Neural stem cells modified to express BDNF antagonize trimethyltin-induced neurotoxicity through PI3K/Akt and MAP kinase pathways

Fabrizio Michetti, Giulio Maira, P Casalbore, Ilaria Barone, A Felsani, I D'Agnano, Carlo Cenciarelli

Risultato della ricerca: Contributo in rivistaArticolo in rivistapeer review

27 Citazioni (Scopus)

Abstract

Abstract In vitro expansion of neural stem cells (NSC) lentivirally transduced with human BDNF may serve as better cellular source for replacing degenerating neurons in disease, trauma and toxic insults. In this study, we evaluate the functional role of forced BDNF expression by means of NSC (M3GFP-BDNF) obtained from cerebral cortex of 1day-old mice respect to NSC-control (M3GFP). We find that M3GFP-BDNF induced to differentiate significantly accumulate BDNF and undergone to high potassiummediated depolarization, show rapid BDNF recycle and activation of Trk receptors signalling. Differentiated M3GFP-BDNF exhibit neurons and oligodendrocytes with extended processes although quantitative analyses of NSC-derived cell lineages show none statistical significance between both cell populations. Moreover, those cells show a significant induction of neuronal and oligodendroglial markers by RT-PCR and Western blot respect to M3GFP, such as βIII-Tubulin, microtubule associated protein 2 (MAP2), neurofilaments heavy (NF-H), oligodendroglial myelin glycoprotein (OMG) and some molecules involved in glutamatergic synapse maturation, such as receptors tyrosine kinases (TRKs), post-synaptic density (PSD-95) and N-methyl-D-aspartate receptors 2 A/B (NMDA2A/B). After treatment with the neurotoxicant trimethyltin (TMT), differentiated M3GFP-BDNF exhibit an attenuation of cellular damage which correlates with a significant activation of MAPK and PI3K/Akt signalling and delayed activation of death signals, while on M3GFP, TMT induces a significant reduction of cell survival, neuronal differentiation and concomitant earlier activation of cleaved caspase-3. We demonstrate that overexpression of BDNF firmly regulate cell survival and differentiation of NSC and protects differentiated NSC against TMT-induced neurotoxicity through the PI3K/Akt and MAPK signalling pathways.
Lingua originaleEnglish
pagine (da-a)710-721
Numero di pagine12
RivistaJournal of Cellular Physiology
Volume2010
Stato di pubblicazionePubblicato - 2010

Keywords

  • Brain-derived neurotrophic factor,
  • neural stem cells

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