32: Peripheral Infusion of Human Umbilical Cord Mesenchymal Stem Cells Improves Acute Liver Failure in Monkeys: A Preclinical Study

Abstract

Introduction: Acute liver failure (ALF) is associated with high mortality, and liver transplantation is the only treatment option. We have previously reported the pathophysiological mechanisms of ALF in a non-human primate model challenged by α-amatoxin. Our data highlighted the critical role of circulating monocyte-derived IL-6 in the initiation and acceleration of cytokine storm and ALF. We also reported that early peripheral infusion of human umbilical cord mesenchymal stem cells (hUC-MSCs) disrupts the development of cytokine storm by inhibiting the activation of circulating monocytes, offering a promising therapeutic strategy to this lethal syndrome. However, it is unknown whether this treatment is still effective when the cytokine storm is fully developed. This study was designed to evaluate the efficacy of hUC-MSC treatment in rhesus monkeys with fully developed ALF. Methods: Sixty healthy male rhesus monkeys, aged at 4–6 years, were randomly and averagely divided into two groups and the monkeys in each group were intraperitoneally administered α-amatoxin at either 20 or 40 μg/kg, respectively. Forty-eight hours after toxin injection, monkeys in each group were further averagely divided into 3 groups and were treated either 1x107 hUC-MSCs, 2x107 hUC-MSCs, or equal value of saline. Blood and liver specimens were harvested and imaging examination was performed at indicated time points. Results: 48 hours after toxin exposure, the liver indices of the monkeys increased significantly. All the monkeys received 20 μg/kg toxin survived and their sera indices returned to normal levels at 312 h, 84 h or 60 h following infusion of saline or 1U cells or 2U cells, respectively. However, in animals received 40 μg/kg toxin, 1, 2, or 3 animals survived when they were treated with saline, 1U cells or 2U cells, respectively. Despite the high mortality, hUC-MSC therapy has also shown potential to protect liver histology and improve system aberrance. Discussion and conclusion: Although systemic inflammatory response has been thoroughly activated, delayed hUC-MSC treatment can decrease cytokine storm and improve liver tissue and systemic inflammatory reaction in a dose-dependent manner. This study provides a promising strategy for the treatment of ALF.