Expression and role of Gas6 protein and of its receptor Axl in hepatic regeneration from oval cells in the rat.
OBJECTIVE
The growth arrest-specific gene 6 (Gas6) protein is a vitamin K-dependent protein that binds to the Axl subfamily of tyrosine kinase receptors and exerts antiapoptotic and proliferative effects. Because Gas6 plays a role in development and tissue remodelling, we studied its expression as well as that of its high-affinity receptor Axl in a well-characterized model of hepatic regeneration from precursor oval cells.


METHODS
Hepatic regeneration was induced by treating rats with acetylaminofluorene followed by partial hepatectomy.


RESULTS
Oval cell accumulation, which predominated in periportal regions, reached a maximum at days 9 and 14 after hepatectomy and declined thereafter. Oval cells expressed Gas6 protein and messenger RNA (mRNA). Axl mRNA hepatic levels paralleled the number of oval cells, and immunohistochemistry showed Axl expression in these cells. WB-F344 cells, a hepatocytic precursor cell line, also expressed Gas6 and Axl. Addition of Gas6 significantly increased the number of WB-F344 cells cultured with or without serum. Gas6 did not increase cell entry in the S phase of the cell cycle but inhibited 15-d-prostaglandin J2-induced WB-F344 cell apoptosis.


CONCLUSIONS
Our data demonstrate an expression of Gas6 and of its receptor Axl by oval cells during hepatic regeneration. Because the Gas6/Axl couple protects from apoptosis a hepatocytic precursor cell line, these results strongly suggest that the Gas6/Axl couple favors oval cell accumulation in regenerating liver by an autocrine/paracrine mechanism.
Couchie
Dominique
D
INSERM U581, Hôpital Henri Mondor, Université Paris XII-Val de Marne, Créteil, France. couchie@im3.inserm.fr
Lafdil
Fouad
F
Martin-Garcia
Nadine
N
Laperche
Yannick
Y
Zafrani
Elie Serge
ES
Mavier
Philippe
P
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D019898:Autocrine Communication / Q000502:physiology; D002478:Cells, Cultured; D015870:Gene Expression / Q000502:physiology; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008099:Liver / Q000166:cytology* / Q000502:physiology*; D008115:Liver Regeneration / Q000502:physiology*; D008297:Male; D015513:Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D019899:Paracrine Communication / Q000502:physiology; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011916:Rats, Inbred F344; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D013234:Stem Cells / Q000502:physiology; D013936:Thymidine / Q000493:pharmacokinetics; D014316:Tritium; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6
D036341:Intercellular Signaling Peptides and Proteins; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D020794:Receptor Protein-Tyrosine Kinases; D013936:Thymidine; D014316:Tritium; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6