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Identification of secretome potency markers and the importance of donor selection in umbilical cord - derived mesenchymal stromal cells.

K E Strange(1,2) R Fernando(1,5) W Grey(4) R Danby(1,3) N P Mayor(1,2) D Hernandez(1,2)

1:Anthony Nolan Research Institute, Royal Free Hospital, London, NW3 2QU; 2:UCL Cancer Institute, Royal Free Campus, London, NW3 2QG; 3:Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, OX3 7LE; 4:York Biomedical Research Institute, Department of Biology, University of York, York, YO10 5NG; 5:UCL Centre for Nephrology, Royal Free Campus, London, NW3 2QG

Mesenchymal Stromal Cells (MSCs) act both in an autocrine and paracrine manner, with the consensus that several factors are required synergistically to mediate immunosuppression. Whilst their use in clinical trials has increased exponentially in recent years, successful translation has been limited due to variable results. This may be explained by donor variability and limited understanding of their mechanism of action. Here we aim to identify differences in the secretome of umbilical cord derived MSCs (UC-MSCs) between donors under in vitro stimulation assays and determine if this correlates with their immunosuppressive ability.

UC-MSCs from 12 different donors were stimulated with IL-1β or TNF-α and IFN-γ, culture supernatants collected, and 46 different analytes were quantified using Luminex-based assays. To assess their in vitro immunosuppressive potency, MSCs were co-cultured with CellTrace Violet – stained PBMCs and suppression of  CD3+ cell proliferation was measured with and without MSCs. We show that the MSC secretome changes considerably between the stimulation conditions, for example with IL-1β stimulation inducing analytes such as MMP3 (p=0.0017) and TIMP1 (p=0.0452), whilst TNF-α/IFN-γ includes IL-10 (p=0.0003) and MCP2 (p<0.0001).  Analyte concentrations also varied between donor MSCs in resting, stimulated and co-culture conditions. Through multivariate analysis tools such as hierarchal clustering, principal component, and correlation analysis, we identify analytes which are significantly altered during in vitro immunosuppression assays, which also correlate with the variable suppression levels of MSCs. We propose several analytes including IL-6, HGF, and MCP1 to be markers of immunosuppressive potency, and be used to screen donor MSCs for clinical translation.

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