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Cytokine Selection of MSC Clones with Different Functionality.

ABSTRACT: Mesenchymal stromal cells (MSCs) are used in many clinical applications. However, ex vivo expansion is required to reach clinically relevant cell numbers, which might lead to selection of clones with different characteristics. To follow clonal selection, we transduced MSC progenitors in umbilical cord pieces (UCPs) with vectors encoding fluorescent proteins and genetic barcodes. After marked MSC cultures grew out from UCPs, we investigated the influence of cytokines on MSC functionality. Specific cytokine conditions selected for clones from common progenitors. MSC secretome analyses revealed differences dependent on the culture conditions used. Clones expanded in human serum containing culture medium secreted a plethora of growth factors. When expanded in the same medium containing TGF-β, MSCs secreted negligible amounts of cytokines but at the same time led to an increased human chimerism after hematopoietic stem cell transplantation into immunodeficient mice. Our results suggest a major influence of cytokine additives on MSC functionality.

SUBMITTER: Selich A

PROVIDER: S-EPMC6700478 | biostudies-other | 2019 Aug

REPOSITORIES: biostudies-other

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Cytokine Selection of MSC Clones with Different Functionality.

Selich Anton A Ha Teng-Cheong TC Morgan Michael M Falk Christine S CS von Kaisenberg Constantin C Schambach Axel A Rothe Michael M

Stem cell reports 20190711 2

Mesenchymal stromal cells (MSCs) are used in many clinical applications. However, ex vivo expansion is required to reach clinically relevant cell numbers, which might lead to selection of clones with different characteristics. To follow clonal selection, we transduced MSC progenitors in umbilical cord pieces (UCPs) with vectors encoding fluorescent proteins and genetic barcodes. After marked MSC cultures grew out from UCPs, we investigated the influence of cytokines on MSC functionality. Specifi ...[more]

PMID: 31303506

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Project description:BackgroundMesenchymal stromal cells (MSC) possess immunomodulatory properties and low immunogenicity, both crucial properties for their development into an effective cellular immunotherapy. They have shown benefit in clinical trials targeting liver diseases; however the efficacy of MSC therapy will benefit from improvement of the immunomodulatory and immunogenic properties of MSC.MethodsMSC derived from human umbilical cords (ucMSC) were treated for 3 days in vitro with various inflammatory factors, interleukins, vitamins and serum deprivation. Their immunogenicity and immunomodulatory capacity were examined by gene-expression analysis, surface-marker expressions, IDO activity, PGE2 secretion and inhibition of T cell proliferation and IFN? production. Furthermore, their activation of NK cell cytotoxicity was investigated via CD107a expression on NK cells. The immunomodulatory capacity, biodistribution and survival of pre-treated ucMSC were investigated in a CCl4-induced liver disease mouse model. In addition, capacity of pre-treated MSC to ameliorate liver inflammation was examined in an ex vivo liver inflammation co-culture model.ResultsIFN-? and a multiple cytokine cocktail (MC) consisting of IFN-?, TGF? and retinoic acid upregulated the expression of immunomodulatory factor PD-L1 and IDO activity. Subsequently, both treatments enhanced the capacity of ucMSC to inhibit CD4 and CD8 T cell proliferation and IFN-? production. The susceptibility of ucMSC for NK cell lysis was decreased by IFN-?, TGF? and MC treatment. In vivo, no immunomodulation was observed by the ucMSC. Four hours after intravenous infusion in mice with CCl4-induced inflammatory liver injury, the majority of ucMSC were trapped in the lungs. Rapid clearance of ucMSC(VitB6), ucMSC(Starv?+?VitB6) and ucMSC(MC) and altered bio-distribution of ucMSC(TGF?) compared to untreated ucMSC was observed. In the ex vivo co-culture system with inflammatory liver slices ucMSC(MC) showed significantly enhanced modulatory capacity compared to untreated ucMSC.ConclusionsThe present study demonstrates the responsiveness of ucMSC to in vitro optimisation treatment. The observed improvements in immunomodulatory capacity as well as immunogenicity after MC treatment may improve the efficacy of ucMSC as immunotherapy targeted towards liver inflammation.

Dataset Information

Cytokine Selection of MSC Clones with Different Functionality.

Publications

Cytokine Selection of MSC Clones with Different Functionality.

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