Lithium increases proliferation of hippocampal neural stem/progenitor cells and rescues irradiation-induced cell cycle arrest  in vitro

Giulia Zanni; Elena Di Martino; Anna Omelyanenko; Michael Andäng; Ulla Delle; Kecke Elmroth; Klas Blomgren

doi:10.18632/oncotarget.5191

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Research Papers: Autophagy and Cell Death:

Lithium increases proliferation of hippocampal neural stem/progenitor cells and rescues irradiation-induced cell cycle arrest in vitro

Giulia Zanni _, Elena Di Martino, Anna Omelyanenko, Michael Andäng, Ulla Delle, Kecke Elmroth and Klas Blomgren

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Oncotarget. 2015; 6:37083-37097. https://doi.org/10.18632/oncotarget.5191

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Abstract

Giulia Zanni1,2,*, Elena Di Martino1,2,*, Anna Omelyanenko3, Michael Andäng3,5, Ulla Delle4, Kecke Elmroth4, Klas Blomgren2

1Center for Brain Repair and Rehabilitation, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

2Karolinska Institute, Department of Women’s and Children’s Health, Stockholm, Sweden

3Karolinska Institute, Department of Physiology and Pharmacology, Stockholm, Sweden

4Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden

5Central European Institute of Technology, Masaryk University, Brno, Czech Republic

*These authors have contributed equally to this work

Correspondence to:

Klas Blomgren, e-mail: [email protected]

Keywords: lithium, hippocampus, radiotherapy, apoptosis, paediatric oncology

Received: July 06, 2015 Accepted: August 04, 2015 Published: September 08, 2015

ABSTRACT

Radiotherapy in children causes debilitating cognitive decline, partly linked to impaired neurogenesis. Irradiation targets primarily cancer cells but also endogenous neural stem/progenitor cells (NSPCs) leading to cell death or cell cycle arrest. Here we evaluated the effects of lithium on proliferation, cell cycle and DNA damage after irradiation of young NSPCs in vitro.

NSPCs were treated with 1 or 3 mM LiCl and we investigated proliferation capacity (neurosphere volume and bromodeoxyuridine (BrdU) incorporation). Using flow cytometry, we analysed apoptosis (annexin V), cell cycle (propidium iodide) and DNA damage (γH2AX) after irradiation (3.5 Gy) of lithium-treated NSPCs.

Lithium increased BrdU incorporation and, dose-dependently, the number of cells in replicative phase as well as neurosphere growth. Irradiation induced cell cycle arrest in G₁ and G₂/M phases. Treatment with 3 mM LiCl was sufficient to increase NSPCs in S phase, boost neurosphere growth and reduce DNA damage. Lithium did not affect the levels of apoptosis, suggesting that it does not rescue NSPCs committed to apoptosis due to accumulated DNA damage.

Lithium is a very promising candidate for protection of the juvenile brain from radiotherapy and for its potential to thereby improve the quality of life for those children who survive their cancer.

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Research Papers: Autophagy and Cell Death:

Lithium increases proliferation of hippocampal neural stem/progenitor cells and rescues irradiation-induced cell cycle arrest in vitro

Abstract