Autocrine Interleukin-6 Drives Skin-Derived Mesenchymal Stem Cell Trafficking via Regulating Voltage-Gated Ca2+ Channels

Mesenchymal stem cells (MSCs) have demonstrated promising therapeutic potential for a variety of diseases including autoimmune disorders. A fundamental requirement for MSC-mediated in vivo immunosuppression is their effective trafficking. However the mechanism underlying MSC trafficking remains elusive. Here we report that skin-derived MSCs (S-MSCs) secrete high levels of interleukin-6 (IL-6) in inflammatory conditions. Disruption of the il6 or its signaling transducer gp130 blocks voltage-gated calcium (Ca2+) channels (VGCC) critically required for cell contraction involved in the sequential adhesion and de-adhesion events during S-MSC migration. Deletion of il6 gene leads to a severe defect in S-MSC's trafficking and immunosuppressive function in vivo. Thus, this unexpected requirement of autocrine IL-6 for activating Ca2+ channels uncovers a previously unrecognized link between the IL-6 signaling and the VGCC and provides novel mechanistic insights for the trafficking and immunomodulatory activities of S-MSCs.