The redox function of APE1 is involved in the differentiation process of stem cells toward a neuronal cell fate

Rossana Domenis, Natascha Bergamin, Giuseppe Gianfranceschi, Carlo Vascotto, Milena Romanello, Silvia Rigo, Giovanna Vagnarelli, Massimo Faggiani, Piercamillo Parodi, Mark Kelley, Carlo Alberto Beltrami, Daniela Cesselli, Gianluca Tell, Antonio Paolo Beltrami

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Article numbere89232
JournalPLoS One
Volume9
Issue number2
DOIs
StatePublished - Feb 19 2014

Fingerprint

Multipotent Stem Cells
Stem cells
Adult Stem Cells
adipose tissue
Oxidation-Reduction
stem cells
Stem Cells
neurons
Adipose Tissue
reactive oxygen species
neurogenesis
Reactive Oxygen Species
phenotype
carcinoma
Neurogenesis
chromatin
Phenotype
Chromatin
Tissue
acetylcysteine

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Domenis, R., Bergamin, N., Gianfranceschi, G., Vascotto, C., Romanello, M., Rigo, S., ... Beltrami, A. P. (2014). The redox function of APE1 is involved in the differentiation process of stem cells toward a neuronal cell fate. PLoS One, 9(2), [e89232]. https://doi.org/10.1371/journal.pone.0089232

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; Beltrami, Carlo Alberto; Cesselli, Daniela; Tell, Gianluca; Beltrami, Antonio Paolo.

In: PLoS One, Vol. 9, No. 2, e89232, 19.02.2014.

Research output: Contribution to journalArticle

Domenis, R, Bergamin, N, Gianfranceschi, G, Vascotto, C, Romanello, M, Rigo, S, Vagnarelli, G, Faggiani, M, Parodi, P, Kelley, M, Beltrami, CA, Cesselli, D, Tell, G & Beltrami, AP 2014, 'The redox function of APE1 is involved in the differentiation process of stem cells toward a neuronal cell fate', PLoS One, vol. 9, no. 2, e89232. https://doi.org/10.1371/journal.pone.0089232
Domenis R, Bergamin N, Gianfranceschi G, Vascotto C, Romanello M, Rigo S et al. The redox function of APE1 is involved in the differentiation process of stem cells toward a neuronal cell fate. PLoS One. 2014 Feb 19;9(2). e89232. https://doi.org/10.1371/journal.pone.0089232
Domenis, Rossana ; Bergamin, Natascha ; Gianfranceschi, Giuseppe ; Vascotto, Carlo ; Romanello, Milena ; Rigo, Silvia ; Vagnarelli, Giovanna ; Faggiani, Massimo ; Parodi, Piercamillo ; Kelley, Mark ; 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. In: PLoS One. 2014 ; Vol. 9, No. 2.
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