Mesenchymal Stem Cells in Liver Fibrosis: A Dose-Dependent Recovery

Mesenchymal stem cells (MSCs) are known to assist liver regeneration. In this study, we show a dose-dependent mode of recovery from liver fibrosis after intravenous injections of MSCs. Male Wistar rats experienced a 42-day-long modeling of liver fibrosis via CCl4 poisoning and received either a single injection of 2.5 × 106 MSCs on Day 3 after the last CCl4 dose or two MSC injections on Days 3 and 10. We dynamically monitored levels of liver cytolysis markers and cytokines in the venous blood and performed a histological study of Mallory-stained liver sections. All experimental groups experienced a nearly complete recovery of biochemical markers up to 4 weeks after the end of CCl4 administration, although we observed anti-inflammatory changes in the cytokine levels only in animals treated by two MSC injections. Histological study revealed minor signs of liver damage up to Day 90 in animals receiving two MSC doses with worse pathology in those who received a single MSC dose. Morphometric values stayed consistent with visual data, demonstrating a significantly larger number of binuclear hepatocytes, a smaller number of false lobules, and a lesser area of connective tissue proper in animals treated by two MSC injections. Our results reflect MSC grafting in applied doses to affect liver fibrosis in a dose-dependent mode. These findings provide a deeper understanding of MSC action in liver fibrosis, and the doses applied may serve as a milestone for further studies in humans.