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Multiple courses of G-CSF in patients with decompensated cirrhosis: consistent mobilization of immature cells expressing hepatocyte markers and exploratory clinical evaluation

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Abstract

Introduction

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.

Patients and 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.

Conclusion

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.

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Abbreviations

BMC:

Bone marrow-derived cells

G-CSF:

Granulocyte colony-stimulating factor

TL:

Telomere length

PB:

Peripheral blood

BM:

Bone marrow

MELD:

Model for end-stage liver disease

CFU-GM:

Colony-forming unit-granulocyte–macrophage

SDF-1:

Stromal derived factor-1

SCF:

Stem cell factor

HGF:

Hepatocyte growth factor

ALB_1:

Albumin 1

AFP-1:

Alpha-feto protein 1

HNF4A-1:

Hepatocyte nuclear factor 4A

CYP2B6_2:

Cytochrome P2 B6

RT-PCR:

Real time polymerase chain reaction

US:

Ultrasound

CP:

Child-Pugh

SD:

Standard deviation

WBC:

White blood cells

c-Met:

Hepatocyte growth-factor receptor

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Acknowledgement

This work was supported in part by grants from the Ministero Italiano Università e Ricerca (MIUR) (PRIN 2006 and Ricerca locale), Rome, Italy; Regione Piemonte (Ricerca Sanitaria Finalizzata and Ricerca Scientifica Applicata), Torino, Italy. G-CSF Lenograstim (rHu G-CSF) (Myelostim®, Italfarmaco) was kindly provided by Azienda Ospedaliero—Universitaria Città della Salute e della Scienza di Torino (ex San Giovanni Battista of Torino). Study sponsors approved the design and protocol but had no involvement in the study design, data collection, analysis and interpretation, or in the writing of the report or the decision to submit the paper for publication.

Conflict of interest

Silvia Gaia, Antonella Olivero, Antonina Smedile, Marco Ruella, Maria Lorena Abate, Maurizio Fadda, Emanuela Rolle, Paola Omedè, Paola Bondesan, Roberto Passera, Alessandra Risso, Manuela Aragno, Alfredo Marzano, Alessia Ciancio, Mario Rizzetto and Corrado Tarella declare that they have no conflict of interest.

Compliance with Ethical Requirements

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008 (5). Informed consent was obtained from all patients for being included in the study. No identifying information about patients is included in the article.

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Authors and Affiliations

  1. 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 Gaia, Antonella Olivero, Antonina Smedile, Maria Lorena Abate, Emanuela Rolle, Alfredo Marzano, Alessia Ciancio & Mario Rizzetto

  2. Division of Hematology and Cell Therapy, University of Torino, Mauriziano Hospital, Turin, Italy

    Marco Ruella & Corrado Tarella

  3. 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

    Maurizio Fadda

  4. 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

    Paola Omedè & Paola Bondesan

  5. 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

    Roberto Passera

  6. Molecular Biotechnology Center, University of Torino, Turin, Italy

    Alessandra Risso

  7. Department of Medicine and Experimental Oncology, University of Torino, Turin, Italy

    Manuela Aragno

Authors
  1. Silvia Gaia
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  2. Antonella Olivero
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  8. Paola Omedè
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  9. Paola Bondesan
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  10. Roberto Passera
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  13. Alfredo Marzano
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  14. Alessia Ciancio
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  15. Mario Rizzetto
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  16. Corrado Tarella
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Corresponding author

Correspondence to Silvia Gaia.

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Gaia, S., Olivero, A., Smedile, A. et al. Multiple courses of G-CSF in patients with decompensated cirrhosis: consistent mobilization of immature cells expressing hepatocyte markers and exploratory clinical evaluation. Hepatol Int 7, 1075–1083 (2013). https://doi.org/10.1007/s12072-013-9473-9

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  • DOI: https://doi.org/10.1007/s12072-013-9473-9

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