Radiotherapy plays a significant role in brain cancer treatment; however, the use of this therapy is often accompanied by neurocognitive decline that is, at least partially, a consequence of radiation-induced damage to neural stem cell populations. Our findings describe features that define the response of neural stem cells (NSCs) to ionizing radiation. We investigated the effects of irradiation on neural stem cells isolated from the ventricular-subventricular zone of mouse brain and cultivated in vitro. Our findings describe the increased transcriptional activity of p53 targets and proliferative arrest after irradiation. Moreover, we show that most cells do not undergo apoptosis after irradiation but rather cease proliferation and start a differentiation program. Induction of differentiation and the demonstrated potential of irradiated cells to differentiate into neurons may represent a mechanism whereby damaged NSCs eliminate potentially hazardous cells and circumvent the debilitating consequences of cumulative DNA damage.

Department of Dosimetry and Application of Ionizing Radiation Faculty of Nuclear Sciences and Physical Engineering Czech Technical University Břehová 7 115 19 Prague 1 Czech Republic

Department of Radiation Dosimetry Nuclear Physics Institute of the Czech Academy of Sciences v v i Husinec 130 250 68 Řež Czech Republic

Laboratory of Cell Differentiation Institute of Molecular Genetics of the Czech Academy of Sciences v v i Vídeňská 1083 142 20 Prague 4 Czech Republic

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Cancer Today. [(accessed on 26 April 2019)]; Available online: http://gco.iarc.fr/today/home.

Mahase S.S., Navrazhina K., Schwartz T.H., Parashar B., Wernicke A.G. Intraoperative brachytherapy for resected brain metastases. Brachytherapy. 2019;18:258–270. doi: 10.1016/j.brachy.2019.01.011. PubMed DOI

Chang E.L., Wefel J.S., Hess K.R., Allen P.K., Lang F.F., Kornguth D.G., Arbuckle R.B., Swint J.M., Shiu A.S., Maor M.H., et al. Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: A randomised controlled trial. Lancet Oncol. 2009;10:1037–1044. doi: 10.1016/S1470-2045(09)70263-3. PubMed DOI

Deangelis L.M., Delattre J.Y., Posner J.B. Radiation-Induced Dementia in Patients Cured of Brain Metastases. Neurology. 1989;39:789–796. doi: 10.1212/WNL.39.6.789. PubMed DOI

Mulhern R.K., Merchant T.E., Gajjar A., Reddick W.E., Kun L.E. Late neurocognitive sequelae in survivors of brain tumours in childhood. Lancet Oncol. 2004;5:399–408. doi: 10.1016/S1470-2045(04)01507-4. PubMed DOI

Gibson E., Monje M. Effect of cancer therapy on neural stem cells: Implications for cognitive function. Curr. Opin. Oncol. 2012;24:672–678. doi: 10.1097/CCO.0b013e3283571a8e. PubMed DOI PMC

Kut C., Redmond K.J. New Considerations in Radiation Treatment, Planning for Brain Tumors: Neural Progenitor Cell-Containing Niches. Semin. Radiat. Oncol. 2014;24:265–272. doi: 10.1016/j.semradonc.2014.06.007. PubMed DOI PMC

Doetsch F., Garcia-Verdugo J.M., Alvarez-Buylla A. Cellular composition and three-dimensional organization of the subventricular germinal zone in the adult mammalian brain. J. Neurosci. 1997;17:5046–5061. doi: 10.1523/JNEUROSCI.17-13-05046.1997. PubMed DOI PMC

Kuhn H.G., Dickinson-Anson H., Gage F.H. Neurogenesis in the dentate gyrus of the adult rat: Age-related decrease of neuronal progenitor proliferation. J. Neurosci. 1996;16:2027–2033. doi: 10.1523/JNEUROSCI.16-06-02027.1996. PubMed DOI PMC

Llorens-Bobadilla E., Zhao S., Baser A., Saiz-Castro G., Zwadlo K., Martin-Villalba A. Single-Cell Transcriptomics Reveals a Population of Dormant Neural Stem Cells that Become Activated upon Brain Injury. Cell Stem Cell. 2015;17:329–340. doi: 10.1016/j.stem.2015.07.002. PubMed DOI

Codega P., Silva-Vargas V., Paul A., Maldonado-Soto A.R., Deleo A.M., Pastrana E., Doetsch F. Prospective identification and purification of quiescent adult neural stem cells from their in vivo niche. Neuron. 2014;82:545–559. doi: 10.1016/j.neuron.2014.02.039. PubMed DOI PMC

Obernier K., Alvarez-Buylla A. Neural stem cells: Origin, heterogeneity and regulation in the adult mammalian brain. Development. 2019;146:dev156059. doi: 10.1242/dev.156059. PubMed DOI PMC

Yu H. Typical cell signaling response to ionizing radiation: DNA damage and extranuclear damage. Chin. J. Cancer Res. 2012;24:83–89. doi: 10.1007/s11670-012-0083-1. PubMed DOI PMC

Sancar A., Lindsey-Boltz L.A., Unsal-Kacmaz K., Linn S. Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints. Annu. Rev. Biochem. 2004;73:39–85. doi: 10.1146/annurev.biochem.73.011303.073723. PubMed DOI

Mizumatsu S., Monje M.L., Morhardt D.R., Rola R., Palmer T.D., Fike J.R. Extreme sensitivity of adult neurogenesis to low doses of X-irradiation. Cancer Res. 2003;63:4021–4027. PubMed

Bellinzona M., Gobbel G.T., Shinohara C., Fike J.R. Apoptosis is induced in the subependyma of young adult rats by ionizing irradiation. Neurosci. Lett. 1996;208:163–166. doi: 10.1016/0304-3940(96)12572-6. PubMed DOI

Daynac M., Chicheportiche A., Pineda J.R., Gauthier L.R., Boussin F.D., Mouthon M.A. Quiescent neural stem cells exit dormancy upon alteration of GABA(A)R signaling following radiation damage. Stem Cell Res. 2013;11:516–528. doi: 10.1016/j.scr.2013.02.008. PubMed DOI

Lazarini F., Mouthon M.A., Gheusi G., de Chaumont F., Olivo-Marin J.C., Lamarque S., Abrous D.N., Boussin F.D., Lledo P.M. Cellular and Behavioral Effects of Cranial Irradiation of the Subventricular Zone in Adult Mice. PLoS ONE. 2009;4:e7017. doi: 10.1371/journal.pone.0007017. PubMed DOI PMC

Monje M.L., Mizumatsu S., Fike J.R., Palmer T.D. Irradiation induces neural precursor-cell dysfunction. Nat. Med. 2002;8:955–962. doi: 10.1038/nm749. PubMed DOI

Pineda J.R., Daynac M., Chicheportiche A., Cebrian-Silla A., Felice K.S., Garcia-Verdugo J.M., Boussin F.D., Mouthon M.A. Vascular-derived TGF- increases in the stem cell niche and perturbs neurogenesis during aging and following irradiation in the adult mouse brain. EMBO Mol. Med. 2013;5:548–562. doi: 10.1002/emmm.201202197. PubMed DOI PMC

Schneider L., Pellegatta S., Favaro R., Pisati F., Roncaglia P., Testa G., Nicolis S.K., Finocchiaro G., di Fagagna F.D. DNA Damage in Mammalian Neural Stem Cells Leads to Astrocytic Differentiation Mediated by BMP2 Signaling through JAK-STAT. Stem Cell Rep. 2013;1:123–138. doi: 10.1016/j.stemcr.2013.06.004. PubMed DOI PMC

Dulken B.W., Leeman D.S., Boutet S.C., Hebestreit K., Brunet A. Single-Cell Transcriptomic Analysis Defines Heterogeneity and Transcriptional Dynamics in the Adult Neural Stem Cell Lineage. Cell Rep. 2017;18:777–790. doi: 10.1016/j.celrep.2016.12.060. PubMed DOI PMC

Meletis K., Wirta V., Hede S.M., Nister M., Lundeberg J., Frisen J. P53 suppresses the self-renewal of adult neural stem cells. Development. 2006;133:363–369. doi: 10.1242/dev.02208. PubMed DOI

El-Deiry W.S., Tokino T., Velculescu V.E., Levy D.B., Parsons R., Trent J.M., Lin D., Mercer W.E., Kinzler K.W., Vogelstein B. WAF1, a potential mediator of p53 tumor suppression. Cell. 1993;75:817–825. doi: 10.1016/0092-8674(93)90500-P. PubMed DOI

Galvin K.E., Ye H., Erstad D.J., Feddersen R., Wetmore C. Gli1 induces G2/M arrest and apoptosis in hippocampal but not tumor-derived neural stem cells. Stem Cells. 2008;26:1027–1036. doi: 10.1634/stemcells.2007-0879. PubMed DOI

Engeland K. Cell cycle arrest through indirect transcriptional repression by p53: I have a DREAM. Cell Death Differ. 2018;25:114–132. doi: 10.1038/cdd.2017.172. PubMed DOI PMC

Ambrosini G., Adida C., Altieri D.C. A novel anti-apoptosis gene, survivin, expressed in cancer and lymphoma. Nat. Med. 1997;3:917–921. doi: 10.1038/nm0897-917. PubMed DOI

Shin S., Sung B.J., Cho Y.S., Kim H.J., Ha N.C., Hwang J.I., Chung C.W., Jung Y.K., Oh B.H. An anti-apoptotic protein human survivin is a direct inhibitor of caspase-3 and-7. Biochemistry. 2001;40:1117–1123. doi: 10.1021/bi001603q. PubMed DOI

Kuwabara M., Takahashi K., Inanami O. Induction of apoptosis through the activation of SAPK/JNK followed by the expression of death receptor Fas in X-irradiated cells. J. Radiat. Res. 2003;44:203–209. doi: 10.1269/jrr.44.203. PubMed DOI

Sheridan J.P., Marsters S.A., Pitti R.M., Gurney A., Skubatch M., Baldwin D., Ramakrishnan L., Gray C.L., Baker K., Wood W.I., et al. Control of TRAIL-induced apoptosis by a family of signaling and decoy receptors. Science. 1997;277:818–821. doi: 10.1126/science.277.5327.818. PubMed DOI

Barazzuol L., Ju L.M., Jeggo P.A. A coordinated DNA damage response promotes adult quiescent neural stem cell activation. PLoS Biol. 2017;15:e2001264. doi: 10.1371/journal.pbio.2001264. PubMed DOI PMC

Ichijima Y., Sakasai R., Okita N., Asahina K., Mizutani S., Teraoka H. Phosphorylation of histone H2AX at M phase in human cells without DNA damage response. Biochem. Biophys. Res. Commun. 2005;336:807–812. doi: 10.1016/j.bbrc.2005.08.164. PubMed DOI

Lee C.L., Blum J.M., Kirsch D.G. Role of p53 in regulating tissue response to radiation by mechanisms independent of apoptosis. Transl. Cancer Res. 2013;2:412–421. PubMed PMC

Lin T.X., Chao C., Saito S., Mazur S.J., Murphy M.E., Appella E., Xu Y. P53 induces differentiation of mouse embryonic stem cells by suppressing Nanog expression. Nat. Cell Biol. 2005;7:165–171. doi: 10.1038/ncb1211. PubMed DOI

Wingert S., Thalheimer F.B., Haetscher N., Rehage M., Schroeder T., Rieger M.A. DNA-Damage Response Gene GADD45A Induces Differentiation in Hematopoietic Stem Cells Without Inhibiting Cell Cycle or Survival. Stem Cells. 2016;34:699–710. doi: 10.1002/stem.2282. PubMed DOI PMC

Pereira Dias G., Hollywood R., Bevilaqua M.C., da Luz A.C., Hindges R., Nardi A.E., Thuret S. Consequences of cancer treatments on adult hippocampal neurogenesis: Implications for cognitive function and depressive symptoms. Neuro-Oncology. 2014;16:476–492. doi: 10.1093/neuonc/not321. PubMed DOI PMC

Hermanto U., Frija E.K., Lii M.F.J., Chang E.L., Mahajan A., Woo S.Y. Intensity-modulated radiotherapy (IMRT) and conventional three-dimensional conformal radiotherapy for high-grade gliomas: Does IMRT increase the integral dose to normal brain? Int. J. Radiat. Oncol. 2007;67:1135–1144. doi: 10.1016/j.ijrobp.2006.10.032. PubMed DOI

Zanni G., Di Martino E., Omelyanenko A., Andang M., Delle U., Elmroth K., Blomgren K. Lithium increases proliferation of hippocampal neural stem/progenitor cells and rescues irradiation-induced cell cycle arrest in vitro. Oncotarget. 2015;6:37083–37097. doi: 10.18632/oncotarget.5191. PubMed DOI PMC

Naseri S., Moghahi S.M.H.N., Mokhtari T., Roghani M., Shirazi A.R., Malek F., Rastegar T. Radio-Protective Effects of Melatonin on Subventricular Zone in Irradiated Rat: Decrease in Apoptosis and Upregulation of Nestin. J. Mol. Neurosci. 2017;63:198–205. doi: 10.1007/s12031-017-0970-5. PubMed DOI

Conti L., Cattaneo E. Neural stem cell systems: Physiological players or in vitro entities? Nat. Rev. Neurosci. 2010;11:176–187. doi: 10.1038/nrn2761. PubMed DOI

Azari H., Rahman M., Sharififar S., Reynolds B.A. Isolation and expansion of the adult mouse neural stem cells using the neurosphere assay. J. Vis. Exp. 2010;45:e2393. doi: 10.3791/2393. PubMed DOI PMC

Walker T.L., Kempermann G. One mouse, two cultures: Isolation and culture of adult neural stem cells from the two neurogenic zones of individual mice. J. Vis. Exp. 2014;84:e51225. doi: 10.3791/51225. PubMed DOI PMC

Effects of Radiation Therapy on Neural Stem Cells