Mesenchymal Stem Cell-Derived Molecules Reverse Fulminant Hepatic Failure

Abstract

Modulation of the immune system may be a viable alternative in the treatment of fulminant hepatic failure (FHF) and can potentially eliminate the need for donor hepatocytes for cellular therapies. Multipotent bone marrow-derived mesenchymal stem cells (MSCs) have been shown to inhibit the function of various immune cells by undefined paracrine mediators in vitro. Yet, the therapeutic potential of MSC-derived molecules has not been tested in immunological conditions in vivo. Herein, we report that the administration of MSC-derived molecules in two clinically relevant forms-intravenous bolus of conditioned medium (MSC-CM) or extracorporeal perfusion with a bioreactor containing MSCs (MSC-EB)-can provide a significant survival benefit in rats undergoing FHF. We observed a cell mass-dependent reduction in mortality that was abolished at high cell numbers indicating a therapeutic window. Histopathological analysis of liver tissue after MSC-CM treatment showed dramatic reduction of panlobular leukocytic infiltrates, hepatocellular death and bile duct duplication. Furthermore, we demonstrate using computed tomography of adoptively transferred leukocytes that MSC-CM functionally diverts immune cells from the injured organ indicating that altered leukocyte migration by MSC-CM therapy may account for the absence of immune cells in liver tissue. Preliminary analysis of the MSC secretome using a protein array screen revealed a large fraction of chemotactic cytokines, or chemokines. When MSC-CM was fractionated based on heparin binding affinity, a known ligand for all chemokines, only the heparin-bound eluent reversed FHF indicating that the active components of MSC-CM reside in this fraction. These data provide the first experimental evidence of the medicinal use of MSC-derived molecules in the treatment of an inflammatory condition and support the role of chemokines and altered leukocyte migration as a novel therapeutic modality for FHF.

Allogeneic human mesenchymal stem cells for treatment of E. coli endotoxin-induced acute lung injury in the ex vivo perfused human lung

“…MSCs secrete multiple paracrine factors that may affect AFC (20,29). In the experiments that used siRNA knockdown, AFC was abolished by 80% with the addition of CM pretreated with the KGF siRNA, indicating the other protective paracrine factors are present in the medium.…”

“…Recent studies have suggested that bone marrow-derived multipotent mesenchymal stem cells (MSCs) may have therapeutic applications in several clinical disorders including myocardial infarction (17), diabetes (18), sepsis (19), hepatic (20), and acute renal failure (21). Recently, allogeneic MSC have been studied in several in vivo models of lung disease (22)(23)(24)(25).…”

Multipotent mesenchymal stromal cells for autoimmune diseases: teaching new dogs old tricks

“…Similarly, it was shown that MSCderived conditioned medium is enriched with many chemokines that are able to reverse fulminant hepatic failure through the inhibition of liver infiltration by leukocytes and subsequent death of hepatocytes. 58 Tissueprotective effects were also seen in a rat kidney model of ischemia/reperfusion injury in which syngeneic MSCs but not fibroblasts were used. These effects were not mediated by MSC transdifferentiation but, in contrast, by bystander mechanisms including the inhibition of pro-inflammatory cytokines and an anti-apoptotic effect on target cells.…”

Implications of the immunoregulatory functions of mesenchymal stem cells in the treatment of human liver diseases

“…In rat models of acute liver injury, human BMSCs or MSC-conditioned medium transplantation significantly reduced rat mortality; this was found to be correlated with a decrease in the number of apoptotic hepatocytes. 8,12 Furthermore, MSCs can also secrete several cytokines such as HGF, epidermal growth factor, IL-6 and TNF-a to stimulate hepatocyte proliferation and maintain hepatocyte function, as indicated by the high levels of albumin and urea secretion. 13 These secreted components of MSCs can enhance liver regeneration in a fulminant hepatic failure (FHF) model.…”

“…These studies have shown that MSC transplantation can partially restore the liver function, ameliorate the symptoms and enhance the survival rates. 12,22 In liver tissues from patients with liver cirrhosis, the formation of pseudolobules has a negative effect on duct construction and can impede the interchange between hepatocytes and serum. MSC transplantation should ideally facilitate duct construction.…”