G-CSF-primed hematopoietic stem cells or G-CSF per se accelerate recovery and improve survival after liver injury, predominantly by promoting endogenous repair programs.
OBJECTIVE
On the basis of the recently recognized potential of bone marrow (BM) cells to give rise to hepatocytes, we investigated the possibility that granulocyte colony-stimulating factor (G-CSF)-mobilized BM cells could home to the injured liver and promote tissue repair. We also examined the origin of cells (endogenous or BM) reconstituting liver after damage.


METHODS
Acute and chronic liver injury models were generated by injecting CCl4 in C57Bl6 mice and G-CSF was administered in hematopoietic stem cell (HSC) mobilization doses. After sex-mismatched BM transplantation into lethally irradiated recipients and treatment with CCl4 +/- G-CSF, sry (sex-determining region for Y chromosome) protein was detected by immunohistochemistry in liver sections. Double immunohistochemistry for sry and ki-67 protein was used to define the origin of proliferating cells reconstituting liver after injury.


RESULTS
In both acute and chronic liver injury model, G-CSF administration ameliorated the histological damage and accelerated the regeneration process. This was accompanied by a strong survival benefit in G-CSF-treated group vs CCl4 group. Quantitative analysis showed higher percentage of BM-origin hepatocytes in the CCl4+G-CSF group compared with the CCl4 group, although the liver engraftment rate still remained rather low. Double staining for ki-67 and sry demonstrated that the recovery acceleration after chemical injury and G-CSF treatment was mainly mediated by increased proliferation of host hepatocytes (ki-67(+)/sry(-)) with less support from BM-origin cells (ki-67(+)/sry(+)).


CONCLUSIONS
G-CSF treatment significantly improved survival and liver histology in chemically injured mice, predominantly by promoting endogenous repair mechanisms. Therefore, mobilization with G-CSF might offer a novel therapeutic approach for the treatment of acute and chronic liver diseases in humans.
Yannaki
Evangelia
E
Gene and Cell Therapy Center, Hematology Department/BMT Unit, G. Papanicolaou Hospital, Thessaloniki, Greece. eyannaki@u.washington.edu
Athanasiou
Evangelia
E
Xagorari
Angeliki
A
Constantinou
Varnavas
V
Batsis
Ioannis
I
Kaloyannidis
Panagiotis
P
Proya
Evangelia
E
Anagnostopoulos
Achilles
A
Fassas
Athanasios
A
D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects / Q000502:physiology; D016026:Bone Marrow Transplantation; D002251:Carbon Tetrachloride; D019070:Cell Lineage; D002465:Cell Movement; D049109:Cell Proliferation; D004195:Disease Models, Animal; D006085:Graft Survival; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage / Q000494:pharmacology*; D019650:Hematopoietic Stem Cell Mobilization / Q000379:methods; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000502:physiology*; D022781:Hepatocytes / Q000166:cytology; D008099:Liver / Q000293:injuries / Q000473:pathology / Q000502:physiology*; D008106:Liver Cirrhosis, Experimental / Q000473:pathology / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D012038:Regeneration / Q000187:drug effects*; D015996:Survival Rate; D016896:Treatment Outcome
D016179:Granulocyte Colony-Stimulating Factor; D002251:Carbon Tetrachloride