Role for TGF‐β1, FGF‐2 and PDGF‐AA in a myelination of CNS aggregate cultures enriched with macrophages

Abstract

The increase in myelin basic protein (MBP) synthesis observed in brain aggregate cultures supplemented with macrophages is reflected in elevated supernatant protein levels of the key promoters of oligodendrocyte proliferation, fibroblast growth factor-2 (FGF-2) and platelet-derived growth factor-AA (PDGF-AA), during the premyelinating phase. Although supernatant levels of transforming growth factor-beta1 (TGF-beta1), the most abundant growth factor produced at the transcriptional and translational levels by phagocytic macrophages, were reduced at this stage, it was the only growth factor for which mRNA expression was increased significantly in macrophage-enriched cultures. TGF-beta1, which supports oligodendrocyte differentiation, was increased in the supernatant of macrophage-enriched cultures only after the onset of myelinogenesis. Hence, standard cultures treated with TGF-beta1 during the premyelinating period reproduced effects of macrophage supplementation, inducing an increase in MBP synthesis and in PDGF-AA and FGF-2 bioavailability. A similar increase in MBP synthesis in PDGF-AA treated cultures emphasises its central role in oligodendrocyte progenitor proliferation. In contrast, FGF-2 blocked MBP synthesis in the cultures. In cultures treated with anti-TGF-beta1 antibody before or after the first detection of MBP, supernatant levels of TGF-beta1, FGF-2, and PDGF-AA were reduced with resultant inhibition of myelination. Paradoxically, supraphysiological TGF-beta1 treatment after the onset of myelination had the same effect on myelin accumulation. These results indicate an enabling and regulatory role for TGF-beta1 in oligodendrocyte development and, as a source of TGF-beta1, macrophages in the inflammatory multiple sclerosis lesion, may have the potential to promote remyelination by modulating the growth factor repertoire in demyelinating disease.

Combinatorial actions of Tgfβ and Activin ligands promote oligodendrocyte development and CNS myelination

“…Our findings showing that Tgfβ1 supports OLP proliferation are compatible with results in Schwann cells, in which it also acts as a mitogen (Ridley et al, 1989;Einheber et al, 1995). However, in studies in aggregate CNS cultures, addition of Tgfβ1 has been shown to enhance myelination (Diemel et al, 2003), whereas Tgfβ1 inhibition potentiates platelet-derived growth factoraa (Pdgf-aa)-driven proliferation in O-2A cells (McKinnon et al, 1993). Notably, aggregate cultures are known to contain Tgfβ-producing cells, and, based on our data, ActB would also likely be present.…”

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).…”

Quetiapine facilitates oligodendrocyte development and prevents mice from myelin breakdown and behavioral changes

“…In the present study, QUE not only instructed NPCs to become CNPase-positive Oligs (Figure 2), but also facilitated the maturation of newly formed Oligs, as indicated by the increase in MBP expression ( Figure 4) and myelination observed in QUE-treated aggregate cultures ( Figure 5 and Supplementary Figures 4 and 5), which provide a system that incorporates a mixed cell population that reliably models in vivo myelinogenesis in developing CNS. 39 In contrast, CLO and OLA did not show any stimulation on the expression of CNP and MBP of NPCs (Figure 2). Currently, we do not know how to explain the differences among the atypical APDs.…”