Neurogenesis occurs throughout life but significantly decreases with age. Human umbilical cord blood mononuclear cells (HUCB MNCs) have been shown to increase the proliferation of neural stem cells (NSCs) in the dentate gyrus (DG) of the hippocampus and the subgranular zone of aging rats (Bachstetter et al., BMC Neurosci 9:22, 2008), but it is unclear which fraction or combination of the HUCB MNCs are responsible for neurogenesis. To address this issue, we examined the ability of HUCB MNCs, CD4+, CD8+, CD3+, CD14+, and CD133+ subpopulations to increase proliferation of NSCs both in vitro and in vivo. NSCs were first grown in conditioned media generated from HUCB cultures, and survival and proliferation of NSC were determined with the fluorescein diacetate/propidium iodide and 5-bromo-2′-deoxyuridine incorporation assays, respectively. In a second study, we injected HUCB cells intravenously in young and aged Fisher 344 rats and examined proliferation in the DG at 1 week (study 2.1) and 2 weeks (study 2.2) postinjection. The effects of the HUCB MNC fractions on dendritic spine density and microglial activation were also assessed. HUCB T cells (CD3+, CD4+, and CD8+ cells) induced proliferation of NSCs (p < 0.001) and increased cell survival. In vivo, HUCB-derived CD4+ cells increased NSC proliferation at both 1 and 2 weeks while also enhancing the density of dendritic spines at 1 week and decreasing inflammation at 2 weeks postinjection. Collectively, these data indicate that a single injection of HUCB-derived T cells induces long-lasting effects and may therefore have tremendous potential to improve aging neurogenesis.
Human umbilical cord blood (HUCB) cell therapies have shown promising results in reducing brain infarct volume and most importantly in improving neurobehavioral function in rat permanent middle cerebral artery occlusion, a model of stroke. In this study, we examined the gene expression profile in neurons subjected to oxygen-glucose deprivation (OGD) with or without HUCB treatment and identified signaling pathways (Akt/MAPK) important in eliciting HUCB-mediated neuroprotective responses. Gene chip microarray analysis was performed using RNA samples extracted from the neuronal cell cultures from four experimental groups: normoxia, normoxia + HUCB, OGD, and OGD + HUCB. Both quantitative RT-PCR and immunohistochemistry were carried out to verify the microarray results. Using the Genomatix software program, promoter regions of selected genes were compared to reveal common transcription factor-binding sites and, subsequently, signal transduction pathways. Under OGD condition, HUCB cells significantly reduced neuronal loss from 68% to 44% [one-way ANOVA, F(3, 16) = 11, p = 0.0003]. Microarray analysis identified mRNA expression of Prdx5, Vcam1, CCL20, Alcam, and Pax6 as being significantly altered by HUCB cell treatment. Inhibition of the Akt pathway significantly abolished the neuroprotective effect of HUCB cells [one-way ANOVA, F(3, 11) = 8.663, p = 0.0031]. Our observations show that HUCB neuroprotection is dependent on the activation of the Akt signaling pathway that increases transcription of the Prdx5 gene. We concluded that HUCB cell therapy would be a promising treatment for stroke and other forms of brain injury by modifying acute gene expression to promote neural cell protection.
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