Inhibiting glucocorticoid receptors enhances adult spinal cord neural stem cell activity and improves outcomes in spinal cord injury

The internal microenvironment plays a critical role in the proliferation and differentiation of endogenous neural stem/progenitor cells (NSPCs). A big change in the spinal cord injury (SCI) microenvironment is the elevated level of glucocorticoids. In this study, we examined the impact of glucocorticoids on endogenous NSPCs in the adult mouse spinal cord. Our findings reveal that adult spinal cord NSPCs express glucocorticoid receptors, but not mineralocorticoid receptors. Glucocorticoids were found to significantly inhibit the proliferation and neurosphere formation of NSPCs via activation of glucocorticoid receptors, and they also impaired their differentiation. Importantly, the glucocorticoid receptor inhibitor CORT125281 was shown to enhance motor function in a traumatic SCI model in mice. Treatment with CORT125281 increased the number of NSPCs at the injury site in vivo. Flow cytometry and RNA sequencing analyses indicated that glucocorticoids induce NSPC arrest in the G1/G0 phase through the p53 signaling pathway. Glucocorticoids increased the expression of cell-cycle regulatory genes p15, p16, p18, and p27 in adult spinal cord NSPCs. In summary, our data suggest that glucocorticoids elevation following SCI suppresses the proliferation of endogenous NSPCs via glucocorticoid receptor activation. Targeting glucocorticoid receptors with specific inhibitors may represent a novel therapeutic strategy to promote recovery after spinal cord injury.