DNA Damage in Mammalian Neural Stem Cells Leads to Astrocytic Differentiation Mediated by BMP2 Signaling through JAK-STAT

Paola Roncaglia,Federica Pisati,Serena Pellegatta,Giuseppe Testa,Leonid Schneider,Rebecca Favaro,Gaetano Finocchiaro,Fabrizio d’Adda di Fagagna,Silvia K. Nicolis

doi:10.1016/j.stemcr.2013.06.004

Abstract

SummaryThe consequences of DNA damage generation in mammalian somatic stem cells, including neural stem cells (NSCs), are poorly understood despite their potential relevance for tissue homeostasis. Here, we show that, following ionizing radiation-induced DNA damage, NSCs enter irreversible proliferative arrest with features of cellular senescence. This is characterized by increased cytokine secretion, loss of stem cell markers, and astrocytic differentiation. We demonstrate that BMP2 is necessary to induce expression of the astrocyte marker GFAP in irradiated NSCs via a noncanonical signaling pathway engaging JAK-STAT. This is promoted by ATM and antagonized by p53. Using a SOX2-Cre reporter mouse model for cell-lineage tracing, we demonstrate irradiation-induced NSC differentiation in vivo. Furthermore, glioblastoma assays reveal that irradiation therapy affects the tumorigenic potential of cancer stem cells by ablating self-renewal and inducing astroglial differentiation.

Highlights

The relationship between cell-cycle control and regulation of differentiation is a major question in stem cell biology
We demonstrate that BMP2 is necessary to induce expression of the astrocyte marker GFAP in irradiated neural stem cells (NSCs) via a noncanonical signaling pathway engaging JAK-STAT
Glioblastoma assays reveal that irradiation therapy affects the tumorigenic potential of cancer stem cells by ablating selfrenewal and inducing astroglial differentiation

Summary

Introduction

The relationship between cell-cycle control and regulation of differentiation is a major question in stem cell biology. NSC cultures can be derived ex vivo from both the developing and adult brain or from embryonic stem (ES) cells and can differentiate into the three brain lineages: neurons, astrocytes, and oligodendrocytes (Conti et al, 2005; Pollard et al, 2006). This differentiation is governed by extracellular ligands and cytokines (Gangemi et al, 2004) and is associated with the downregulation of NSC markers such as Nestin, SOX2, and PAX6 (Conti et al, 2005; Gomez-Lopez et al, 2011). Self-renewing cells with gene expression patterns similar to normal NSCs can be found in glioblastoma multiforme (GBM), supporting the concept of cancer stem cells (Nicolis, 2007)

Results

Discussion

Conclusion