Granulocyte-colony stimulating factor induces proliferation of hepatic progenitors in alcoholic steatohepatitis: A randomized trial

Abstract

Liver failure is the major cause of death in alcoholic steatohepatitis (ASH). In experimental hepatitis, granulocyte-colony stimulating factor (G-CSF) mobilizes hematopoietic stem cells, induces liver regeneration, and improves survival. We studied the short-term effects of G-CSF on CD34؉ stem cell mobilization, liver cell proliferation, and liver function in patients with ASH. Twenty-four patients (mean age 54 years) with alcoholic cirrhosis [Child-Turcotte-Pugh score 10 (7-12)] and concomitant biopsy-proven ASH [Maddrey score 36 (21-60)] were randomized to standard care associated with 5 days of G-CSF (10 g/kg/day, group A, n ‫؍‬ 13) or standard care alone (group B, n ‫؍‬ 11). Serial measurement of CD34؉ cells, liver tests, cytokines [hepatocyte growth factor (HGF); tumor necrosis factor ␣; tumor necrosis factor-R1; interleukin-6; alfa-fetoprotein], and 13 C-aminopyrine breath tests were performed. Proliferating hepatic progenitor cells [HPC; double immunostaining (Ki67/cytokeratin 7)], histology, and neutrophils were assessed on baseline and day 7 biopsies. Abstinent alcoholic patients with cirrhosis served as controls for immunohistochemistry. G-CSF was well tolerated. At day 7, both CD34؉ cells (؉747% versus ؊6%, P < 0.003), and HGF (؉212% versus ؊7%, P < 0.03) increased in group A but not in group B. Cytokines and aminopyrine breath test changes were similar between groups. On repeat biopsy, a >50% increase in proliferating HPC was more frequent in group A than in group B (11 versus 2, P < 0.003). Changes in Ki67؉/cytokeratin 7؉ cells correlated with changes in CD34؉ cells (r ‫؍‬ 0.65, P < 0.03). Neutrophils and histological changes were similar in both groups. Conclusion: G-CSF mobilizes CD34؉ cells, increases HGF, and induces HPC to proliferate within 7 days of administration. Larger trials would be required to determine whether these changes translate into improved liver function. (HEPATOLOGY 2008;48:221-229.)

Status of and candidates for cell therapy in liver cirrhosis: overcoming the “point of no return” in advanced liver cirrhosis

“…Furthermore, several routes of cell administration have been investigated, included peripheral veins, the hepatic artery, and the portal vein [45][46][47][48][49][50][51][52][53][54]. In a randomized control study, Spahr et al reported that there were no significant differences in treatment outcomes when using autologous BMNCs harvested after G-CSF infusion through the hepatic artery, although several other randomized studies have shown favorable results, suggesting the usefulness of these therapies [50]. More recently, the Repeated AutoLogous Infusion of Stem cells In Cirrhosis (REALISTIC), a multicenter, phase II, open-label, randomized controlled trial of repeated autologous infusion of G-CSF-mobilized CD133?…”

Stem cells in liver regeneration, fibrosis and cancer: the good, the bad and the ugly

“…Transplanted oval cells can make a modest (∼2% after 1 month, falling to 0.4% at 6 months) contribution to the hepatocyte population in the CCl 4 -damaged mouse liver [92]. The progenitor response can be manipulated in vivo; in the 2-AAF/PH model the oval cell reaction can be significantly boosted by G-CSF [93], and a small study of patients with alcoholic steatohepatitis found that 5 days of G-CSF treatment resulted in a four-fold increase in proliferating HPCs [94].…”

Bone marrow injection stimulates hepatic ductular reactions in the absence of injury via macrophage-mediated TWEAK signaling

“…Whereas transplantation of HPCs has been successful in rodents (9), isolation of human HPCs is not a practical therapeutic option (10). Manipulation of the liver's endogenous DRs and HPCs represents a more realistic therapeutic approach (11,12).…”