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Brain Advance Access published online on August 30, 2008
Brain, doi:10.1093/brain/awn198
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© 2008 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Persistent inflammation alters the function of the endogenous brain stem cell compartment

Stefano Pluchino1,2, Luca Muzio1,2, Jaime Imitola3, Michela Deleidi1,2, Clara Alfaro-Cervello4, Giuliana Salani1,2, Cristina Porcheri1,2, Elena Brambilla1,2, Francesca Cavasinni1,2, Andrea Bergamaschi1,2, Jose Manuel Garcia-Verdugo4,5, Giancarlo Comi2, Samia J. Khoury3,* and Gianvito Martino1,2,*

1Neuroimmunology Unit, DIBIT, 2Institute of Experimental Neurology (INSPE), San Raffaele Scientific Institute, 20132 Milan, Italy, 3Center for Neurologic Diseases and Partners Multiple Sclerosis Center, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA, 4Department Comparative Neurobiology, Instituto Cavanilles, University of Valencia, 46980 Valencia and 5Department of Cellular Therapy, Centro de Investigación Príncipe Felipe, 46013 Valencia, Spain *These authors contributed equally to this work.

Correspondence to: Gianvito Martino, MD, Neuroimmunology Unit – DIBIT and INSPE, San Raffaele Scientific Institute, Via Olgettina 58, 20132 Milano, Italy E-mail: martino.gianvito{at}hsr.it

Endogenous neural stem/precursor cells (NPCs) are considered a functional reservoir for promoting tissue homeostasis and repair after injury, therefore regenerative strategies that mobilize these cells have recently been proposed. Despite evidence of increased neurogenesis upon acute inflammatory insults (e.g. ischaemic stroke), the plasticity of the endogenous brain stem cell compartment in chronic CNS inflammatory disorders remains poorly characterized. Here we show that persistent brain inflammation, induced by immune cells targeting myelin, extensively alters the proliferative and migratory properties of subventricular zone (SVZ)-resident NPCs in vivo leading to significant accumulation of non-migratory neuroblasts within the SVZ germinal niche. In parallel, we demonstrate a quantitative reduction of the putative brain stem cells proliferation in the SVZ during persistent brain inflammation, which is completely reversed after in vitro culture of the isolated NPCs. Together, these data indicate that the inflamed brain microenvironment sustains a non cell-autonomous dysfunction of the endogenous CNS stem cell compartment and challenge the potential efficacy of proposed therapies aimed at mobilizing endogenous precursors in chronic inflammatory brain disorders.

Key Words: neurogenesis; neural stem cells; inflammation; experimental autoimmune encephalomyelitis; multiple sclerosis

Abbreviations: BrdU, 5'-bromo-2'-deoxyuridine; CFA, complete Freund's adjuvant; dpi, days post-immunization; EAE, experimental autoimmune encephalomyelitis; EGF, epidermal growth factor; EM, electron microscopy; FGF-II, fibroblast growth factor; GFAP, glial-fibrillary acidic protein; HC, healthy control; IddU, 5'-iodo-2'-deoxyuridine; IFN-{gamma}, interferon-{gamma}; IL-1β, interleukin-1β; L.I., labelling index; MOG, myelin oligodendrocyte glycoprotein; NCFCA, Neural Colony Forming Cell Assay; NS-A, Neurosphere Assay; NPC, neural stem/precursor cells; OB, olfactory bulb; PDGF, platelet-derived growth factor; PSA-NCAM, polysialylated form of neural cell adhesion molecule; RMS, rostral migratory stream; SVZ, subventricular zone; TLDA, TaqMan® Low-Density Array; TNF-{alpha}, tumour necrosis factor-{alpha}

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Received March 10, 2008. Revised July 27, 2008. Accepted July 31, 2008.

*These authors contributed equally to this work


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