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In ischemic stroke, the third most frequent cause of mortality in industrialized countries, therapeutic options have until now been limited to the first hours after disease onset. Cell transplantation has emerged in various neurological disorders, including experimental stroke, as a successful recovery-promoting approach also in the post-acute stroke phase. However, before envisaging any translation into humans of such promising cell-based approaches we still need to clarify: (i) the ideal cell source for transplantation, (ii) the most appropriate route of cell administration, and, last but not least, (iii) the best approach to achieve an appropriate and functional integration of transplanted cells into the host tissue. Here we discuss, with special emphasis on neural stem/precursor cells, potential mechanisms that may be involved in the action of cell-based therapies in stroke.

Adult multipotent neural stem/precursor cells (NPCs) have the capacity to self-renew and generate functional differentiated cells (e.g. neurons, astrocytes or oligodendrocytes) within discrete tissue-specific germinal niches, such as the subventricular zone of the lateral ventricles and the subgranular zone of the dentate gyrus of the hippocampus. Due to their intrinsic plasticity NPCs can be considered an essential part of the cellular mechanism(s) by which the central nervous system (CNS) tries to repair itself after an injury and, as a consequence, they also represents an attractive therapeutic tool for the treatment of neurological disorders. Here we will discuss not only the role of NPC-based transplantation therapies in multiple sclerosis (MS) but also recent data suggesting that endogenous NPCs, while contributing to CNS repair in MS, may also become the target of the disease itself.

Cell renewal in the adult central nervous system (CNS) is limited, and is blocked in inflammatory brain conditions. We show that both neurogenesis and oligodendrogenesis of adult neural progenitor cells in mice are blocked by inflammation-associated (endotoxin-activated) microglia, but induced by microglia activated by cytokines (IL-4 or low level of IFN-gamma) associated with T-helper cells. Blockage was correlated with up-regulation of microglial production of tumor necrosis factor-alpha. The effect induced by IL-4-activated microglia was mediated, at least in part, by insulin-like growth factor-I. The IL-4-activated microglia showed a bias towards oligodendrogenesis whereas the IFN-gamma-activated microglia showed a bias towards neurogenesis. It thus appears that microglial phenotype critically affects their ability to support or impair cell renewal from adult stem cell.