To identify targets for mitigating the proinflammatory potential of mesenchymal stem cells (MSC) from people with multiple sclerosis (MS), which can be used to improve the immunomodulatory abilities of MSC in clinical autologous treatment interventions.

MSC are a potential cellular treatment for MS, however autologous MSC did not demonstrate an effect on MRI markers of acute inflammation in a phase-2 clinical trial in active MS (MESEMS). We previously showed  that MSC from MS patients have lower immunomodulatory properties than those from healthy controls (HC). Here, we aimed to identify pathways to alleviate this proinflammatory potential.

MSC obtained by bone marrow aspiration from five people with MS and seven HC were co-cultured with autologous peripheral blood mononuclear cells (PBMC; stimulated in monoculture or co-culture with MSC). Gene expression profiling was performed on MSC with the Lexogen QuantSeq platform. Differential expressed genes were identified through bioinformatic analysis. The pathway of the candidate gene identified as up-regulated in MS MSC was further assessed after co-culture in the presence of Natalizumab, which blocks the α4β1 interaction with the candidate gene.

Unstimulated MSC from people with MS produced less IL-10 (p=0.03) and more osteopontin (p=0.002) secretion than those from HC. Gene expression profiling (Lexogen QuantSeq platformRNA seq and Ingenuity Pathway Analysis) showed an increase of ADAM28 in the MS MSC, confirmed at mRNA and protein levels. Co-cultures of MS MSC and autologous PBMC in the presence of Natalizumab, a monoclonal antibody that binds α4β1 and blocks its interaction both with ADAM28 and osteopontin, resulted in a reduction of Th17 cells. Adding IL-10 to the co-cultures abrogated the increase in Th17 cells.

Blocking ADAM-28 and osteopontin interaction with cognate receptors, or increasing IL-10 can reduce the proinflammatory potential of MS MSC. Such approaches could be used in clinical autologous MSC treatment in MS.