Abstract
Mesenchymal stromal cells (MSC) have been used in over 800 clinical trials with encouraging results in the field of transplant medicine and chronic inflammatory diseases. Today, Umbilical Cord (UC)-derived MSC are the second leading source used for clinical purposes, mainly due to its easy access and superior immune modulatory effects. Although the underlying molecular mechanisms of immune suppressive activities have not been fully understood, research over the last decade strongly suggests that MSC-mediated benefits are closely related to activation of secretome networks. Nevertheless, recent findings also point to cytokine-independent mechanisms as key players of MSC-mediated immune modulation. Here, we set up a robust in vitro immune assay using phytohemagglutinin- or anti-CD3/CD28-treated human peripheral blood mononuclear cells in cell-to-cell interaction or in cell-contact independent format with UC-MSC and conducted integrated transcriptome and secretome analyses to dissect molecular pathways driving UC-MSC-mediated immune modulation. Under inflammatory stimuli, multiparametric analyses of the secretome led us to identify cytokine/chemokine expression patterns associated with the induction of MSC-reprogrammed macrophages and T cell subsets ultimately leading to immune suppression. UC-MSC transcriptome analysis under inflammatory challenge allowed the identification of 47 differentially expressed genes, including chemokines, anti- and pro-inflammatory cytokines and adhesion molecules found also in UC-MSC-immunosupressive secretomes, including the novel candidate soluble IL-2R. This study enabled us to track functionally activated UC-MSC during immune suppression and opened an opportunity to explore new pathways involved in immunity control by UC-MSC. We propose that identified immunomodulatory molecules and pathways could potentially be translated into clinical settings in order to improve UC-MSC-therapy quality and efficacy.
Highlights
Mesenchymal stromal cells (MSC) are instrumental in modulating immune responses in the context of inflammation
This report introduces an analytic approach based on the application of combined transcriptome and secretome tools in the context of experimental immune activation, to validate molecular pathways linked to MSC-driven immune modulation and outline new cellular and molecular mechanisms present in human Umbilical Cord (UC)-MSC
By taking advantage of this strategy, we evidenced the activation of major regulatory processes triggered by UC-MSC under induced inflammation and T cell activation, that effectively impacted on the remodeling of monocyte and T lymphocyte function, leading to the control of enhanced immune responses
Summary
Mesenchymal stromal cells (MSC) are instrumental in modulating immune responses in the context of inflammation. MSC have shown a robust biosafety profile and partial objective responses, displaying in many cases control of immune and inflammatory responses, symptom alleviation and improved quality of life on treated patients [2]. These promising data have paved the way to enhance cell manufacturing processes, reduced burden in clinical scaling and gained comparability between studies that results in more efficient therapies applied to immune-related disorders. Given its fetal origin, UC-derived MSC display particular advantages such as improved multipotency, enhanced stemness, and longer proliferation capacity [3]. As long as research addressing immune modulatory functions of UC-MSC continues to expand, there will be increasing opportunities to deliver better and more efficient strategies for immune cell therapy
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
