Activated and nonactivated MSCs increase survival in humanized mice after acute liver injury through alcohol binging

Abstract

The ability of the liver to regenerate after injury makes it an ideal organ to study for potential therapeutic interventions. Mesenchymal stem cells (MSCs) possess self-renewal and differentiation properties, as well as anti-inflammatory properties that make them an ideal candidate for therapy of acute liver injury. The primary aim of this study is to evaluate the potential for reversal of hepatic injury using human umbilical cord-derived MSCs. Secondary aims include comparison of various methods of administration as well as comparison of activated versus nonactivated human umbilical cord stem cells. To induce liver injury, humanized mice were fed high-cholesterol high-fat liquid diet with alcohol binge drinking. Mice were then treated with either umbilical cord MSCs, activated umbilical cord MSCs, or a placebo and followed for survival. Blood samples were obtained at the end of the binge drinking and at the time of death to measure alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Histology of all mouse livers was reported at time of death. Activated MSCs that were injected intravenously, intraperitoneally, or both routes had superior survival compared with nonactivated MSCs and with placebo-treated mice. AST and ALT levels were elevated in all mice before treatment and improved in the mice treated with stem cells. Conclusion:Activated stem cells resulted in marked improvement in survival and in recovery of hepatic chemistries. Activated umbilical cord MSCs should be considered an important area of investigation in acute liver injury.

Mesenchymal stromal/stem cells and their extracellular vesicles in liver diseases: insights on their immunomodulatory roles and clinical applications

“…When liver tissue damage occurs, neutrophils are recruited from the peripheral blood to respond to chemokines released from the injured liver, and the infiltration of neutrophils is commonly observed, especially in mice and patients with alcoholic steatohepatitis [ 33 , 34 ]. Several studies have reported that MSCs isolated from bone marrow alleviate alcohol-induced liver injury via suppressing hepatic neutrophil and macrophage infiltration, and oxidative stress [ 35 – 37 ]. However, the underlying mechanism by which MSCs alleviate alcohol-induced liver injury by inhibiting hepatic neutrophil and macrophage infiltration remains unclear.…”

Mesenchymal stem/stromal cells armored by FGF21 ameliorate alcohol-induced liver injury through modulating polarization of macrophages

“… 11 In humanized mice, preconditioning MSCs with cytokines can dramatically reduce acute liver injury caused by alcohol consumption, leading to a notable improvement in both survival and hepatic function. 14 In addition, engineered MSCs can be armed as “Trojan horses” to safely deliver cytokines, including TRAIL, type I IFNs, and IL-2. 15 – 17 Thus, the versatile development of engineering strategies in MSC-based clinical applications contributes to strengthening innate functions (eg, immunomodulatory and regenerative properties) and expanding the therapeutic scope of MSCs, thereby maximizing clinical potency in treating diseases.…”