition around the injury area similarly was reduced in moesin-deficient liver. The linker protein moesin is essential for HSC activation and migration in response to injury. Fibrogenesis is coupled to migration and reduced in moesin-deficient mice. Agents that target moesin may be beneficial for chronic progressive fibrosis.
Okayama
Tokunari
T
Department of Surgery, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto 602-8566, Japan.
Kikuchi
Shojiro
S
Ochiai
Toshiya
T
Ikoma
Hisashi
H
Kubota
Takeshi
T
Ichikawa
Daisuke
D
Fujiwara
Hitoshi
H
Okamoto
Kazuma
K
Sakakura
Chouhei
C
Sonoyama
Teruhisa
T
Kokuba
Yukihito
Y
Doi
Yoshinori
Y
Tsukita
Sachiko
S
Bissell
D Montgomery
DM
Otsuji
Eigo
E
D000818:Animals; D001652:Bile Ducts / Q000473:pathology; D002425:Cautery; D002465:Cell Movement; D002478:Cells, Cultured; D003094:Collagen / Q000096:biosynthesis; D003598:Cytoskeletal Proteins / Q000378:metabolism; D022781:Hepatocytes / Q000473:pathology*; D006358:Hot Temperature; D008026:Ligation; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000378:metabolism* / Q000473:pathology*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000172:deficiency* / Q000378:metabolism; D014945:Wound Healing; D000099149:Ezrin
D003094:Collagen; D003598:Cytoskeletal Proteins; D008565:Membrane Proteins; D008840:Microfilament Proteins; D000099149:Ezrin; C071058:moesin; C071776:radixin