Multipotent mesenchymal stromal cells and the innate immune system

Multipotent mesenchymal stromal cells (MSCs) are multipotent cells that were initially isolated from the bone marrow. They have been identified in almost all tissues and have a large number of immunomodulatory effects.Based on their immunosuppressive activity, regenerative capacity and immunoprivileged status, MSCs are attractive tools for cellular therapy in inflammatory diseases and are currently being investigated in several clinical studies.MSCs and the components of the innate immune system communicate at several levels, regulating for example the stem cell niche and antimicrobial responses.MSCs residing in the bone marrow are strongly involved in the regulation of haematopoietic stem cell (HSC) homeostasis. Macrophages are an important partner in this process, as they positively regulate the expression of HSC-promoting factors by MSCs.MSCs control the polarization of macrophages. Through the production of cyclooxygenase 2 and the expression of indoleamine 2,3-dioxygenase, MSCs induce interleukin-10-expressing anti-inflammatory M2 macrophages.MSCs attract, activate and increase the lifespan of neutrophils. These beneficial effects can be enhanced by triggering innate immune sensors in MSCs and might support the clearance of pathogens.Two types of MSC have been described, based on their pro-inflammatory (MSC1) and anti-inflammatory (MSC2) phenotypes. Microenvironmental stimuli — such as ligands for Toll-like receptor 3 (TLR3) and TLR4 — are fundamentally involved in this bidirectional polarization.MSCs express several TLRs. Triggering them differentially can affect several biological functions, such as the differentiation, proliferation, migration, antioxidative repertoire and suppressive potency of MSCs.The inflammatory pre-activation of MSCs, for example by interferon-γ, tumour necrosis factor or TLR ligands, is known as 'licensing' and enhances the suppressive activity of MSCs. Deciphering the underlying molecular mechanisms of this effect could help to improve the efficacy of MSC-based cell therapy.