Peripherally derived FGF21 promotes remyelination in the central nervous system
Mariko Kuroda ... Hideki Mochizuki, Toshihide Yamashita
Mariko Kuroda ... Hideki Mochizuki, Toshihide Yamashita
Published September 1, 2017
Citation Information: J Clin Invest. 2017;127(9):3496-3509. doi:10.1172/JCI94337.
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Categories: Research Article Angiogenesis Neuroscience

Peripherally derived FGF21 promotes remyelination in the central nervous system

Abstract

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 β-klotho, an essential coreceptor of FGF21. We further confirmed that human OPCs expressed β-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.

Authors

Mariko Kuroda, Rieko Muramatsu, Noriko Maedera, Yoshihisa Koyama, Machika Hamaguchi, Harutoshi Fujimura, Mari Yoshida, Morichika Konishi, Nobuyuki Itoh, Hideki Mochizuki, Toshihide Yamashita

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OPC proliferation is promoted under vascular disruption. (A) Representat...

Figure 1

OPC proliferation is promoted under vascular disruption.

(A) Representative images of spinal cord sections visualized with Alexa Fluor 488–conjugated cadaverine (top) and endogenous IgG (bottom). Spinal cord sections were prepared at the indicated times after LPC injection. (B) Quantitation of Evans blue leakage in the spinal cord (n = 3); **P < 0.01. (C) Representative images of spinal cord sections labeled for PDGFRα (top) and Ki67 (middle). Spinal cord sections were prepared at the indicated days after LPC injection. Arrows indicate cells that are colabeled with PDGFRα and Ki67. (D) Graph shows quantitation as indicated in each image (n = 3 for control, 3 for d3, 4 for d7, 4 for d14); *P < 0.05. (E) Representative images of spinal cord sections labeled for MBP. Spinal cord sections were prepared at the indicated days after LPC injection. (F) Graph shows quantitation as indicated in each image (n = 3 for control, 3 for d3, 3 for d7, 4 for d14); P = 0.002, 0.0424, 0.0018 (left to right). *P < 0.05, **P < 0.01. (G) Representative images of brain sections visualized with MBP (top) and endogenous IgG (bottom) the indicated number of days after LPC injection. (H) Graph shows the time course of demyelination after LPC injection (n = 3 for control, 6 for d3, 7 for d7, 4 for d14); *P < 0.05, **P < 0.01, determined by ANOVA with Tukey’s post hoc test or Dunnett’s test. Error bars represent SEM. Scale bars: 200 μm (A and E); 50 μm (C); 100 μm (G).