Background: Mesenchymal stem cells (MSCs) display profound immunomodulatory properties and tissue repairing capability under inflammatory conditions. However, it is unknown how MSCs may affect immunity in liver inflammatory injury. This study was designed to dissect the molecular mechanisms of MSCs in regulating immune response in liver ischemia and reperfusion injury (IRI). Methods: Bone marrow-derived MSCs were transfected with a CRISPR/Cas9-mediated Cox2, β-catenin or XIAP knockout vector (p-Cox2 KO, p-β-catenin KO, and p-XIAP KO), and then co-cultured with bone marrow-derived macrophages (BMMs) using a transwell system followed by LPS (100 ng/ml) stimulation. Using liver IRI model, mice (n=6/gr) were injected i.v. with 1×10⁶ MSCs 24h prior to liver ischemia. Mice were sacrificed after 6h of reperfusion. Results: The expression of Cox2 and PGE2 was enhanced in LPS-stimulated MSCs. Macrophages co-cultured with MSCs reduced M1 macrophage iNOS yet strongly augmented arginase-1, an M2 macrophage phenotype, with increased expression of IL-10/TGF-β. Transfection of p-Cox2 KO in MSCs decreased PGE2 secretion, β-catenin, XIAP expression, and IL-10/TGF-β production. Induction of β-catenin enhanced XIAP and Akt phosphorylation whereas knockout of β-catenin resulted in reduced XIAP and increased TNFα/IL-6. Moreover, XIAP knockout augmented JNK yet diminished Akt phosphorylation and arginase-1 expression. Unlike in controls, adoptive transfer of MSCs in mice ameliorated IR-induced liver damage, as evidenced by reduced sALT levels and liver Suzuki's scores, which was accompanied by increased Cox2, PGE2, β-catenin, XIAP, p-Akt, and arginase-1 expression, with reduced proinflammatory mediators in ischemic livers. Conclusion: This study demonstrates that MSC-mediated immune regulation through activation of PGE2/β-catenin/XBP1 signaling, which in turn reprograms host macrophage differentiation towards an anti-inflammatory M2 phenotype in IR-triggered liver inflammation. This might imply a novel therapeutic potential for the management of liver IRI in transplant recipients.

CITATION INFORMATION: Li C., Yue S., Jiang L., Zhu Q., Farmer D., Busuttil R., Kupiec-Weglinski J., Ke B. PGE2/Beta-Catenin/XBP1 Signaling Controls Mesenchymal Stem Cell-Mediated Immune Regulation in Liver Ischemia and Reperfusion Injury Am J Transplant. 2017;17 (suppl 3).

« Back to 2018 American Transplant Congress