Silencing miR-21 induces polarization of astrocytes to the A2 phenotype and improves the formation of synapses by targeting glypican 6 via the signal transducer and activator of transcription-3 pathway after acute ischemic spinal cord injury

Abstract

Ischemic spinal cord injury (ISCI) results in the motor sensory dysfunction of the limbs below the injury site. In response to the injury, astrocytes develop into neuroprotective astrocytes [(neurotrophic reactive astrocytes (A2s)] to mitigate the damage. MicroRNA (miR)-21 can promote the development of neuroinflammation in previous studies. Our aim was to investigate the effect of miR-21 on its polarization. We used the abdominal aortic occlusion model in vivo. Immunohistochemistry was used to detect the distribution of A2s in the spinal cord. We used an oxygen glucose deprivation method to model astrocytes ischemia in vitro and tested proliferation, migration, and excitability of A2s using an 5-ethynyl -2'-deoxyuridine kit, wound scratch assay, and calcium-ion probe. After adjustment, we detected the model and target genes of A2s using PCR, Western blot, immunofluorescence, and chromatin immunoprecipitation. We demonstrated in vivo that naive astrocytes were transformed into A2s by ischemia. And in vitro miR-21, which can regulate the signal transducer and activator of transcription-3 pathway, can transform neurotoxic reactive astrocyte into A2. Moreover, we also verified the mechanism of A2s promoting synaptic formation and nerve growth. miR-21 is a switch to regulate the polarization of reactive astrocyte, and it promoted synapsis formation and nerites growth after acute ISCI.-Su, Y., Chen, Z., Du, H., Liu, R., Wang, W., Li, H., Ning, B. Silencing miR-21 induces polarization of astrocytes to the A2 phenotype and improves the formation of synapses by targeting glypican 6 via the signal transducer and activator of transcription-3 pathway after acute ischemic spinal cord injury.

Keywords: STAT3; microRNA-21; neurotoxic reactive astrocytes; neurotrophic reactive astrocytes.