Abstract
Human umbilical cord blood (HUCB) cells protect the brain against ischemic injury, yet the mechanism of protection remains unclear. Using both in vitro and in vivo paradigms, this study examined the role of Akt signaling and peroxiredoxin 4 expression in human umbilical cord blood cell-mediated protection of oligodendrocytes from ischemic conditions. As previously reported, the addition of HUCB cells to oligodendrocyte cultures prior to oxygen glucose deprivation significantly enhanced oligodendrocyte survival. The presence of human umbilical cord blood cells also increased Akt phosphorylation and elevated peroxiredoxin 4 expression in oligodendrocytes. Blocking either Akt or peroxiredoxin 4 activity with Akt Inhibitor IV or a peroxiredoxin 4-neutralizing antibody, respectively, negated the protective effects of human umbilical cord blood cells. In vivo, systemic administration of human umbilical cord blood cells 48 h after middle cerebral artery occlusion increased Akt phosphorylation and peroxiredoxin 4 protein expression while reducing proteolytic cleavage of caspase 3 in oligodendrocytes residing in the ipsilateral external capsule. Moreover, human umbilical cord blood cells protected striatal white matter bundles from degeneration following middle cerebral artery occlusion. These results suggest that the soluble factors released from human umbilical cord blood cells converge on Akt to elevate peroxiredoxin 4 levels, and these effects contribute to oligodendrocyte survival.
Highlights
Human umbilical cord blood cells are an effective experimental treatment for stroke
Akt Inhibition Negated Human umbilical cord blood (HUCB) Cell Protection in Vitro—To assess the role of Akt in HUCB cell protection, four Akt inhibitors were applied to OL cultures that were co-cultured with HUCB cells and exposed to oxygen glucose deprivation (OGD) (Fig. 1A)
The inhibition of Akt phosphorylation eliminated the protective effects of HUCB cells, because cell death was significantly increased relative to HUCB-treated groups
Summary
Human umbilical cord blood cells are an effective experimental treatment for stroke. Results: These cells activate Akt to increase peroxiredoxin 4 and are essential for oligodendrocyte survival during ischemia. Systemic administration of human umbilical cord blood cells 48 h after middle cerebral artery occlusion increased Akt phosphorylation and peroxiredoxin 4 protein expression while reducing proteolytic cleavage of caspase 3 in oligodendrocytes residing in the ipsilateral external capsule. Human umbilical cord blood cells protected striatal white matter bundles from degeneration following middle cerebral artery occlusion. These results suggest that the soluble factors released from human umbilical cord blood cells converge on Akt to elevate peroxiredoxin 4 levels, and these effects contribute to oligodendrocyte survival. Immunohistochemical analysis showed that systemic administration of HUCB cells 48 h post-MCAO increased Akt phosphorylation and Prdx protein expression while reducing proteolytic cleavage of caspase 3 in the external capsule. There was no effect of treatment on OLs exposed to normoxic conditions (B)
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