Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. C URRENT O PINION Neural stem cell transplantation in central nervous system disorders: from cell replacement to neuroprotection Donatella De Feo a,b , Arianna Merlini a,b , Cecilia Laterza a , and Gianvito Martino a,b Purpose of review Transplantation of neural stem/precursor cells (NPCs) has been proposed as a promising therapeutic strategy in almost all neurological disorders characterized by the failure of central nervous system (CNS) endogenous repair mechanisms in restoring the tissue damage and rescuing the lost function. Nevertheless, recent evidence consistently challenges the limited view that transplantation of these cells is solely aimed at protecting the CNS from inflammatory and neurodegenerative damage through cell replacement. Recent findings Recent preclinical data confirmed that transplanted NPCs may also exert a ‘bystander’ neuroprotective effect and identified a series of molecules – for example, immunomodulatory substances, neurotrophic growth factors, stem cell regulators as well as guidance molecules – whose in-situ secretion by NPCs is temporally and spatially orchestrated by environmental needs. A better understanding of the molecular and cellular mechanisms sustaining this ‘therapeutic plasticity’ is of pivotal importance for defining crucial aspects of the bench-to-beside translation of neural stem cell therapy, that is route and timing of administration as well as the best cellular source. Further insight into those latter issues is eagerly expected from the ongoing phase I/II clinical trials, while, on the other hand, new cellular sources are being developed, mainly by exploiting the new possibilities offered by cellular reprogramming. Summary Nowadays, the research on NPC transplantation in neurological disorders is advancing on two different fronts: on one hand, recent preclinical data are uncovering the molecular basis of NPC therapeutic plasticity, offering a more solid rational framework for the design of clinical studies. On the other hand, pilot trials are highlighting the safety and feasibility issues of neural stem cell transplantation that need to be addressed before efficacy could be properly evaluated. Keywords bystander effect, cell replacement, neural stem/precursor cells, neurodegeneration, neuroinflammation, thera- peutic plasticity INTRODUCTION Inflammation and degeneration are the prototypi- cal pathological processes promoting irreversible tissue damage and clinical disability in central nerv- ous system (CNS) disorders. These processes are only apparently distinct because, as soon as the patho- logical disorders turn into a chronic phase, they have the tendency to become strictly interrelated [1 & ,2,3]. Primary neurodegeneration triggers a sec- ondary inflammatory reaction, whereas primary inflammatory reactions lead to chronic neuro- degeneration. To prevent irreversible tissue damage, the CNS has evolutionarily developed a series of molecular and cellular repair mechanisms that are activated in response to chronic inflammation and neuro- degeneration. Humoral and cellular inflammatory a Neuroimmunology Unit, Institute of Experimental Neurology (INSpe), Division of Neuroscience, San Raffaele Scientific Institute and b Depart- Department of Neurology and Neurophysiology, San Raffaele Scientific Institute, Universita ` Vita-Salute, Milan, Italy Correspondence to Gianvito Martino, MD, Neuroimmunology Unit, Insti- tute of Experimental Neurology (INSpe), Division of Neuroscience, San Raffaele Hospital, Via Olgettina 58, 20132 Milan, Italy. Tel: +39 2 2643 4853; fax: +39 2 2643 4855; e-mail: martino.gianvito@hsr.it Curr Opin Neurol 2012, 25:322–333 DOI:10.1097/WCO.0b013e328352ec45 www.co-neurology.com Volume 25  Number 3  June 2012 REVIEW