Abstract
Background aims
Given their low immunogenicity, immunoregulatory effects and multiple differentiation
capacity, mesenchymal stromal cells (MSCs) have the potential to be used for “off-the-shelf”
cell therapy to treat various diseases. However, the allorejection of MSCs indicates
that they are not fully immune-privileged. In this study, the authors investigated
the immunogenicity of human adipose-derived MSCs (Ad-MSCs) and identified potential
immunogenic molecules.
Methods
To evaluate the immunogenicity of human Ad-MSCs in vivo, cells were transplanted into humanized mice (hu-mice), then T-cell infiltration
and clearance of human Ad-MSCs were observed by immunofluorescence and bioluminescence
imaging. One-way mixed lymphocyte reaction and flow cytometry were performed to evaluate
the immunogenicity of human Ad-MSCs in vitro. High-throughput T-cell receptor (TCR) repertoire sequencing and mass spectrometry
were applied to identified potential immunogenic molecules.
Results
The authors observed that allogeneic Ad-MSCs recruited human T cells and caused faster
clearance in hu-mice than non-humanized NOD.Cg-Prkdcscid IL2rgtm1Wjl/SzJ (NSG) mice. The proliferation and activation of T cells were significantly enhanced
during in vitro co-culture with human Ad-MSCs. In addition, the level of HLA-II expression on human
Ad-MSCs was dramatically increased after co-culture with human peripheral blood mononuclear
cells (PBMCs). High-throughput sequencing was applied to analyze the TCR repertoire
of the Ad-MSC-recruited T cells to identify dominant TCR CDR3 sequences. Using synthesized
TCR CDR3 peptides, the authors identified several potential immunogenic candidates,
including alpha-enolase (ENO1). The ENO1 expression level of Ad-MSCs significantly increased after co-culture with PBMCs,
whereas ENO1 inhibitor (ENOblock) treatment decreased the expression level of ENO1 and Ad-MSC-induced proliferation of T cells.
Conclusions
The authors’ findings improve the understanding of the immunogenicity of human Ad-MSCs
and provide a theoretical basis for the safe clinical application of allogeneic MSC
therapy.
Key Words
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Article info
Publication history
Published online: December 02, 2021
Accepted:
October 15,
2021
Received:
July 7,
2021
Identification
Copyright
© 2021 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.
