FGF21 siRNAs were mixed with in vivo–jetPEI reagent. Mice received intrapancreatic injection of either in vivo-jetPEI-conjugated FGF21 siRNA or in vivo-jetPEI-conjugated nontargeting siRNA (0.02 μg/mouse, 3 points of a pancreas) as previously described with slight modifications just after LPC injection. The tissue was lysed after 48 hours, and the lysates were subjected to real-time PCR. Injection of siRNA into the pancreas did not result in any signs of toxicity at the behavioral level.

Demyelination in the central nervous system (CNS) leads to severe neurological deficits that can be partially reversed by spontaneous remyelination. Because the CNS is isolated from the peripheral milieu by the blood-brain barrier, remyelination is thought to be controlled by the CNS microenvironment. However, in this work we found that factors derived from peripheral tissue leak into the CNS after injury and promote remyelination in a murine model of toxin-induced demyelination. Mechanistically, leakage of circulating fibroblast growth factor 21 (FGF21), which is predominantly expressed by the pancreas, drives proliferation of oligodendrocyte precursor cells (OPCs) through interactions with beta-klotho, an essential coreceptor of FGF21. We further confirmed that human OPCs expressed beta-klotho and proliferated in response to FGF21 in vitro. Vascular barrier disruption is a common feature of many CNS disorders; thus, our findings reveal a potentially important role for the peripheral milieu in promoting CNS regeneration.