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.
Piscaglia
Anna C
AC
Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, Florida 32610, USA. piscag@pathology.ufl.edu
Shupe
Thomas D
TD
Oh
Seh-Hoon
SH
Gasbarrini
Antonio
A
Petersen
Bryon E
BE
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