Activation, Proliferation and Commitment of Endogenous Stem/Progenitor Cells to the Oligodendrocyte Lineage by TS1 in a Rat Model of Dysmyelination

Abstract

Wild-type and myelin-deficient rats received a single intraparenchymal injection of TS1, a specific combination of IGF-1 and transferrin (Tf), into their corpus callosum at postnatal day 4. The fate of endogenous stem cells in the brain was examined by the expression of the stem cell marker nestin, together with Tf, neurofilaments and glial fibrillary acidic protein from 2 to 14 days after injection. Treated mutants lacked nestin expression in the ventricular wall and had an increase in nestin-labeled radial cell processes in the subventricular regions, and extended into the parenchyma. The subventricular zone was populated by healthy new oligodendrocytes (OLs). BrdU incorporation showed that these cells originated by proliferation and were identified as OLs based upon Tf expression. Thus, TS1 is an effective treatment to promote endogenous subventricular zone progenitor proliferation, migration and OL lineage specification. This strategy offers for the first time the possibility of myelin restoration to treat myelin disorders.

The Insulin-Like Growth Factor (IGF) Receptor Type 1 (IGF1R) as an Essential Component of the Signalling Network Regulating Neurogenesis

“…IGF-I is amongst the most potent scattering factors for breast cancer cells [231] and can also modify migratory behaviour of other transformed and untransformed cells, such as glioblastoma [232] and cardiac fibroblasts [233]. The activation of the receptor tyrosine kinases of FGFR family [234], PDGFRα [235,236] and IGF1R [237][238][239] has been shown to stimulate migration of neural cells at different developmental stages. Molecular events underlying the ability of receptor tyrosine kinases to promote cell migration have been elucidated in transformed cells, but their nature in neural cells is largely unknown.…”

White Matter Loss in a Mouse Model of Periventricular Leukomalacia Is Rescued by Trophic Factors

“…Each experiment consisted of three time points and five conditions: Non-treated mice, Saline, NMDA, NMDA + TSC1 simultaneously injected (N + TSC1 0 day) and NMDA + injection of TSC1 delayed 3 days (N + TSC1 3 day). The stereotaxic intraparenchymal injections in brain, collection and sectioning of tissues for the characterization of cell phenotypes were performed as described [23]. Assessment of cellular stress was monitored through HSP-32 expression.…”

“…Three separate experiments were performed to assess the effects of NMDA alone or with TSC1 on endogenous OLP survival, proliferation and maturation. Intraparenchymal injections were performed according to previously described methods [23,24]. …”

“…Brain collection and sectioning for the characterization of cell phenotypes was performed as previously described [23]. To determine the effectiveness of the treatment, OLs and myelin were determined through the expression of cyclic nucleotide 3′-phosphohydrolase (CNPase).…”

“…Non-radioactive in situ hybridization for Olig2 was performed as previously described [23,25]. The cells were counted using the interactive AxioVision Rel 4.6 program from Zeiss.…”