NFAT signaling in human mesenchymal stromal cells affects extracellular matrix remodeling and antifungal immune responses

Federico Tidu; Marco De Zuani; Shyam Sushama Jose; Kamila Bendickova; Lukas Kubala; Frank Caruso; Francesca Cavalieri; Giancarlo Forte; Jan Fric

Journal article

NFAT signaling in human mesenchymal stromal cells affects extracellular matrix remodeling and antifungal immune responses

Federico Tidu, Marco De Zuani, Shyam Sushama Jose, Kamila Bendickova, Lukas Kubala, Frank Caruso, Francesca Cavalieri, Giancarlo Forte, Jan Fric

ISCIENCE | CELL PRESS | Published : 2021

DOI: 10.1016/j.isci.2021.102683

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Abstract

Mesenchymal stromal cells (MSCs) combined with calcineurin-nuclear factor of activated T cell (CN-NFAT) inhibitors are being tested as a treatment for graft-versus-host disease (GvHD). The immunosuppressive properties of MSCs seem beneficial; however, their response during fungal infection, which is an important cause of mortality in patients with GvHD , is unknown. We report that MSCs phagocytose the fungal component zymosan, resulting in phosphorylation of spleen tyrosine kinase (Syk), increase in cytosolic calcium levels, and ultimately, increase in NFAT1 nuclear translocation. RNA sequencing analysis of zymosan-treated MSCs showed that CN-NFAT inhibition affects extracellular matrix (ECM..

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University of Melbourne Researchers

Frank Caruso Author Chemical Engineering

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Grants

Awarded by European Regional Development Fund-Project MAGNET

Awarded by National Program of Sustainability II (MEYS CR)

Awarded by Ministry of Health of the Czech Republic

Awarded by DRO (Institute of Hematology and Blood Transfusion -UHKT)

Awarded by European Union

Awarded by National Health and Medical Research Council

Awarded by Australian Research Council (ARC)

Awarded by NCMG research infrastructure - MEYS CR

Awarded by European Regional Development Fund-Project ENOCH

Awarded by European Regional Development Fund

Funding Acknowledgements

This study was supported by the European Social Fund and European Regional Development Fund-Project MAGNET (grant no. CZ.02.1.01/0.0/0.0/15_003/0000492) and ENOCH (CZ.02.1.01/0.0/0.0/16_ 019/0000868); the European Regional Development Fund in frame of the project Kompetenzzentrum MechanoBiologie (grant no. ATCZ133) in the Interreg V-A Austria -Czech Republic program; the National Program of Sustainability II (MEYS CR) (grant no. LQ1605); and the Ministry of Health of the Czech Republic (grant no. NV18-06-00529) and DRO (Institute of Hematology and Blood Transfusion -UHKT, 00023736). This project also received funding from the European Union's Horizon 2020 Research and Innovation Program under grant agreement No 690901 (NANOSUPREMI). Caruso acknowledges the award of a National Health and Medical Research Council Senior Principal Research Fellowship (GNT1135806). F. Cavalieri acknowledges the award of an Australian Research Council (ARC) Future Fellowship scheme (FT140100873). This work was performed in part at the Materials Characterisation and Fabrication Platform (MCFP) at The University of Melbourne.The authors would like to thank the technical support team at the Center of Translational Medicine, the CF Genomics of CEITEC supported by the NCMG research infrastructure (LM2015091 funded by MEYS CR) for their support with obtaining scientific data presented in this paper, the Biostatistics Core Facility at FNUSAICRC for support in RNA sequencing analysis, and Dr Jessica Tamanini of Insight Editing London for reviewing and editing the manuscript prior to submission.