Proinflammatory Effect of Mesenchymal Stem Cells From Patients With Multiple Sclerosis: Potential Modulation Targets.

Background and objectives: Mesenchymal stem cells (MSCs) represent a potential cellular therapy for multiple sclerosis (MS). It has been suggested that MSCs from patients with MS have lower immunomodulatory properties than those from healthy controls (HCs). The aims of this study were to compare the immunomodulatory abilities of MSCs from patients with MS and HCs against autologous immune cells and to identify potential targets affecting this ability.

Methods: MSCs were obtained by bone marrow aspiration from 5 people with MS and 7 HCs. Autologous peripheral blood mononuclear cells (PBMCs) were stimulated in monoculture or co-culture with MSCs and tested for T-cell expression of IL-17, IFN-γ, and granulocyte-macrophage colony-stimulating factor (GM-CSF) by flow cytometry. Supernatants of monoculture unstimulated MSCs were tested for a panel of cytokines and chemokines using multiplex array or individual ELISA. Gene expression profiling in MSCs was studied using Lexogen QuantSeq RNA-seq platform and subsequent Ingenuity Pathway Analysis.

Results: The MSCs from HCs reduced the proportion of autologous T cells expressing IL-17 (Th17, p = 0.046), IFN-γ (Th1, p = 0.03), and GM-CSF (p = 0.012), whereas MSCs from patients with MS had an opposite effect, increasing both autologous Th17 cells (p = 0.01) and GM-CSF-expressing T cells (p = 0.03), with no changes in Th1 cell abundance. Unstimulated MSCs from patients with MS produced less IL-10 (p = 0.03) and more osteopontin (OPN) (p = 0.002) than those from HCs. Gene expression profiling suggested an increase of ADAM28 in the MS MSCs. This was further confirmed at mRNA (by quantitative polymerase chain reaction [qPCR]) and protein (by flow cytometry) levels. Co-cultures of MS MSCs and autologous PBMCs in the presence of natalizumab, a monoclonal antibody that binds α4β1 and blocks its interaction with both ADAM28 and OPN, resulted in a reduction of Th17 cells. In addition, adding IL-10 to the co-cultures abrogated the increase in Th17 cells, potentially interfering with MS MSC inflammatory effect.

Discussion: Our results suggest that blocking ADAM-28 and OPN interaction with cognate receptors or increasing IL-10 reduces the proinflammatory potential of MSCs from people with MS. Similar approaches could be used in clinical MSC treatments.