Cargando…

The Redox Function of APE1 Is Involved in the Differentiation Process of Stem Cells toward a Neuronal Cell Fate

Low-to-moderate levels of reactive oxygen species (ROS) govern different steps of neurogenesis via molecular pathways that have been decrypted only partially. Although it has been postulated that redox-sensitive molecules are involved in neuronal differentiation, the molecular bases for this process...

Descripción completa

Detalles Bibliográficos
Autores principales: Domenis, Rossana, Bergamin, Natascha, Gianfranceschi, Giuseppe, Vascotto, Carlo, Romanello, Milena, Rigo, Silvia, Vagnarelli, Giovanna, Faggiani, Massimo, Parodi, Piercamillo, Kelley, Mark R., Beltrami, Carlo Alberto, Cesselli, Daniela, Tell, Gianluca, Beltrami, Antonio Paolo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3929656/
https://www.ncbi.nlm.nih.gov/pubmed/24586617
http://dx.doi.org/10.1371/journal.pone.0089232
_version_ 1782304426426368000
author Domenis, Rossana
Bergamin, Natascha
Gianfranceschi, Giuseppe
Vascotto, Carlo
Romanello, Milena
Rigo, Silvia
Vagnarelli, Giovanna
Faggiani, Massimo
Parodi, Piercamillo
Kelley, Mark R.
Beltrami, Carlo Alberto
Cesselli, Daniela
Tell, Gianluca
Beltrami, Antonio Paolo
author_facet Domenis, Rossana
Bergamin, Natascha
Gianfranceschi, Giuseppe
Vascotto, Carlo
Romanello, Milena
Rigo, Silvia
Vagnarelli, Giovanna
Faggiani, Massimo
Parodi, Piercamillo
Kelley, Mark R.
Beltrami, Carlo Alberto
Cesselli, Daniela
Tell, Gianluca
Beltrami, Antonio Paolo
author_sort Domenis, Rossana
collection PubMed
description Low-to-moderate levels of reactive oxygen species (ROS) govern different steps of neurogenesis via molecular pathways that have been decrypted only partially. Although it has been postulated that redox-sensitive molecules are involved in neuronal differentiation, the molecular bases for this process have not been elucidated yet. The aim of this work was therefore to study the role played by the redox-sensitive, multifunctional protein APE1/Ref-1 (APE1) in the differentiation process of human adipose tissue-derived multipotent adult stem cells (hAT-MASC) and embryonic carcinoma stem cells (EC) towards a neuronal phenotype. Methods and results: Applying a definite protocol, hAT-MASC can adopt a neural fate. During this maturation process, differentiating cells significantly increase their intracellular Reactive Oxygen Species (ROS) levels and increase the APE1 nuclear fraction bound to chromatin. This latter event is paralleled by the increase of nuclear NF-κB, a transcription factor regulated by APE1 in a redox-dependent fashion. Importantly, the addition of the antioxidant N-acetyl cysteine (NAC) to the differentiation medium partially prevents the nuclear accumulation of APE1, increasing the neuronal differentiation of hAT-MASC. To investigate the involvement of APE1 in the differentiation process, we employed E3330, a specific inhibitor of the APE1 redox function. The addition of E3330, either to the neurogenic embryonic carcinoma cell line NT2-D1or to hAT-MASC, increases the differentiation of stem cells towards a neural phenotype, biasing the differentiation towards specific subtypes, such as dopaminergic cells. In conclusion, during the differentiation process of stem cells towards a neuroectodermic phenotype, APE1 is recruited, in a ROS-dependent manner, to the chromatin. This event is associated with an inhibitory effect of APE1 on neurogenesis that may be reversed by E3330. Therefore, E3330 may be employed both to boost neural differentiation and to bias the differentiation potential of stem cells towards specific neuronal subtypes. These findings provide a molecular basis for the redox-mediated hypothesis of neuronal differentiation program.
format Online
Article
Text
id pubmed-3929656
institution National Center for Biotechnology Information
language English
publishDate 2014
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-39296562014-02-25 The Redox Function of APE1 Is Involved in the Differentiation Process of Stem Cells toward a Neuronal Cell Fate Domenis, Rossana Bergamin, Natascha Gianfranceschi, Giuseppe Vascotto, Carlo Romanello, Milena Rigo, Silvia Vagnarelli, Giovanna Faggiani, Massimo Parodi, Piercamillo Kelley, Mark R. Beltrami, Carlo Alberto Cesselli, Daniela Tell, Gianluca Beltrami, Antonio Paolo PLoS One Research Article Low-to-moderate levels of reactive oxygen species (ROS) govern different steps of neurogenesis via molecular pathways that have been decrypted only partially. Although it has been postulated that redox-sensitive molecules are involved in neuronal differentiation, the molecular bases for this process have not been elucidated yet. The aim of this work was therefore to study the role played by the redox-sensitive, multifunctional protein APE1/Ref-1 (APE1) in the differentiation process of human adipose tissue-derived multipotent adult stem cells (hAT-MASC) and embryonic carcinoma stem cells (EC) towards a neuronal phenotype. Methods and results: Applying a definite protocol, hAT-MASC can adopt a neural fate. During this maturation process, differentiating cells significantly increase their intracellular Reactive Oxygen Species (ROS) levels and increase the APE1 nuclear fraction bound to chromatin. This latter event is paralleled by the increase of nuclear NF-κB, a transcription factor regulated by APE1 in a redox-dependent fashion. Importantly, the addition of the antioxidant N-acetyl cysteine (NAC) to the differentiation medium partially prevents the nuclear accumulation of APE1, increasing the neuronal differentiation of hAT-MASC. To investigate the involvement of APE1 in the differentiation process, we employed E3330, a specific inhibitor of the APE1 redox function. The addition of E3330, either to the neurogenic embryonic carcinoma cell line NT2-D1or to hAT-MASC, increases the differentiation of stem cells towards a neural phenotype, biasing the differentiation towards specific subtypes, such as dopaminergic cells. In conclusion, during the differentiation process of stem cells towards a neuroectodermic phenotype, APE1 is recruited, in a ROS-dependent manner, to the chromatin. This event is associated with an inhibitory effect of APE1 on neurogenesis that may be reversed by E3330. Therefore, E3330 may be employed both to boost neural differentiation and to bias the differentiation potential of stem cells towards specific neuronal subtypes. These findings provide a molecular basis for the redox-mediated hypothesis of neuronal differentiation program. Public Library of Science 2014-02-19 /pmc/articles/PMC3929656/ /pubmed/24586617 http://dx.doi.org/10.1371/journal.pone.0089232 Text en © 2014 Domenis et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Domenis, Rossana
Bergamin, Natascha
Gianfranceschi, Giuseppe
Vascotto, Carlo
Romanello, Milena
Rigo, Silvia
Vagnarelli, Giovanna
Faggiani, Massimo
Parodi, Piercamillo
Kelley, Mark R.
Beltrami, Carlo Alberto
Cesselli, Daniela
Tell, Gianluca
Beltrami, Antonio Paolo
The Redox Function of APE1 Is Involved in the Differentiation Process of Stem Cells toward a Neuronal Cell Fate
title The Redox Function of APE1 Is Involved in the Differentiation Process of Stem Cells toward a Neuronal Cell Fate
title_full The Redox Function of APE1 Is Involved in the Differentiation Process of Stem Cells toward a Neuronal Cell Fate
title_fullStr The Redox Function of APE1 Is Involved in the Differentiation Process of Stem Cells toward a Neuronal Cell Fate
title_full_unstemmed The Redox Function of APE1 Is Involved in the Differentiation Process of Stem Cells toward a Neuronal Cell Fate
title_short The Redox Function of APE1 Is Involved in the Differentiation Process of Stem Cells toward a Neuronal Cell Fate
title_sort redox function of ape1 is involved in the differentiation process of stem cells toward a neuronal cell fate
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3929656/
https://www.ncbi.nlm.nih.gov/pubmed/24586617
http://dx.doi.org/10.1371/journal.pone.0089232
work_keys_str_mv AT domenisrossana theredoxfunctionofape1isinvolvedinthedifferentiationprocessofstemcellstowardaneuronalcellfate
AT bergaminnatascha theredoxfunctionofape1isinvolvedinthedifferentiationprocessofstemcellstowardaneuronalcellfate
AT gianfranceschigiuseppe theredoxfunctionofape1isinvolvedinthedifferentiationprocessofstemcellstowardaneuronalcellfate
AT vascottocarlo theredoxfunctionofape1isinvolvedinthedifferentiationprocessofstemcellstowardaneuronalcellfate
AT romanellomilena theredoxfunctionofape1isinvolvedinthedifferentiationprocessofstemcellstowardaneuronalcellfate
AT rigosilvia theredoxfunctionofape1isinvolvedinthedifferentiationprocessofstemcellstowardaneuronalcellfate
AT vagnarelligiovanna theredoxfunctionofape1isinvolvedinthedifferentiationprocessofstemcellstowardaneuronalcellfate
AT faggianimassimo theredoxfunctionofape1isinvolvedinthedifferentiationprocessofstemcellstowardaneuronalcellfate
AT parodipiercamillo theredoxfunctionofape1isinvolvedinthedifferentiationprocessofstemcellstowardaneuronalcellfate
AT kelleymarkr theredoxfunctionofape1isinvolvedinthedifferentiationprocessofstemcellstowardaneuronalcellfate
AT beltramicarloalberto theredoxfunctionofape1isinvolvedinthedifferentiationprocessofstemcellstowardaneuronalcellfate
AT cessellidaniela theredoxfunctionofape1isinvolvedinthedifferentiationprocessofstemcellstowardaneuronalcellfate
AT tellgianluca theredoxfunctionofape1isinvolvedinthedifferentiationprocessofstemcellstowardaneuronalcellfate
AT beltramiantoniopaolo theredoxfunctionofape1isinvolvedinthedifferentiationprocessofstemcellstowardaneuronalcellfate
AT domenisrossana redoxfunctionofape1isinvolvedinthedifferentiationprocessofstemcellstowardaneuronalcellfate
AT bergaminnatascha redoxfunctionofape1isinvolvedinthedifferentiationprocessofstemcellstowardaneuronalcellfate
AT gianfranceschigiuseppe redoxfunctionofape1isinvolvedinthedifferentiationprocessofstemcellstowardaneuronalcellfate
AT vascottocarlo redoxfunctionofape1isinvolvedinthedifferentiationprocessofstemcellstowardaneuronalcellfate
AT romanellomilena redoxfunctionofape1isinvolvedinthedifferentiationprocessofstemcellstowardaneuronalcellfate
AT rigosilvia redoxfunctionofape1isinvolvedinthedifferentiationprocessofstemcellstowardaneuronalcellfate
AT vagnarelligiovanna redoxfunctionofape1isinvolvedinthedifferentiationprocessofstemcellstowardaneuronalcellfate
AT faggianimassimo redoxfunctionofape1isinvolvedinthedifferentiationprocessofstemcellstowardaneuronalcellfate
AT parodipiercamillo redoxfunctionofape1isinvolvedinthedifferentiationprocessofstemcellstowardaneuronalcellfate
AT kelleymarkr redoxfunctionofape1isinvolvedinthedifferentiationprocessofstemcellstowardaneuronalcellfate
AT beltramicarloalberto redoxfunctionofape1isinvolvedinthedifferentiationprocessofstemcellstowardaneuronalcellfate
AT cessellidaniela redoxfunctionofape1isinvolvedinthedifferentiationprocessofstemcellstowardaneuronalcellfate
AT tellgianluca redoxfunctionofape1isinvolvedinthedifferentiationprocessofstemcellstowardaneuronalcellfate
AT beltramiantoniopaolo redoxfunctionofape1isinvolvedinthedifferentiationprocessofstemcellstowardaneuronalcellfate