Steroid-dependent regulation of central nervous system remyelination: From gonadal hormones to chemokine signaling

Efficient remyelination in the adult central nervous system remains limited and poorly understood. Recent experimental studies reveal that gonadal steroid hormones are essential regulators of myelin repair and that cooperation between androgen receptor (AR) and CXCR4 chemokine receptor signaling in astrocytes controls oligodendrocyte-mediated remyelination. Evidence for this mechanism comes from mouse models of axonal demyelination followed by oligodendrocyte-dependent remyelination, a regenerative process involving the recruitment and differentiation of oligodendrocyte progenitor cells (OPCs). In the absence of testicular function, oligodendrocyte-mediated remyelination fails completely but is fully restored by physiological testosterone treatment. The remyelinating effect of testosterone depends on AR expression in astrocytes, where AR cooperates with CXCR4. This cooperation may reflect an evolutionary convergence between AR signaling and the CXCL12-CXCR4 chemokine axis associated with the emergence of myelination in jawed vertebrates. In the absence of astrocytic AR or CXCR4 signaling, axons are instead remyelinated by Schwann cells. Immunostaining of spinal cord sections from patients with multiple sclerosis supports the relevance of AR-CXCR4 signaling in myelin repair. Similarly, loss of ovarian function abolishes oligodendrocyte-mediated remyelination in female mice. Testosterone restores remyelination in a CXCR4-dependent manner, whereas estradiol, the principal ovarian hormone, acts through a CXCR4-independent mechanism. Together, these findings identify gonadal steroid hormones as essential regulators of oligodendrocyte-mediated remyelination and provide a mechanistic framework for investigating hormone-dependent strategies to enhance myelin repair in multiple sclerosis.