Myelin is the material sheathing nerves, essential to their function. Demyelinating conditions such as multiple sclerosis are unpleasant, disabling, and ultimately fatal, but their effects are an exaggerated version of what takes place in everyone over the course of aging. The myelin sheathing of the nervous system is degraded to some degree in all older individuals, probably a consequence of the general reduction or disruption of tissue maintenance of all sorts that takes place in aging, and this is one of the issues that degrades cognitive function in later life. Researchers here examine the repair processes that respond to loss of myelin, and identify a role for FGF21 in spurring myelin maintenance. Given a way to reliably delivery FGF21 past the blood-brain barrier, this might be a basis for therapy.
Central nervous system (CNS) damage, a hallmark of many CNS disorders, is causatively associated with severe neurological deficits in motor, sensory, cognitive, and other functions. Because damaged CNS can spontaneously regenerate after injury, these neurological deficits partially recover over time. One such regenerative process in the mammalian CNS, remyelination, is initiated by proliferation of oligodendrocyte precursor cells (OPCs), which are distributed widely throughout the mammalian CNS. OPC proliferation and subsequent remyelination processes (e.g., migration, differentiation into mature oligodendrocytes) ensure the restoration of saltatory conduction, provision of trophic support for axons, and promotion of functional recovery; therefore, the mechanism of remyelination has attracted considerable attention in regard to its potential applications in regenerative medicine aimed at treating CNS demyelinating diseases.
Disruption of vascular barriers occurs in several types of disease, including multiple sclerosis, cerebral ischemia, brain tumors, and other neurological diseases. Disrupted vascular barriers can lead to hemorrhage, brain hypoperfusion, and transmigration of inflammatory cells into the CNS; consequently, vascular barrier disruption may exacerbate pathological processes. However, OPC proliferation increases in proximity to demyelinating lesions, which are often characterized by vascular barrier disruption. In addition, some of the cells in the CNS express peripheral-hormone receptors, such as the insulin and mineralocorticoid receptors, which regulate neurogenesis in the adult CNS. Although the role of vascular barrier disruption in CNS regeneration has not yet been clarified, we hypothesized that vascular barrier disruption mediated by CNS injury induces the leakage of circulating factors into the CNS, resulting in remyelination.
In this study, we found that circulating FGF21 promotes OPC proliferation. OPC proliferation was elevated in the spinal cords of mice with toxin-induced demyelination, and this proliferation was inhibited by silencing of FGF21 expression in the pancreas. OPCs expressed β-klotho, an essential coreceptor for FGF21, and inhibition of β-klotho expression in OPCs prevented the increase in OPC proliferation and subsequent remyelination. The results of this study reveal an unexpected role of FGF21, which has been previously characterized as a metabolic regulator. In reviewing previous findings regarding FGF21 function in the CNS, we noted that FGF21 can cross the blood-brain barrier, but the FGF21 level in the cerebrospinal fluid of healthy patients is approximately 40% of that in the plasma. Thus, CNS entry of peripheral FGF21 is limited in normal adult subjects.
We should note that FGF21-mediated OPC proliferation is only one of the mechanisms of remyelination. In terms of molecular mechanism, we just focused on the direct action of FGF21 on OPC proliferation; however, FGF also regulates expression of VEGF receptor 2. Because VEGF signaling is related to brain homeostasis, including OPC migration, a process that involves remyelination, an indirect effect of FGF21 on OPCs may also contribute to oligodendrocyte development and remyelination. Meanwhile, FGF21-associated drugs for treating diabetes have recently been developed by pharmaceutical companies, and some of these compounds have reached the stage of clinical trials. We believe that these FGF21-associated drugs may exert FGF21-mediated remyelination effect and provide clinical benefits in patients with CNS demyelination.