Enhancement of ventricular-subventricular zone-derived neurogenesis and oligodendrogenesis by erythropoietin and its derivatives

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.

Erythropoietin: Emerging Role of Erythropoietin in Neonatal Neuroprotection

“…This spontaneous regeneration is insufficient to provide functional and structural recovery on its own. Epo not only promotes neurogenesis and oligodendrogenesis (16, 17) , it also increases migration in and around the injured area through secretion of matrix metalloproteinases (76, 77). …”

Erythropoietin for the Repair of Cerebral Injury in Very Preterm Infants (EpoRepair)

“…Apart from stimulating the production of red blood cells, recombinant human erythropoietin (rEPO) has been shown to exert neuroprotective action in a variety of animal models with brain damage [20]. Administration of rEPO even several days after the insult can enhance neurogenesis and oligodendrogenesis and promotes the recovery of neurological function weeks to months after the insult [21].…”

Neuroprotective effects of erythropoietin against oxidant injury following brain irradiation: an experimental study

“…In an attempt to augment oxygen delivery as a response to hypoxia, EPO exerts its action through the up-regulation of specific receptors that have been shown to be abundant not only in the bone marrow, but also in a variety of tissues including the brain. Besides the expression the EPO receptors in the brain, autocrine production of EPO has been reported in the astrocytes as well as the oligodendrocytes, the glial cells and the endothelial cells [24]. …”

“…After a single high-dose intravenous injection, EPO is detectable in the brain within hours, reaching a peak concentration at 3–4 hours in the brain or cerebrospinal fluid in humans and other animals [24]. …”