A Novel Immunomodulatory Mechanism Dependent On Acetylcholine Secreted By Human Bone Marrow-Derived Mesenchymal Stem Cells

Background and Objectives: Mesenchymal stem cells (MSCs) are used to treat autoimmune or inflammatory diseases. Our aim was to determine the immunomodulatory mechanisms elicited by MSCs during inflammation.Methods and Results: We cocultured MSCs with peripheral blood mononuclear cells for a mixed lymphocyte reaction or stimulated them by phytohcmagglutinin. Morphological changes of MSCs and secretion of acetylcholine (ACh) from iSCs were measured. The effects of an ACh antagonist and ACh agonist on lymphocyte proliferation and proinflammatory-cytokine production were determined. The inflammatory milieu created by immune-cell activation caused MSCs to adopt a neuronlike phenotype and induced them to release ACh. Additionally, nicotinic acetylcholine receptors nAChRs) were upregulated in activated peripheral blood mononuclear cells. We observed that ACh hound to nAChR on activated immune cells and led to the inhibition of lymphocyte proliferation and of prointlammatory-cytokine production. MSC-mediated immunosuppression through ACh activity was reversed by an ACh antagonist called alpha-bungarotoxin, and lymphocyte proliferation was inhibited by an ACh agonist, ACh chloride.Conclusions: Our findings point to a novel immunomodulatory mechanism in which ACh secreted by MSCs under inflammatory conditions might modulate immune cells. This study may provide a novel method for the treatment autoimmune diseases by means of MSCs.