PT  - JOURNAL ARTICLE
AU  - Rabea J. Madel
AU  - Verena Börger
AU  - Robin Dittrich
AU  - Michel Bremer
AU  - Tobias Tertel
AU  - Nhi Ngo Thi Phuong
AU  - Hideo A. Baba
AU  - Lambros Kordelas
AU  - Jan Buer
AU  - Peter A. Horn
AU  - Astrid M. Westendorf
AU  - Sven Brandau
AU  - Carsten J. Kirschning
AU  - Bernd Giebel
TI  - Independent human mesenchymal stromal cell-derived extracellular vesicle preparations differentially affect symptoms in an advanced murine Graft-versus-Host-Disease model
AID  - 10.1101/2020.12.21.423658
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.12.21.423658
4099  - http://biorxiv.org/content/early/2020/12/22/2020.12.21.423658.short
4100  - http://biorxiv.org/content/early/2020/12/22/2020.12.21.423658.full
AB  - Extracellular vesicles (EVs) harvested from cell culture supernatants of human mesenchymal stromal cells (MSCs) suppress acute inflammation in preclinical models of various diseases. Furthermore, they promote regeneration of damaged tissues. Following successful clinical treatment of a steroid-refractory Graft-versus-Host-Disease (GvHD) patient with EVs prepared from conditioned media of human bone marrow (BM)-derived MSCs, we aim to improve MSC-EV production and quality control towards clinical application. Observing functional differences of independent MSC-EV preparations in vitro, we established an optimized murine GvHD model for the analysis of independent MSC-EV preparations in vivo. To this end, T cell depleted allogeneic BM cells co-transplanted with naïve allogeneic spleen-derived T cells induced GvHD symptoms with reproducible strengths in mice being preconditioned by ionizing irradiation. Administration of MSC-EV preparations with confirmed in vitro immune modulatory properties at three consecutive days significantly suppressed GvHD symptoms. In contrast, application of MSC-EV preparations lacking these in vitro immune modulating capabilities failed to suppress GvHD symptoms. Thus, our results reveal therapeutic differences among independent MSC-EV preparations that had been produced in a standardized manner. Thus, given this functional heterogeneity, any individual MSC-EV preparation considered for the clinical application should be evaluated for its potency prior to administration to patients.Competing Interest StatementBG is a scientific advisory board member of Evox Therapeutics and Innovex Therapeutics SL. All other authors report no conflicts of interest.