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Neural stem cells modified to express BDNF antagonize trimethyltin‐induced neurotoxicity through PI3K/Akt and MAP kinase pathways
Author(s) -
Casalbore Patrizia,
Barone Ilaria,
Felsani Armando,
D'Agnano Igea,
Michetti Fabrizio,
Maira Giulio,
Cenciarelli Carlo
Publication year - 2010
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.22170
Subject(s) - tropomyosin receptor kinase b , microbiology and biotechnology , neural stem cell , biology , trk receptor , brain derived neurotrophic factor , neurotrophic factors , protein kinase b , neuroscience , stem cell , receptor , signal transduction , biochemistry
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 1‐day‐old mice respect to NSC‐control (M3GFP). We find that M3GFP‐BDNF induced to differentiate significantly accumulate BDNF and undergone to high potassium‐mediated depolarization, show rapid BDNF recycle and activation of Trk receptors signaling. 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 signaling 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 signaling pathways. J. Cell. Physiol. 224: 710–721, 2010. © 2010 Wiley‐Liss, Inc.