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. Exp Hematol

Gene and Cell Therapy Center, Hematology Department/BMT Unit, G. Papanicolaou Hospital, Thessaloniki, Greece.
Experimental Hematology (Impact Factor: 2.48). 02/2005; 33(1):108-19. DOI: 10.1016/j.exphem.2004.09.005
Source: PubMed


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.
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.
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(+)).
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.

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    • "In previous studies we have demonstrated that granulocyte colony-stimulating factor (GCSF) either on its own or by mobilizing HSCs promotes endogenous repair programs in acute and chronic liver injury [7]. Acute liver injury represents a serious condition with high mortality rate. "
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    ABSTRACT: The aim of this study was to investigate the role of Mesenchymal Stem Cell (MSC) conditioned medium (CMMSC) on apoptosis of cultured mouse primary hepatocytes after in vivo carbon tetrachloride (CCl4)-induced acute liver injury. The acute liver injury was induced by injecting CCl4 intraperitoneally in C57/BL6 mice. Hepatocytes were isolated by liver perfusion, cultured in a defined medium to maintain their differentiation and characterized by reverse transcriptase polymerase chain reaction (RT-PCR) using the hepatic cell specific genes albumin, hepatocyte nuclear factor 4 (HNF4) and cytokeratin 18 (CK18). CMMSC was generated from cultured bone marrow-derived MSCs (BM-MSCs). BM-MSCs were positive for CD73, CD90, CD44 by flow cytometry and able to differentiate into chondrocytes, adipocytes and osteocytes. Apoptosis was evaluated by both annexin V. CMMSC were examined by flow cytometry to detect MSC-derived annexin V- and CD54/CD44-positive microparticles (MPs). In the CCl4-CMMSC treated hepatocytes, interleukin-6 (IL-6) was increased on the first day of culture compared to control and CCl4 and was followed by upregulation of fibroblast-like-protein (FGL1) expression after 48 hrs. This was associated with a significant decrease of annexin V positive CCl4-CMMSC treated hepatocytes at day 3 post plating. Recombinant IL-6 was induced FGL1 expression in hepatocytes derived from CCl4-treated mice suggesting that CMMSC, which is enriched also in microparticles, attenuates CCl4-induced early apoptosis in hepatocytes through activation of FGL1.
    International journal of clinical and experimental pathology 05/2013; 6(5):831-40. · 1.89 Impact Factor
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    • "G-CSF has been shown to be secreted by granulosa cells at ovulation (Salmassi et al., 2004), then during the luteal phase within the endometrium and finally during gestation in the placenta (Duan, 1990). FF G-CSF may promote local maternofetal tolerance (Rutella et al., 2005) or influence the oocyte's own mRNA levels or its potential for self-repair (Yannaki et al., 2005). It might also interact with environmental cells to produce cytokines and growth factors which are necessary for the embryo's development and implantation. "

    Embryology - Updates and Highlights on Classic Topics, 03/2012; , ISBN: 978-953-51-0465-0
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    • "In this regard many investigators demonstrate that G-CSF decreases aminotransferases activity and subsequently enhance liver regeneration in chemical– induced liver injury in animal models (Theocharis et al., 2003). Other investigators report that G-CSF administration significantly improves survival of animals in the liver injury model induced by chemical liver injury (Yannaki et al., 2005). Similar results were obtained in the present study. "
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    ABSTRACT: Previous investigators have suggested that granulocyte colony-stimulating factor (G-CSF) may accelerate the healing process of liver lesions. This hypothesis has been discussed by some researchers. The action mechanisms remains unclear and further studies are needed to clarify this mechanism. To test this, we establish a rat model of liver injury using dimethylnitrosamine (DMN), transplanted the G-CSF into the rats. To determine whether G-CSF could prevent liver injury in DMN-intoxicated rats, we employed the model of acute and chronic liver injury induced by DMN: our study was limited to the characteristic changes in biochemical and histological parameters seen in liver damage. The DMN injections were given twice weekly for four weeks to establish liver damage. Rat was treated with DMN by intraperitoneal (IP) injection. On the 1st, 7th or 28th days, rats were sacrificed and liver histology was examined. Serial 5 μm sections of the liver were stained with hematoxylin and eosin (H&E). The serial measurement of the end products of hepatic synthetic activity also was used to assess liver damage. Liver injury was determined by biochemical and histological examination. As it is evident from results after administration of DMN, in addition to histologically changes of liver tissue, central vein, liver cord, sinusoids and bile duct were not normal, the activities of the serum liver enzymes also rose. Administration of G-CSF caused a statistically significantly decrease in the liver enzymes activity and sever of biochemical synthesis disruption in the liver. The protective role of G-CSF was showed in this rat model of acute and chronic liver damage induced by DMN. Our results showed beneficial effects of G-CSF treatment after liver injury on liver function. Histological and biochemical assessment of liver function revealed that liver tissue have a unique regenerative capability.
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