Stem cell Mobilization is Life Saving in a Large Animal Model of Acute Liver Failure
Andrew Cameron*, Ali R. Ahmadi*, Maria Chicco*, Tyler Creamer*, Yongchun Wang*, Jinny Huang*, George M. Williams, Zhaoli Sun*
The Johns Hopkins University School of Medicine, Baltimore, MD
OBJECTIVE(S): Acute Liver Failure (ALF) affects 2,000 Americans each year with no treatment short of Liver Transplantation. We showed previously that mobilization of endogenous stem cells is protective against ALF in rat. The objective here was to assess whether stem cell mobilizing drugs are life saving in a large animal preclinical model of ALF, to determine readiness for clinical trial.
METHODS: Male Yorkshire pigs (13-18 kg) were divided into control (N=6) and treatment (N=6) groups. All animals received a central catheter and then intravenous bolus of the hepatotoxin D-galactosamine (0.5g/kg) and were followed up to 28 days. Treatment animals received simultaneous intramuscular injection of stem cell mobilizing agents AMD3100 (1mg/kg) and G-CSF (2ɥg/kg) at 0, 24 and 48 hours after toxin infusion. Control animals received saline.
RESULTS: All control animals (6/6) succumbed to liver failure within 91 hours, confirmed by biochemical changes and encephalopathy. In the treatment group (5/6) animals survived indefinitely despite comparable biochemical changes during the first 48 hours (P = 0.003). White blood cell count increased by 4x in the treatment group (P= 0.002). Histopathology of the control group showed hepatocyte loss, inflammation, and necrosis.
CONCLUSIONS: Stem cell mobilizing drugs are life saving in a large animal preclinical model of ALF. As few therapeutic options beyond liver transplant are available for these critically ill patients a multicenter clinical trial is now warranted.
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