Adult stem cell therapies for neurological disorders: benefits beyond neuronal replacement?

The modest capacity of endogenous repair processes in the central nervous system (CNS) justifies the broad interest in the development of effective stem cell based therapies for neurodegenerative disorders and other acute or chronic lesions. Motivated by the ambitious expectation to achieve functional neuronal replacement, several studies have already evidenced a potential benefit of stem cell grafts in animal models of human disorders. Nevertheless, growing evidence suggests that the effects orchestrated by stem cells, in most experimental cases, are not necessarily associated with the generation of new neurons. This hypothesis correlates with the versatile properties of adult and embryonic stem cells. When introduced into the lesioned CNS, nondifferentiated stem cells can have a positive influence through intrinsic neuroprotective capacities related to the production of neurotrophic factors, stimulation of endogenous neurogenesis, and modulation of neuroinflammation. Stem cells are also endowed with a multipotent differentiation profile, suggesting that a positive outcome could result from the replacement of nonneuronal cell types, in particular astrocytes and oligodendrocytes. Focusing on adult stem cells, this Review aims at summarizing experimental observations supporting the concept that, in cell-based therapies, stem cells operate not through a unidirectional mechanism (e.g., generating neurons) but rather as cellular mediators of a multitude of biological activities that could provide a favorable outcome for diverse nervous disorders.