Abstract
BackgroundErythropoietin (EPO), a hematopoietic cytokine, enhances neurogenesis and angiogenesis during stroke recovery. In the present study, we examined the effect of EPO on oligodendrogenesis in a rat model of embolic focal cerebral ischemia.Methodology and Principal FindingsRecombinant human EPO (rhEPO) at a dose of 5,000 U/kg (n = 18) or saline (n = 18) was intraperitoneally administered daily for 7 days starting 24 h after stroke onset. Treatment with rhEPO augmented actively proliferating oligodendrocyte progenitor cells (OPCs) measured by NG2 immunoreactive cells within the peri-infarct white matter and the subventricular zone (SVZ), but did not protect against loss of myelinating oligodendrocytes measured by cyclic nucleotide phosphodiesterase (CNPase) positive cells 7 days after stroke. However, 28 and 42 days after stroke, treatment with rhEPO significantly increased myelinating oligodendrocytes and myelinated axons within the peri-infarct white matter. Using lentivirus to label subventricular zone (SVZ) neural progenitor cells, we found that in addition to the OPCs generated in the peri-infarct white matter, SVZ neural progenitor cells contributed to rhEPO-increased OPCs in the peri-infarct area. Using bromodeoxyuridine (BrdU) for birth-dating cells, we demonstrated that myelinating oligodendrocytes observed 28 days after stroke were derived from OPCs. Furthermore, rhEPO significantly improved neurological outcome 6 weeks after stroke. In vitro, rhEPO increased differentiation of adult SVZ neural progenitor cells into oligodendrocytes and enhanced immature oligodendrocyte cell proliferation.ConclusionsOur in vivo and in vitro data indicate that EPO amplifies stroke-induced oligodendrogenesis that could facilitate axonal re-myelination and lead to functional recovery after stroke.
Highlights
Oligodendrocytes are the myelin-forming glial cells in the adult brain and are highly vulnerable to ischemic insult [1,2,3]
Mature oligodendrocytes in adult rodent brain are derived from non-myelinating oligodendrocyte progenitor cells (OPCs) that are present in the corpus callosum and the striatum [6,7] Neural progenitor cells in the subventricular zone (SVZ) of the lateral ventricles give rise to OPCs that disperse throughout the corpus callosum and striatum [8]
OPCs were identified by NG2 positive cells, while myelinating oligodendrocytes were detected by cyclic nucleotide phosphodiesterase (CNPase) or myelin basic protein (MBP) immunoreactive cells [20]
Summary
Oligodendrocytes are the myelin-forming glial cells in the adult brain and are highly vulnerable to ischemic insult [1,2,3]. Garcia and his colleagues demonstrate that as early as 30 minutes after middle cerebral artery occlusion (MCAo), animals exhibit swelling of oligodendrocytes followed by white matter injury [2]. There are a paucity of studies that have investigated regeneration of oligodendrocytes in the ischemic brain during long-term stroke recovery [12]. Understanding of how OPCs and new oligodendrocytes contribute to ischemic repair is important for the development of therapies aimed at facilitating generation of mature oligodendrocytes that could promote remyelination leading to functional improvement after stroke. We examined the effect of EPO on oligodendrogenesis in a rat model of embolic focal cerebral ischemia
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