Thyroid hormone induces glial lineage of primary neurospheres derived from non‐pathological and pathological rat brain: implications for remyelination‐enhancing therapies

Abstract

Thyroid hormone exerts a critical role in developmental myelination, acting on the production and maturation of oligodendrocyte, and on the expression of genes encoding for myelin protein. Since remyelination is considered a recapitulation of cellular and molecular events occurring during development, we tested the possibility of stimulating the oligodendroglial lineage and maturation in neurospheres derived from the subventricular zone of adult rats using 3,5,3'-L-triiodothyronine (T3). Both non-pathological and pathological brains derived from rats affected by the inflammatory-demyelinating disease experimental allergic encephalomyelitis (EAE) were included in the study. We investigated the effect of in vitro T3 exposure on: (i) the expression of nuclear thyroid hormone receptors; (ii) proliferation rate; (iii) differentiation into neurons, astrocytes and oligodendrocytes, focusing our attention on oligodendrocyte maturation. T3 reduced the proliferation rate of neurospheres when cultured in the presence of mitogens, shifting towards oligodendroglial lineage as indicated by increased expression of olig-1, and also favoring oligodendrocyte maturation, as indicated by the expression of antigens associated with different maturation stages. Neurospheres derived from EAE rats show a strong limitation in oligodendrocyte generation, which is completely restored by T3 treatment. These results indicate that T3 is a key factor in regulating neurosphere biology, when derived either from non-pathological or pathological adult brains, suggesting that T3 might be an important factor in favoring remyelination in demyelinating disorders.

Excess Thyroid Hormone Inhibits Embryonic Neural Stem/Progenitor Cells Proliferation and Maintenance through STAT3 Signalling Pathway

“…In our experiments, treatments of NSCs were carried out with supraphysiological doses of free T3 (3 and 30 nM), and the culture condition we used was widely applied to address the effects of T3 on neural cells (Carreon-Rodriguez et al 2009;Fernandez et al 2009;Haas et al 2005). The physiological concentration of free T3 in fetal brain is difficult to detect precisely.…”

“…BrdU incorporation and the CCK-8 assay showed that excess T3 had a significant inhibitory effect on NSC proliferation and maintenance, indicating that excess T3 could reduce the NSC number and change the fate of embryonic NSCs. Previous studies have proved that T3 is critical for maturation of neurons and glia cells (Benvenuti et al 2008;Fernandez et al 2009), but few investigation have addressed the effects of T3 on embryonic NSCs. However, some studies revealed that T3 could promote NSC proliferation in adult rat subventricular zone and hippocampus (Desouza et al 2005;Fernandez et al 2004).…”

Tissue transglutaminase activity is involved in the differentiation of oligodendrocyte precursor cells into myelin‐forming oligodendrocytes during CNS remyelination

“…Alternatively, impaired proliferation and differentiation of OPCs into myelin producing OLGs can be limiting for remyelination (Franklin, 2002). Several factors have been shown to be involved in OPC differentiation, including hormones and transferrin (Fernandez et al, 2009;Paez et al, 2005). Furthermore, growth factors such as platelet-derived growth factor (PDGF)-A, fibroblast growth factor (FGF)-2, insulin-like growth factor-1, and transforming growth factor-b have been identified within the adult CNS as important factors in the regulation of OPC proliferation and differentiation (reviewed in Franklin et al, 2001).…”

Intermediate Filaments as a Target of Signaling Mechanisms in Neurotoxicity

“…In brain, these hormones are essential for myelination [43,44], neuritogenesis [45], synaptic plasticity [46][47][48], IF phosphorylation [49][50][51][52][53][54], cell differentiation and maturation [55]. Considering the role of these hormones on brain development, thyroid diseases might account for brain injury as well as alteration in mood and cognition [56].…”