Overcoming immunoregulatory plasticity of mesenchymal stem cells for accelerated clinical applications

Mesenchymal stem cells (MSCs) are multipotent stromal cells with the potential to differentiate into different tissue lineages. In addition to their differentiation potential, MSCs possess immunomodulatory properties that have created growing interest in both pre-clinical and clinical research. Over the years, MSCs have been applied rapidly in the clinic in a wide variety of immune-mediated disorders; however, MSC therapy has shown contradictory results, often with poor clinical outcomes. Recently, studies on MSC-based immune modulation have provided possible explanations for the conflicting clinical reports. It is now generally recognized that the immunomodulatory properties of MSCs are not constitutive but are induced by various mediators present in the inflammatory microenvironment. Different inflammatory stimuli are able to polarize MSCs to elicit distinct immunomodulatory phenotypes. Thus, the concepts of plasticity and polarization of MSC-based immune modulation may have important therapeutic implications in the clinic. In this review, we focus on the underlying mechanisms of MSC-mediated immune regulation that contribute to their therapeutic potential. Importantly, we discuss novel strategic approaches that enhance the therapeutic potential of MSCs through a consideration of MSC plasticity in immune modulation.