Liver Transpl. 2018 Mar 3. doi: 10.1002/lt.25049. [Epub ahead of print]

Crosstalk between mesenchymal stem cells and T regulatory cells is crucially important for the attenuation of acute liver injury.

Gazdic M¹, Simovic Markovic B², Arsenijevic A², Jovicic N³, Acovic A⁴, Harrell CR⁵, Fellabaum C⁵, Djonov V⁶, Arsenijevic N², Lukic ML², Volarevic V².

Abstract

One of the therapeutic options for the treatment of fulminant hepatitis is re-population of intrahepatic regulatory cells since their pool is significantly reduced during acute liver failure. Although it is known that mesenchymal stem cells (MSCs), which have beneficent effects in the therapy of fulminant hepatitis, may promote expansion of T regulatory cells (Tregs) and B regulatory cells (Bregs), the role of these regulatory cells in MSC-mediated attenuation of acute liver injury is unknown. Herewith, we described the molecular mechanisms involved in the crosstalk between MSCs and liver regulatory cells and analyzed the potential of MSC-based therapy for the expansion of intrahepatic regulatory cells in mouse model of acute liver failure. MSC-dependent attenuation of α-galactosylceramide (α-GalCer)-induced acute liver injury in mice was accompanied with an increased presence of IL-10 producing CD4⁺ CD25⁺ FoxP3⁺ Tregs and IL-10 and TGF-β producing marginal zone (MZ)-like Bregs in the liver. Depletion of Bregs did not alter MSC-based alleviation of acute liver failure, while depletion of Tregs completely abrogated hepato-protective effects of MSCs and inhibit their capacity to attenuate hepatotoxicity of liver natural killer T (NKT) cells, indicating that Tregs, and not Bregs, were critically involved in MSC-based modulation of acute liver inflammation. MSCs, in paracrine, indoleamine 2,3-dioxygenase (IDO)-dependent manner, significantly increased capacity of Tregs to produce immunosuppressive IL-10 and to suppress hepatotoxicity of liver NKT cells. Accordingly, adoptive transfer of MSC-primed Tregs resulted with the complete attenuation of α-GalCer-induced acute liver failure. In conclusion, our findings highlighted the crucial importance of Tregs for MSC-based attenuation of acute liver failure and indicate the significance of MSC-mediated priming of Tregs as new therapeutic approach in Tregs-based therapy of acute liver injury. This article is protected by copyright. All rights reserved.