Stem Cell Mobilization is Life Saving in an Animal Model of Acute Liver Failure

Overview

Journal Ann Surg

Specialty General Surgery

Date 2010 Oct 1

PMID 20881764

Citations 22

Authors

Anthony L Mark

Zhaoli Sun

Daniel S Warren

Bonnie E Lonze

Matthew K Knabel

George M Melville Williams

Jayme E Locke

Robert A Montgomery

Andrew M Cameron

Affiliations

Soon will be listed here.

Abstract

Objective: No therapy except liver transplantation currently exists for patients with acute liver failure (ALF). The aim of this study was to determine whether pharmacologic mobilization of endogenous hematopoietic stem cells (HSCs) can aid in liver repair and improve survival in an animal model of ALF.

Methods: Rodents were treated with a single near-lethal intraperitoneal injection of carbon tetrachloride (CCl4). After 12 hours, animals were randomized to receive plerixafor and granulocyte colony-stimulating factor (G-CSF), agents known to mobilize marrow-derived stem cells, or saline vehicle injection. Mice were observed for survival, and serial assessment of liver injury by serum transaminase measurements, and histologic analysis was performed.

Results: In our ALF model, 7-day survival after injection of CCl4 was 25%. Administration of plerixafor and G-CSF following CCl4 resulted in 87% survival (n = 8, P < 0.05). On serial histopathologic analysis, animals treated with plerixafor and G-CSF demonstrated less hepatic injury compared with control animals. Evaluation of peripheral blood demonstrated an increase in circulating HSCs in response to plerixafor and G-CSF, and immunostaining suggested the infiltration of HSCs into the hepatic parenchyma after stem cell mobilization.

Conclusions: Our results suggest a possible new treatment strategy for patients with ALF, a group for whom either liver transplantation or death is frequently the outcome. Pharmacologic agents that mobilize HSCs may lead to an infiltration of the injured liver with cells that may participate in or expedite liver regeneration. This therapy has the potential to avert liver transplantation in some patients with ALF and may be of benefit in a wide variety of medical and surgical patients with liver injury.

Citing Articles

Current and emerging therapies for alcohol-associated hepatitis.

Idalsoaga F, Ayares G, Diaz L, Arnold J, Ayala-Valverde M, Hudson D Liver Res. 2025; 7(1):35-46.

PMID: 39959695 PMC: 11792060. DOI: 10.1016/j.livres.2023.03.002.

New advances in drug development for metabolic dysfunction-associated diseases and alcohol-associated liver disease.

Zhang J, Li Y, Yang L, Ma N, Qian S, Chen Y Cell Biosci. 2024; 14(1):90.

PMID: 38971765 PMC: 11227172. DOI: 10.1186/s13578-024-01267-9.

Preclinical models of acute liver failure: a comprehensive review.

Hefler J, Marfil-Garza B, Pawlick R, Freed D, Karvellas C, Bigam D PeerJ. 2021; 9:e12579.

PMID: 34966588 PMC: 8667744. DOI: 10.7717/peerj.12579.

Granulocyte colony-stimulating factor for alcoholic hepatitis: A systematic review and meta-analysis of randomised controlled trials.

Marot A, Singal A, Moreno C, Deltenre P JHEP Rep. 2020; 2(5):100139.

PMID: 32775975 PMC: 7396826. DOI: 10.1016/j.jhepr.2020.100139.

Effect of Stem Cell Treatment on Acute Liver Failure Model Using Scaffold.

Kang H, Won Jun D, Jang K, Hoh J, Lee J, Saeed W Dig Dis Sci. 2018; 64(3):781-791.

PMID: 30421375 DOI: 10.1007/s10620-018-5363-2.

References

Lee W, Squires Jr R, Nyberg S, Doo E, Hoofnagle J . Acute liver failure: Summary of a workshop. Hepatology. 2008; 47(4):1401-15. PMC: 3381946. DOI: 10.1002/hep.22177. View

Sun Z, Zhang X, Locke J, Zheng Q, Tachibana S, Diehl A . Recruitment of host progenitor cells in rat liver transplants. Hepatology. 2008; 49(2):587-97. PMC: 4447094. DOI: 10.1002/hep.22653. View

Ince H, Petzsch M, Kleine H, Eckard H, Rehders T, Burska D . Prevention of left ventricular remodeling with granulocyte colony-stimulating factor after acute myocardial infarction: final 1-year results of the Front-Integrated Revascularization and Stem Cell Liberation in Evolving Acute Myocardial Infarction.... Circulation. 2005; 112(9 Suppl):I73-80. DOI: 10.1161/CIRCULATIONAHA.104.524827. View

Stravitz R, Kramer D . Management of acute liver failure. Nat Rev Gastroenterol Hepatol. 2009; 6(9):542-53. DOI: 10.1038/nrgastro.2009.127. View

Gaia S, Smedile A, Omede P, Olivero A, Sanavio F, Balzola F . Feasibility and safety of G-CSF administration to induce bone marrow-derived cells mobilization in patients with end stage liver disease. J Hepatol. 2006; 45(1):13-9. DOI: 10.1016/j.jhep.2006.02.018. View

Uy G, Rettig M, Cashen A . Plerixafor, a CXCR4 antagonist for the mobilization of hematopoietic stem cells. Expert Opin Biol Ther. 2008; 8(11):1797-804. DOI: 10.1517/14712598.8.11.1797. View

Liu F, Liu Z, Wu N, Cong X, Fei R, Chen H . Transplanted endothelial progenitor cells ameliorate carbon tetrachloride-induced liver cirrhosis in rats. Liver Transpl. 2009; 15(9):1092-100. DOI: 10.1002/lt.21845. View

Leone A, Rutella S, Bonanno G, Contemi A, De Ritis D, Giannico M . Endogenous G-CSF and CD34+ cell mobilization after acute myocardial infarction. Int J Cardiol. 2005; 111(2):202-8. DOI: 10.1016/j.ijcard.2005.06.043. View

De Silvestro G, Vicarioto M, Donadel C, Menegazzo M, Marson P, Corsini A . Mobilization of peripheral blood hematopoietic stem cells following liver resection surgery. Hepatogastroenterology. 2004; 51(57):805-10. View

10.

Petersen B, BOWEN W, Patrene K, Mars W, Sullivan A, Murase N . Bone marrow as a potential source of hepatic oval cells. Science. 1999; 284(5417):1168-70. DOI: 10.1126/science.284.5417.1168. View

11.

Michalopoulos G, Defrances M . Liver regeneration. Science. 1997; 276(5309):60-6. DOI: 10.1126/science.276.5309.60. View

12.

Farmer D, Anselmo D, Ghobrial R, Yersiz H, McDiarmid S, Cao C . Liver transplantation for fulminant hepatic failure: experience with more than 200 patients over a 17-year period. Ann Surg. 2003; 237(5):666-75; discussion 675-6. PMC: 1514517. DOI: 10.1097/01.SLA.0000064365.54197.9E. View

13.

Simmons D, Satterthwaite A, Tenen D, Seed B . Molecular cloning of a cDNA encoding CD34, a sialomucin of human hematopoietic stem cells. J Immunol. 1992; 148(1):267-71. View

14.

Stokman G, Leemans J, Claessen N, Weening J, Florquin S . Hematopoietic stem cell mobilization therapy accelerates recovery of renal function independent of stem cell contribution. J Am Soc Nephrol. 2005; 16(6):1684-92. DOI: 10.1681/ASN.2004080678. View

15.

Di Campli C, Zocco M, Saulnier N, Grieco A, Rapaccini G, Addolorato G . Safety and efficacy profile of G-CSF therapy in patients with acute on chronic liver failure. Dig Liver Dis. 2007; 39(12):1071-6. DOI: 10.1016/j.dld.2007.08.006. View

16.

Hahn T, Wingard J, Anderson K, Bensinger W, Berenson J, Brozeit G . The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of multiple myeloma: an evidence-based review. Biol Blood Marrow Transplant. 2003; 9(1):4-37. DOI: 10.1053/bbmt.2003.50002. View

17.

Okumoto K, Saito T, Onodera M, Sakamoto A, Tanaka M, Hattori E . Serum levels of stem cell factor and thrombopoietin are markedly decreased in fulminant hepatic failure patients with a poor prognosis. J Gastroenterol Hepatol. 2007; 22(8):1265-70. DOI: 10.1111/j.1440-1746.2006.04497.x. View

18.

Dar A, Kollet O, Lapidot T . Mutual, reciprocal SDF-1/CXCR4 interactions between hematopoietic and bone marrow stromal cells regulate human stem cell migration and development in NOD/SCID chimeric mice. Exp Hematol. 2006; 34(8):967-75. DOI: 10.1016/j.exphem.2006.04.002. View

19.

Lorenzini S, Isidori A, Catani L, Gramenzi A, Talarico S, Bonifazi F . Stem cell mobilization and collection in patients with liver cirrhosis. Aliment Pharmacol Ther. 2008; 27(10):932-9. DOI: 10.1111/j.1365-2036.2008.03670.x. View

20.

Di Campli C, Piscaglia A, Giuliante F, Rutella S, Bonanno G, Zocco M . No evidence of hematopoietic stem cell mobilization in patients submitted to hepatectomy or in patients with acute on chronic liver failure. Transplant Proc. 2005; 37(6):2563-6. DOI: 10.1016/j.transproceed.2005.06.072. View