Over the past two decades, regenerative therapies using stem cell technologies have been developed for various neurological diseases. Although stem cell therapy is an attractive option to reverse neural tissue damage and to recover neurological deficits, it is still under development so as not to show significant treatment effects in clinical settings. In this review, we discuss the scientific and clinical basics of adult neural stem cells (aNSCs), and their current developmental status as cell therapeutics for neurological disease. Compared with other types of stem cells, aNSCs have clinical advantages, such as limited proliferation, inborn differentiation potential into functional neural cells, and no ethical issues. In spite of the merits of aNSCs, difficulties in the isolation from the normal brain, and in the in vitro expansion, have blocked preclinical and clinical study using aNSCs. However, several groups have recently developed novel techniques to isolate and expand aNSCs from normal adult brains, and showed successful applications of aNSCs to neurological diseases. With new technologies for aNSCs and their clinical strengths, previous hurdles in stem cell therapies for neurological diseases could be overcome, to realize clinically efficacious regenerative stem cell therapeutics.

Neural stem cells are emerging as a regenerative therapy for spinal cord injury (SCI), since they differentiate into functional neural cells and secrete beneficial paracrine factors into the damaged microenvironment. Previously, we successfully isolated and cultured adult human multipotent neural cells (ahMNCs) from the temporal lobes of epileptic patients. In this study, we investigated the therapeutic efficacy and treatment mechanism of ahMNCs for SCI using rodent models. When 1 × 10 ahMNCs were transplanted into injured spinal cords at 7 days after contusion, the injection group showed significantly better functional recovery than the control group (media injection after contusion), which was determined by the Basso, Beattie and Bresnahan (BBB) score. Although transplanted ahMNCs disappeared continuously, remained cells expressed differentiated neural cell markers (Tuj1) or astrocyte marker (GFAP) in the injured spinal cords. Moreover, the number of CD31-positive microvessels significantly increased in the injection group than that of the control group. The paracrine pro-angiogenic activities of ahMNCs were confirmed by in vitro tube formation assay and in vivo Matrigel plug assay. Together, these results indicate that ahMNCs have significant therapeutic efficacy in SCI via replacement of damaged neural cells and pro-angiogenic effects on the microenvironment of SCI.

ObjectiveThe purpose of this study was to find an optimal delivery route for clinical trials of intrathecal cell therapy for spinal cord injury in preclinical stage.MethodsWe compared in vivo distribution of Cy5.5 fluorescent dye in the spinal cord region at various time points utilizing in vivo optical imaging techniques, which was injected into the lateral ventricle (LV) or cisterna magna (CM) of rats.ResultsAlthough CM locates nearer to the spinal cord than the LV, significantly higher signal of Cy5.5 was detected in the thoracic and lumbar spinal cord region at all time points tested when Cy5.5 was injected into the LV. In the LV injection Cy5.5 signal in the thoracic and lumbar spinal cord was observed within 12 hours after injection, which was maintained until 72 hours after injection. In contrast, Cy5.5 signal was concentrated at the injection site in the CM injection at all time points.ConclusionThese data suggested that the LV might be suitable for preclinical injection route of therapeutics targeting the spinal cord to test their treatment efficacy and biosafety for spinal cord diseases in small animal models.

Neurodegenerative diseases provoke robust immunological reactions in the central nervous system (CNS), which further deteriorate the neural tissue damage. We hypothesized that the expression levels of indoleamine 2,3-dioxygenase (IDO), an enzyme that has potent immune suppressive activities, in neural stem cells (NSCs) would have synergistic therapeutic effects against neurodegenerative diseases, since NSCs themselves have low IDO expression. In this study, the synergistic immune suppressive effects of rat fetal NSCs expressing IDO (rfNSCs-IDO) were validated by mixed leukocyte reaction (MLR) in vitro and an experimental autoimmune encephalomyelitis (EAE) animal model in vivo. rfNSCs-IDO showed significantly more suppressive effects on T cell proliferation in the MLR compared to control rfNSCs (rfNSCs-Cont). Importantly, IDO inhibition using 1-methyl-DL-tryptophan (1-MT), an IDO inhibitor, reversed the synergistic effects, confirming IDO-specific effects in rfNSCs-IDO. In the EAE animal model, systemic rfNSCs-IDO injections resulted in significant local immune suppression in the cervical lymph nodes and CNS, evidenced by a reduction in the number of activated T lymphocytes and an increase in regulatory T cell numbers, which induced significantly fewer clinical symptoms and faster recovery. In contrast, rfNSCs-Cont failed to reduce symptoms in the EAE animal models, although they showed local immune suppression, which was significantly less than that in rfNSCs-IDO. Taken together, IDO expression in NSCs synergistically potentiates the immune suppression activities of NSCs and could be applicable for the development of therapeutic modalities against various neurodegenerative diseases.