Spatial and Temporal Profiles of Growth Factor Expression during CNS Demyelination Reveal the Dynamics of Repair Priming

Abstract

Demyelination is the cause of disability in various neurological disorders. It is therefore crucial to understand the molecular regulation of oligodendrocytes, the myelin forming cells in the CNS. Growth factors are known to be essential for the development and maintenance of oligodendrocytes and are involved in the regulation of glial responses in various pathological conditions. We employed the well established murine cuprizone model of toxic demyelination to analyze the expression of 13 growth factors in the CNS during de- and remyelination. The temporal mRNA expression profile during demyelination and the subsequent remyelination were analyzed separately in the corpus callosum and cerebral cortex using laser microdissection and real-time PCR techniques. During demyelination a similar pattern of growth factor mRNA expression was observed in both areas with a strong up-regulation of NRG1 and GDNF and a slight increase of CNTF in the first week of cuprizone treatment. HGF, FGF-2, LIF, IGF-I, and TGF-ß1 were up-regulated mainly during peak demyelination. In contrast, during remyelination there were regional differences in growth factor mRNA expression levels. GDNF, CNTF, HGF, FGF-2, and BDNF were elevated in the corpus callosum but not in the cortex, suggesting tissue differences in the molecular regulation of remyelination in the white and grey matter. To clarify the cellular source we isolated microglia from the cuprizone lesions. GDNF, IGF-1, and FGF mRNA were detected in the microglial fraction with a temporal pattern corresponding to that from whole tissue PCR. In addition, immunohistochemical analysis revealed IGF-1 protein expression also in the reactive astrocytes. CNTF was located in astrocytes. This study identified seven different temporal expression patterns for growth factors in white and grey matter and demonstrated the importance of early tissue priming and exact orchestration of different steps during callosal and cortical de- and remyelination.

TREM2 sustains microglial expansion during aging and response to demyelination

“…Consistent with previous reports (38), WT mice showed a peak of microgliosis at 4 weeks which hinders subsequent myelin regeneration. This conclusion was supported by immunohistochemical analysis of ODC.…”

Identification of a microglia phenotype supportive of remyelination

“…We found upregulation of Pdgfa, Pdgfb, Vegfa, Vegfb, Tgfb1, Igf1, and Spp1, all of which have been reported to promote oligodendrocyte differentiation (Baumann and Pham-Dinh, 2001;Bradl and Lassmann, 2010;Chesik et al, 2008;Diemel et al, 2003;Frost et al, 2003;Hinks and Franklin, 1999;Hsieh et al, 2004;Kim et al, 2009;Selvaraju et al, 2004;Vela et al, 2002;Woodruff et al, 2004). Interestingly, we did not find upregulation of Gdnf or Fgf2, as reported by Gudi et al (2011). In their study, Gdnf induction in microglia peaked at 1 week of cuprizone treatment after which it abruptly declined, whereas the highest expression of Fgf2 was observed at 3.5 weeks of demyelination.…”

Behaviour of CD11b-Positive Cells in an Animal Model of Laser-Induced Choroidal Neovascularisation

“…Hu et al [27] concluded that FGF-2 was important as an initial regulator of neovascularisation, and VEGF may be important during later phases of angiogenesis. In some neurological disorders, it was reported that microglia was one source of FGF-2 [46,47] . There are no studies so far that document whether microglial cells produce FGF-2 in AMD.…”