Granulocyte-colony stimulating factor promotes liver repair and induces oval cell migration and proliferation in rats.
OBJECTIVE
Hepatic regeneration is a heterogeneous phenomenon involving several cell populations. Oval cells are considered liver stem cells, a portion of which derive from bone marrow (BM). Recent studies have shown that granulocyte-colony stimulating factor (G-CSF) may be effective in facilitating liver repair. However, it remains unclear if G-CSF acts by mobilizing BM cells, or if it acts locally within the liver microenvironment to facilitate the endogenous restoration program. In the present study, we assessed the involvement of G-CSF during oval cell activation.


METHODS
Dipeptidyl-peptidase-IV-deficient female rats received BM transplants from wild-type male donors. Four weeks later, rats were subjected to the 2-acetylaminofluorene/partial hepatectomy model of oval cell-mediated liver regeneration, followed by administration of either nonpegylated G-CSF or pegylated G-CSF. Control animals did not receive further treatments after surgery. The magnitude of oval cell reaction, the entity of BM contribution to liver repopulation, as well as the G-CSF/G-CSF-receptor expression levels were evaluated. In addition, in vitro proliferation and migration assays were performed on freshly isolated oval cells.


RESULTS
Oval cells were found to express G-CSF receptor and G-CSF was produced within the regenerating liver. G-CSF administration significantly increased both the magnitude of the oval cell reaction, and the contribution of BM to liver repair. Finally, G-CSF acted as a chemoattractant and a mitogen for oval cells in vitro.


CONCLUSIONS
We have shown that G-CSF facilitates hepatic regeneration by increasing the migration of BM-derived progenitors to the liver, as well as enhancing the endogenous oval cell reaction.
Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, Florida 32610, USA. piscag@pathology.ufl.edu
Anna C
AC
Piscaglia
Thomas D
TD
Shupe
Seh-Hoon
SH
Oh
Antonio
A
Gasbarrini
Bryon E
BE
Petersen
D015073:2-Acetylaminofluorene / Q000494:pharmacology; D000818:Animals; D030801:Animals, Genetically Modified; D019898:Autocrine Communication; D001854:Bone Marrow Cells / Q000187:drug effects / Q000201:enzymology / Q000276:immunology / Q000378:metabolism*; D016026:Bone Marrow Transplantation; D002273:Carcinogens / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D018819:Dipeptidyl Peptidase 4 / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism* / Q000494:pharmacology; D006498:Hepatectomy; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000276:immunology / Q000378:metabolism* / Q000601:surgery; D008115:Liver Regeneration / Q000187:drug effects; D008297:Male; D023421:Models, Animal; D019899:Paracrine Communication; D051381:Rats; D011916:Rats, Inbred F344 / Q000235:genetics; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000378:metabolism*; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000187:drug effects / Q000201:enzymology / Q000276:immunology / Q000378:metabolism*; D018800:Thy-1 Antigens / Q000032:analysis; D013997:Time Factors
D002273:Carcinogens; D016188:Receptors, Granulocyte Colony-Stimulating Factor; D018800:Thy-1 Antigens; D016179:Granulocyte Colony-Stimulating Factor; D015073:2-Acetylaminofluorene; D018819:Dipeptidyl Peptidase 4