Biological Function And Molecular Mechanism Of Tenascin-C In Peripheral Nerve Regeneration

Peripheral nerve injury is a common clinical problem. The peripheral nervous system (PNS) differs from the central nervous system (CNS) in that it is capable of remarkable regeneration even after severe injury. Peripheral nerve regeneration requires precise coordination and dynamic interaction among various types of cells in the tissue. It remains unclear, however, whether the cellular crosstalk between fibroblasts and Schwann cells (SCs) is related to phenotype modulation of SCs, a critical cellular process after peripheral nerve injury. In this study, microarray analysis revealed that a total of 6046 genes were differentially expressed in the proximal nerve segment after sciatic nerve transection in rats, and bioinformatics analysis further identified tenascin-C (TNC), an extracellular matrix (ECM) protein, as a key gene regulator. TNC was found to be abundantly produced by nerve fibroblasts accumulating at the lesion site, rather than SCs as usually expected. The following in vitro assay showed that, in co-culture of fibroblasts and SCs, inhibition of fibroblasts secreted TNC by siRNA transfection would suppress SC migration; besides, the exogenous purified TNC protein could significantly promote SC migration while has no effect on proliferation rate of SCs. To study the underlying molecular mechanism of TNC on SC migration, the expression or activity of β1-integrin in SC was inhibited by siRNA transfection or β1-integrin blocking antibody, then the effect of TNC on SC migration was examined. Results showed that the SC migration induced by TNC was significantly decreased by inhibition of β1-integrin expression or activity. A following co-immunoprecipitation assay demonstrated that TNC could directly bind to β1-integrin. Subsequently, we found that cell-migration downstream of TNC/β1-integrin signaling is mediated by a Rho family GTPase member, Rac1. In vivo, the evidence also showed that exogenous TNC protein could promote the migratory ability of SCs and regrowth of axons. Our results highlight that TNC-mediated cellular interaction between fibroblasts and SCs may regulate SC migration through β1-integrin dependent pathway during peripheral nerve regeneration.