Hypoxic Bone Mesenchymal Stem Cell-Derived Exosomes Direct Schwann Cells Proliferation, Migration, and Paracrine to Accelerate Facial Nerve Regeneration via circRNA_Nkd2/miR-214-3p/MED19 Axis.

Background: Facial nerves have the potential for regeneration following injury, but this process is often challenging and slow. Schwann cells (SCs) are pivotal in this process. Bone mesenchymal stem cells (BMSC)-derived exosomes promote tissue repair through paracrine action, with hypoxic preconditioning enhancing their effects. The main purpose of this study was to determine whether hypoxia-preconditioned BMSC-derived exosomes (Hypo-Exos) exhibit a greater therapeutic effect on facial nerve repair/regeneration and reveal the mechanism. Methods: CCK-8, EdU, Transwell, and ELISA assays were used to evaluate the functions of Hypo-Exos in SCs. Histological analysis and Vibrissae Movements (VMs) recovery were used to evaluate the therapeutic effects of Hypo-Exos in rat model. circRNA array was used to identify the significantly differentially expressed exosomal circRNAs between normoxia-preconditioned BMSC-derived exosomes (Nor-Exos) and Hypo-Exos. miRDB, TargetScan, double luciferase assay, qRT-PCR and WB were used to predict and identify potential exosomal cirRNA_Nkd2-complementary miRNAs and its target gene. The function of exosomal circRNA_Nkd2 in facial nerve repair/regeneration was evaluated by cell and animal experiments. Results: This study confirmed that Hypo-Exos more effectively promote SCs proliferation, migration, and paracrine function, accelerating facial nerve repair following facial nerve injury (FNI) compared with Nor-Exos. Furthermore, circRNA analysis identified significant enrichment of circRNA_Nkd2 in Hypo-Exos compared with Nor-Exos. Exosomal circRNA_Nkd2 positively regulates mediator complex subunit 19 (MED19) expression by sponging rno-miR-214-3p. Conclusion: Our results demonstrated a mechanism by which Hypo-Exos enhanced SCs proliferation, migration, and paracrine function and facial nerve repair and regeneration following FNI through the circRNA_Nkd2/miR-214-3p/Med19 axis. Hypoxic preconditioning is an effective and promising method for optimizing the therapeutic action of BMSC-derived exosomes in FNI.

Branched-chain aminotransferase 1 promotes Schwann cell migration and proliferation to accelerate facial nerve regeneration through the Twist/FoxC1 and Sox2 pathways.

Facial paralysis caused by injury to the facial nerve is common clinical presentation resulting in significant physical and psychological damage. In addition, due to the lack of understanding about the mechanisms of injury and repair and the lack of effective treatment targets, the clinical treatment outcomes for such patients remain poor. Schwann cells (SCs) have a central role in the regeneration of nerve myelin. In a rat model of facial nerves crush injury, we found that branched-chain aminotransferase 1 (BCAT1) was upregulated after injury. Moreover, it had a positive role in nerve repair. Using intervention methods such as gene knockdown, overexpression, and protein-specific inhibitors, combined with detection methods such as CCK8, Transwell, EdU, and flow cytometry, we demonstrated that BCAT1 significantly enhanced the migration and proliferation of SCs. It affected SC cell migration by regulating the Twist/Foxc1 signal axis and promoted cell proliferation by directly regulating the expression of SOX2. Similarly, animal experiments demonstrated that BCAT1 promotes facial nerve repair, improving nerve function and myelin regeneration by activating both the Twist/Foxc1 and SOX2 axes. In sum, BCAT1 promotes SC migration and proliferation, suggesting its potential as a key molecular target for improving the outcome of facial nerve injury repairs.

Relationship between serum gonadal hormone levels and synkinesis in postmenopausal women and man with idiopathic facial paralysis.

OBJECTIVE: To investigate whether serum gonadal hormone levels are correlated to the development of facial synkinesis following Bell's palsy in postmenopausal women and man. METHODS: A total of 149 patients with Bell's palsy were enrolled in this study. All patients were instructed in standard treatment strategy by expert staff from their first visit. The degree of synkinesis was evaluated at 12 months after the onset of facial nerve palsy based on the synkinesis scores of Sunnybrook facial grading system. The patients were divided into two groups by gender. RESULTS: Serum estradiol levels were significantly higher in patients with facial synkinesis than in patients without facial synkinesis following Bell's palsy in postmenopausal female. Male patients with facial synkinesis following Bell's palsy had a higher serum estradiol and testosterone levels. Baseline ENoG values (OR=11.144, 95% CI=1.001-124.126, p=0.008) and serum estradiol levels (OR=1.145, 95% CI=1.033-1.270, p=0.010) were the two independent predictors for facial synkinesis in postmenopausal female patients. Meanwhile, baseline ENoG values (OR=5.312, 95% CI=0.626-45.069, p=0.035), HbA1c values (OR=27.470, 95% CI=2.001-43.084, p=0.016), serum E2 levels (OR=1.298, 95% CI=1.092-1.542, p=0.003), and serum testosterone levels (OR=1.892, 95% CI=1.309-2.734, p=0.001) were the independent predictors for facial synkinesis in male patients. CONCLUSION: Serum estradiol levels are associated with the development of facial synkinesis following Bell's palsy in postmenopausal female patients. Serum estradiol and testosterone levels are associated with the development of facial synkinesis following Bell's palsy in male patients. Serum gonadal hormone levels might be acted as potential biomarker for predicting facial synkinesis following Bell's palsy.