Role of CD44 in epithelial wound repair: migration of rat hepatic stellate cells utilizes hyaluronic acid and CD44v6.
The hyaluronic acid receptor, CD44, exists as multiple splice variants that appear to have a role in migration of tumor cells. The role of this receptor and its variants in normal wound repair is poorly understood. A central feature of wound repair in the liver is activation and migration of perisinusoidal stellate cells. We have examined CD44 expression by stellate cells from normal or injured rat liver, finding that it increases with injury and involves a distinct set of CD44 splice variants. Among the latter, variants containing the v6 exon (CD44v6) are strikingly increased. Analysis of migration of primary cells on transwell filter inserts reveals that only cells isolated from injured liver are migratory. Also, they move more rapidly on hyaluronic acid than on collagen I or collagen IV. A polyclonal antibody to recombinant CD44v6 blocks migration by 50%, whereas antibody to CD44v4 has no effect. The inhibition is specific for cells migrating on hyaluronic acid and is reversed by synthetic peptide representing the N terminus of the v6 protein. In conclusion, activated stellate cells use CD44v6 and hyaluronic acid for migration. Given the evidence that migration is required for progression of injury with scar formation, blockers of CD44v6 expression or function are candidates for preventing the deleterious effects of chronic fibrosis.
Kikuchi
Shojiro
S
Department of Medicine and Liver Center, University of California, San Francisco, California 94143, USA.
Griffin
Courtney T
CT
Wang
Shao-Shean
SS
Bissell
D Montgomery
DM
D017398:Alternative Splicing; D000818:Animals; D002465:Cell Movement; D002478:Cells, Cultured; D003001:Cloning, Molecular; D003094:Collagen / Q000378:metabolism; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005091:Exons; D005355:Fibrosis; D006023:Glycoproteins / Q000737:chemistry; D018960:Hyaluronan Receptors / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D006820:Hyaluronic Acid / Q000494:pharmacology; D008099:Liver / Q000166:cytology* / Q000293:injuries / Q000378:metabolism / Q000473:pathology; D008297:Male; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000737:chemistry; D013997:Time Factors; D014945:Wound Healing
C112697:CD44v6 antigen; D016895:Culture Media, Serum-Free; D006023:Glycoproteins; D018960:Hyaluronan Receptors; D020033:Protein Isoforms; D012333:RNA, Messenger; D011994:Recombinant Proteins; D006820:Hyaluronic Acid; D003094:Collagen