title: Multiple courses of G-CSF in patients with decompensated cirrhosis: consistent mobilization of immature cells expressing hepatocyte markers and exploratory clinical evaluation.
abstract: BACKGROUND
  Bone marrow-derived cells (BMCs) include stem cells capable of self-renewal and differentiation into a variety of cell types. Administration of granulocyte colony-stimulating factor (G-CSF) induces the circulation of BMCs in the peripheral blood. A phase II prospective trial was carried out for evaluation of BMC mobilization induced by multiple courses of G-CSF in cirrhotic patients.
  
  
  METHODS
  Fifteen patients with advanced liver cirrhosis (Child-Pugh score ≥6 points) were enrolled and treated with a 3-day G-CSF course, administered at 3-month intervals for a total of four courses. BMC mobilization was assessed by evaluating CD34+ve cells using flow cytometry. Expressions of multiple hepatic and stem markers were assessed on mobilized CD34+ve cells. Feasibility and safety were explored; clinical and adverse events were compared to those of a control group. Telomere length was monitored to rule out early cell aging caused by G-CSF.
  
  
  RESULTS
  A significant increase in G-CSF-induced circulating CD34+ve cells was consistently observed, although a progressive reduction of peak values was documented from cycle I to IV (p < 0.005). Mobilized CD34+ve cells expressed both stem and multiple hepatocyte markers, including mRNA of albumin and CYP2B6 (cytochrome P2 B6). Treatment was well tolerated, with no severe adverse events and no significant telomere length shortening following G-CSF. The procedure was safe. Overall, ten patients had either improved or had stable liver function tests (such as the Child-Pugh score), whereas five worsened and died from liver-related causes.
  
  
  CONCLUSIONS
  This study demonstrates that G-CSF can be safely administrated up to four times over a 1-year period in decompensated cirrhotic patients. The repeated BMC mobilization favors the circulation of stem cells coexpressing hepatic markers and mRNA of liver-related genes.
authors.affiliation: Department of Gastro-hepatology, A.O. Città della Salute e della Scienza, S. Giovanni Battista Hospital, University of Turin, C. Bramante 88, 10126, Turin, Italy. silvia.gaia74@gmail.com.
authors.forename: Silvia
authors.initials: S
authors.lastname: Gaia
authors.affiliation: Department of Gastro-hepatology, A.O. Città della Salute e della Scienza, S. Giovanni Battista Hospital, University of Turin, C. Bramante 88, 10126, Turin, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Olivero
authors.affiliation: Department of Gastro-hepatology, A.O. Città della Salute e della Scienza, S. Giovanni Battista Hospital, University of Turin, C. Bramante 88, 10126, Turin, Italy.
authors.forename: Antonina
authors.initials: A
authors.lastname: Smedile
authors.affiliation: Division of Hematology and Cell Therapy, University of Torino, Mauriziano Hospital, Turin, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Ruella
authors.affiliation: Department of Gastro-hepatology, A.O. Città della Salute e della Scienza, S. Giovanni Battista Hospital, University of Turin, C. Bramante 88, 10126, Turin, Italy.
authors.forename: Maria Lorena
authors.initials: ML
authors.lastname: Abate
authors.affiliation: Department of Clinical Nutrition, A.O. Città della Salute e della Scienza, S. Giovanni Battista Hospital, University of Turin, C. Bramante 88, 10126, Turin, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Fadda
authors.affiliation: Department of Gastro-hepatology, A.O. Città della Salute e della Scienza, S. Giovanni Battista Hospital, University of Turin, C. Bramante 88, 10126, Turin, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Rolle
authors.affiliation: Division of Hematology 1, A.O. Città della Salute e della Scienza, S. Giovanni Battista Hospital, University of Turin, C. Bramante 88, 10126, Turin, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Omedè
authors.affiliation: Division of Hematology 1, A.O. Città della Salute e della Scienza, S. Giovanni Battista Hospital, University of Turin, C. Bramante 88, 10126, Turin, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Bondesan
authors.affiliation: Division of Nuclear Medicine 2, A.O. Città della Salute e della Scienza, S. Giovanni Battista Hospital, University of Turin, C. Bramante 88, 10126, Turin, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Passera
authors.affiliation: Molecular Biotechnology Center, University of Torino, Turin, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Risso
authors.affiliation: Department of Medicine and Experimental Oncology, University of Torino, Turin, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Aragno
authors.affiliation: Department of Gastro-hepatology, A.O. Città della Salute e della Scienza, S. Giovanni Battista Hospital, University of Turin, C. Bramante 88, 10126, Turin, Italy.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Marzano
authors.affiliation: Department of Gastro-hepatology, A.O. Città della Salute e della Scienza, S. Giovanni Battista Hospital, University of Turin, C. Bramante 88, 10126, Turin, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Ciancio
authors.affiliation: Department of Gastro-hepatology, A.O. Città della Salute e della Scienza, S. Giovanni Battista Hospital, University of Turin, C. Bramante 88, 10126, Turin, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Rizzetto
authors.affiliation: Division of Hematology and Cell Therapy, University of Torino, Mauriziano Hospital, Turin, Italy.
authors.forename: Corrado
authors.initials: C
authors.lastname: Tarella
keywords: Bone marrow-derived stem cells; CD34+ve cells; G-CSF; Hepatic markers; Liver advanced cirrhosis; Mobilization