Abstract
Regenerative medicine for cerebral ischemia includes the activation of proliferation, migration, and differentiation of endogenous neuronal stem cell, as well as transplantation of stem cell. Neurogenesis is well described in the subventricular zone (SVZ) and subgranular cell layer (SGL) in the dentate gyrus of the hippocampus in adult mammals. Recent studies have shown the existence of neuronal stem cells in the SVZ and in the dentate gyrus of the hippocampus throughout life. To date, it has been shown that ischemic stress activates regeneration of newborn neurons in the SGL and SVZ in several animal stroke models. A previous study showed that transient forebrain ischemia in rats was followed by replacement of hippocampal CA1 pyramidal neurons by recruitment of endogenous neural progenitor cells, and its recruitment is increased by neurotrophic factors. In a recent study, we visualized the proliferation, migration and differentiation of neuronal progenitor cells in the dentate gyrus induced by ischemic stress using improved retroviral vector. Furthermore, we showed that ischemic stress promoted the proliferation and normal development of neurons at this site. Considerable basic research on regenerative treatment using neuronal stem cell transplantation has been reported. Part of the regenerative treatment by stem cell transplantation has progressed to clinical trials. Recently, it has been reported that transplantation of bone marrow stem cells into areas of cerebral infarction merits further attention. Recent studies have shown that the hematopoietic cytokine, granulocyte colony-stimulating factor (G-CSF) has a neuroprotective effect through the signaling pathway for anti-apoptotic cascade. We tested the hypothesis that G-CSF has neuroprotective effects in cerebral ischemia and that such an effect is mediated through the anti-apoptotic pathway by activating the JAK/STAT pathway, in addition to the reduction of iNOS activity. Our findings indicate that G-CSF exerts a neuroprotective effect through direct activation of the anti-apoptotic pathway, and suggested that G-CSF is important for expansion of the therapeutic time window in patients with cerebral ischemia. Some research groups reported that various cytokines appear to play roles in neurogenesis and neuronal regeneration. Another recent study showed that administration of G-CSF and stem cell factor in the subacute phase after focal cerebral ischemia effectively promotes cytokine-induced generation of neuronal cells from bone marrow-derived cells. However, there are many problems to be resolved before clinical application as a real regenerative treatment using stem cells in ischemic stroke.
