Amniotic-Fluid–Derived Mesenchymal Stem Cells Overexpressing Interleukin-1 Receptor Antagonist Improve Fulminant Hepatic Failure

Abstract

Uncontrolled hepatic immunoactivation is regarded as the primary pathological mechanism of fulminant hepatic failure (FHF). The major acute-phase mediators associated with FHF, including IL-1β, IL-6, and TNF-α, impair the regeneration of liver cells and stem cell grafts. Amniotic-fluid–derived mesenchymal stem cells (AF-MSCs) have the capacity, under specific conditions, to differentiate into hepatocytes. Interleukin-1–receptor antagonist (IL-1Ra) plays an anti-inflammatory and anti-apoptotic role in acute and chronic inflammation, and has been used in many experimental and clinical applications. In the present study, we implanted IL-1Ra–expressing AF-MSCs into injured liver via the portal vein, using D-galactosamine–induced FHF in a rat model. IL-1Ra expression, hepatic injury, liver regeneration, cytokines (IL-1β, IL-6), and animal survival were assessed after cell transplantation. Our results showed that AF-MSCs over-expressing IL-1Ra prevented liver failure and reduced mortality in rats with FHF. These animals also exhibited improved liver function and increased survival rates after injection with these cells. Using green fluorescent protein as a marker, we demonstrated that the engrafted cells and their progeny were incorporated into injured livers and produced albumin. This study suggests that AF-MSCs genetically modified to over-express IL-1Ra can be implanted into the injured liver to provide a novel therapeutic approach to the treatment of FHF.

Anti-Inflammatory Effects of Adult Stem Cells in Sustained Lung Injury: A Comparative Study

“…The AM-MSC induced increase in IL-1RA would be anti-inflammatory and provide another explanation for the actions of AM-MSC. This observation is in line with a study that demonstrated IL-1RA released from amniotic mesenchymal stem cells reduced hepatic injury in mice [36]. Furthermore, we have shown that AM-MSC secrete GM-CSF unlike the other stem cells studied.…”

Microencapsulated human mesenchymal stem cells decrease liver fibrosis in mice

“…We further showed that MSCs secrete IL-1Ra in vitro and in vivo. This natural inhibitor of the pro-inflammatory effect of IL-1 could be responsible for the anti-inflammatory effects of MSCs, as suggested by others [16,38,39]. In contrast, increased levels of pro-inflammatory MCP-1 [40] in MSC-CM seem to be in contradiction with the anti-inflammatory effect of MSCs.…”

Cell-based Therapy for Acute Organ Injury

“…Most of the studies used intravenous MSC administration, but others chose the intra-portal route 29,215 aiming at circumventing trapping in the pulmonary circulation 215 . Overall, MSC decreased the severity of histological liver injury 74,75,210,213–215 , improved liver function 75,210–212,215 and finally enhanced survival 29,74,75,210,213–215 . In contrast, Boeykens et al did not find any benficial effects of intraportally administrated MSC in terms of improved liver recovery 218 .…”

“…Most preclinical studies using MSC used mice and rats with carbon tetrachloride 30,76,209–212 , thioacetamide 118 , D-galactosamine 29,74,75,213,214 or I/R-induced liver injury 116,215,216 . However, two studies used D-galactosamine induced fulminant hepatic failure in pigs 29,213 .…”