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.
"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 . Acute liver injury represents a serious condition with high mortality rate. "
[Show abstract][Hide abstract] 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
"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. "
[Show abstract][Hide abstract] ABSTRACT: Only liver transplantation is currently available therapy for the patients with acute liver failure (ALF). This study was designed to determine whether administration of granulocyte colony-stimulating factor (G-CSF) has therapeutic efficacy in animals with ALF. Female Sprague-Dawley (SD) rats were intraperitoneally injected with a single dose of d-galactosamine (d-GalN, 1.4g/kg) to induce ALF. After 2h, the rats were randomized to receive G-CSF (50μg/kg/day), or saline vehicle injection for 5 days. Rats were observed for survival and assessed for liver injury by serum alanine transaminase (ALT) measurement and histological analysis. CD34+ cells in bone marrow were assessed by flow cytometry. CD34+ cells and Ki-67+ hepatocytes in liver tissue were evaluated by immunohistochemistry. In the ALF model, 5-day survival after d-GalN injection was 33.3% (10/30), while G-CSF administration following d-GalN resulted in 53.3% (16/30) survival (p=0.027). G-CSF treated rats had lower ALT level and less hepatic injury compared with saline vehicle rats. The increases of CD34+ cells in bone marrow and liver tissue and Ki-67+ cells in liver tissue in G-CSF treated rats were higher than those in saline rats. No correlation was observed between CD34+ cells and Ki-67+ hepatocytes in liver tissue in both G-CSF and vehicle rats. It is suggested that G-CSF increases survival rate, decreases liver injury and enhances hepatocyte proliferation in rats with d-GalN-induced ALF possibly through actions including but not limiting to CD34+ cell mobilization, and that G-CSF may be of potential value in treating ALF.
Gregory S Calip, Judith A Malmgren, Wan-Ju Lee, Stephen M Schwartz, Henry G Kaplan
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