Cytokines as the major mechanism of mesenchymal stem cell clinical activity: expanding the spectrum of cell therapy.

Mesenchymal stem cells, or mesenchymal stromal cells, have emerged as a major new cell technology with a diverse spectrum of potential clinical applications. MSCs were originally conceived as stem/progenitor cells to rebuild diseased or damaged tissues. Over the last 14 years, since the first report of MSC infusions in patients, the cells have been shown to suppress graft vs. host disease, stimulate linear growth in a genetic disorder of bone, and foster engraftment of haplo-identical hematopoietic stem cells. In all cases, few, if any, MSCs were identified at the site of clinical activity. This experience suggests a remarkable clinical potential, but a different general mechanism of action. Systemically infused MSCs seem to exert a therapeutic effect through the release of cytokines that act on local, or perhaps distant, target tissues. Rather than serving as stem cells to repair tissues, they serve as cellular factories that secrete mediators to stimulate the repair of tissues or elicit other beneficial effects. Since both the tissue source of MSCs and the ex vivo expansion system may significantly impact the cytokine expression profile, these parameters may be critically important determinants of clinical activity. Furthermore, cell processing protocols may be developed to optimize the cell product for a specific clinical indication. For example, MSC-like cells isolated from placenta and expanded in a three-dimensional bioreactor have recently been shown to increase blood flow in critical limb ischemia. Future efforts to understand the cytokine expression profile will undoubtedly expand the range of MSC clinical applications.