IL-1 beta-Induced Mesenchymal Stem Cell Migration Involves MLCK Activation via PKC Signaling

摘要

dMesenchymal stem cells (MSCs) migrate via the bloodstream to sites of injury, possibly attracted by inflammatory cytokines. Although many cytokines can induce stem cell migration, the underlying mechanism is not fully understood. We found that tail vein-injected MSCs migrate to the pancreas in nonobese diabetic (NOD) mice. An ELISA assay revealed that hyperglycemic NOD mice have higher pancreatic levels of interleukin-1 beta (IL-1 beta) than normal NOD mice and that IL-1 beta stimulates MSC migration in a Transwell assay and electric cell-substrate impedance sensing system. Microarray analysis showed that myosin light chain kinase (MLCK) is involved in IL-1 beta-induced MSC migration, while Western blots showed that IL-1 beta stimulates MLCK expression and activation and that MLCK-siRNA transfection reduces MSC migration. Kinase inhibitors, chromatin immunoprecipitation, and a knockdown study revealed that IL-1 beta-induced MLCK expression is regulated by the PKC delta/NF kappa B signaling pathway, and a kinase inhibitor study revealed that MAD-induced MLCK activation occurs via the PKC alpha/MEK/ERK signaling pathway. These results show that IL-1 beta released from the pancreas of hyperglycemic NOD mice induces MSC migration and that this is dependent on MLCK expression via the PKC delta/NF-kappa B pathway and on MLCK activation via the PKC alpha/MEK/ERK signaling cascade. This study increases our understanding of the mechanisms by which MSCs home to injury sites.