Abstract
In the postnatal mammalian brain, stem cells in the ventricular-subventricular zone (V-SVZ) continuously generate neuronal and glial cells throughout life. Genetic labeling of cells of specific lineages have demonstrated that the V-SVZ is an important source of the neuroblasts and/or oligodendrocyte progenitor cells (OPCs) that migrate toward injured brain areas in response to several types of insult, including ischemia and demyelinating diseases. However, this spontaneous regeneration is insufficient for complete structural and functional restoration of the injured brain, so interventions to enhance these processes are sought for clinical applications. Erythropoietin (EPO), a clinically applied erythropoietic factor, is reported to have cytoprotective effects in various kinds of insult in the central nervous system. Moreover, recent studies suggest that EPO promotes the V-SVZ-derived neurogenesis and oligodendrogenesis. EPO increases the proliferation of progenitors in the V-SVZ and/or the migration and differentiation of their progenies in and around injured areas, depending on the dosage, timing, and duration of treatment, as well as the type of animal model used. On the other hand, EPO has undesirable side effects, including thrombotic complications. We recently demonstrated that a 2-week treatment with the EPO derivative asialo-EPO promotes the differentiation of V-SVZ-derived OPCs into myelin-forming mature oligodendrocytes in the injured white matter of neonatal mice without causing erythropoiesis. Here we present an overview of the multifaceted effects of EPO and its derivatives in the V-SVZ and discuss the possible applications of these molecules in regenerative medicine.
Highlights
NEW NEURON PRODUCTION IN THE V-SVZ Neural stem cells (NSCs) in the ventricular-subventricular zone (V-SVZ), located at the lateral walls of the lateral ventricles, have been investigated as an endogenous cell source for neurons (Belvindrah et al, 2009; Kriegstein and Alvarez-Buylla, 2009; Ihrie and Alvarez-Buylla, 2011; Ming and Song, 2011) and oligodendrocytes (Nait-Oumesmar et al, 2008; GonzalezPerez and Alvarez-Buylla, 2011) in the postnatal brain
NSCs extend their process with an endfoot that makes contact with blood vessels (Mirzadeh et al, 2008; Tavazoie et al, 2008), the transit-amplifying progenitors reside very close to vessels (Shen et al, 2008; Tavazoie et al, 2008; Kokovay et al, 2010), and the neuroblasts frequently migrate along vessels (Snapyan et al, 2009; Whitman et al, 2009)
V-SVZ is an important source of forebrain oligodendrocyte progenitor cells (OPCs) (Levison and Goldman, 1993; Luskin, 1993; Ivanova et al, 2003; Suzuki and Goldman, 2003)
Summary
Genetic labeling of cells of specific lineages have demonstrated that the V-SVZ is an important source of the neuroblasts and/or oligodendrocyte progenitor cells (OPCs) that migrate toward injured brain areas in response to several types of insult, including ischemia and demyelinating diseases. This spontaneous regeneration is insufficient for complete structural and functional restoration of the injured brain, so interventions to enhance these processes are sought for clinical applications. A portion of the OPCs remain as progenitors, which are called NG2 glia due to their expression of the Frontiers in Cellular Neuroscience www.frontiersin.org
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