Endogenous erythropoietin from astrocyte protects the oligodendrocyte precursor cell against hypoxic and reoxygenation injury

Kato, Shin; Aoyama, Mineyoshi; Kakita, Hiroki; Hida, Hideki; Kato, Ineko; Ito, Tetsuya; Goto, Tatenobu; Hussein, Mohamed Hamed; Sawamoto, Kazunobu; Togari, Hajime; Asai, Kiyofumi

doi:10.1002/jnr.22702

Cited by 59 publications

(50 citation statements)

References 66 publications

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“…In terms of repair, increased expression of myelin genes might contribute to the overall effect of EPO, along with prevention of oligodendrocyte cell death (34,35), stimulation of neurogenesis and angiogenesis (4), and induction of neuronal plasticity (6). This might be relevant to demyelinating diseases, and it is interesting to note that EPO is effective not only in animal models of MS but also in a pilot clinical trial (36).…”

Section: Resultsmentioning

confidence: 99%

Erythropoietin (EPO) Increases Myelin Gene Expression in CG4 Oligodendrocyte Cells through the Classical EPO Receptor

Cervellini

Annenkov

Brenton

et al. 2013

Mol Med

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Erythropoietin (EPO) has protective effects in neurodegenerative and neuroinflammatory diseases, including in animal models of multiple sclerosis, where EPO decreases disease severity. EPO also promotes neurogenesis and is protective in models of toxic demyelination. In this study, we asked whether EPO could promote neurorepair by also inducing remyelination. In addition, we investigated whether the effect of EPO could be mediated by the classical erythropoietic EPO receptor (EPOR), since it is still questioned if EPOR is functional in nonhematopoietic cells. Using CG4 cells, a line of rat oligodendrocyte precursor cells, we found that EPO increases the expression of myelin genes (myelin oligodendrocyte glycoprotein [MOG] and myelin basic protein [MBP]). EPO had no effect in wild-type CG4 cells, which do not express EPOR, whereas it increased MOG and MBP expression in cells engineered to overexpress EPOR (CG4-EPOR). This was reflected in a marked increase in MOG protein levels, as detected by Western blot. In these cells, EPO induced by 10-fold the early growth response gene 2 (Egr2), which is required for peripheral myelination. However, Egr2 silencing with a siRNA did not reverse the effect of EPO, indicating that EPO acts through other pathways. In conclusion, EPO induces the expression of myelin genes in oligodendrocytes and this effect requires the presence of EPOR. This study demonstrates that EPOR can mediate neuroreparative effects.

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Section: Resultsmentioning

confidence: 99%

Erythropoietin (EPO) Increases Myelin Gene Expression in CG4 Oligodendrocyte Cells through the Classical EPO Receptor

Cervellini

Annenkov

Brenton

et al. 2013

Mol Med

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“…OPCs are adjacent to astrocytes [6, 25], and OPCs seeded on astrocytes exhibit higher motility than OPCs on laminin-coated plates in vitro [14]. Besides the direct interaction, astrocytic-derived factors are also reported to help OPCs against several kinds of insults in vitro [2, 19]. Similarly, cerebral endothelial cells may also regulate OPC function.…”

Section: Discussionmentioning

confidence: 99%

Potential interactions between pericytes and oligodendrocyte precursor cells in perivascular regions of cerebral white matter

Maki

Maeda

Uemura

et al. 2015

Neuroscience Letters

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Pericytes are embedded within basal lamina and play multiple roles in the perivascular niche in brain. Recently, oligodendrocyte precursor cells (OPCs) have also been reported to associate with cerebral endothelium. Is it possible that within this gliovascular locus, there may also exist potential spatial and functional interactions between pericytes and OPCs? Here, we demonstrated that in the perivascular region of cerebral white matter, pericytes and OPCs may attach and support each other. Immunostaining showed that pericytes and OPCs are localized in close contact with each other in mouse white matter at postnatal days 0, 60 and 240. Electron microscopic analysis confirmed that pericytes attached to OPCs via basal lamina in the perivascular region. The close proximity between these two cell types was also observed in postmortem human brains. Functional interaction between pericytes and OPCs was assessed by in vitro media transfer experiments. When OPC cultures were treated with pericyte-conditioned media, OPC number increased. Similarly, pericyte number increased when pericytes were maintained in OPC-conditioned media. Taken together, our data suggest a potential anatomical and functional interaction between pericytes and OPCs in cerebral white matter.

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“…We hypothesized that during HI, the microvasculature in the injured core area of the brain underwent multiple rapid responses to HI. Although cerebral ischemia causes neuronal death, glial cell changes and brain injury, a regenerative response is also triggered in the tissue adjacent to the ischemic core area [23]. We proposed that this might involve endogenous EPO.…”

Section: Discussionmentioning

confidence: 99%

Recombinant Human Erythropoietin Augments Angiogenic Responses in a Neonatal Rat Model of Cerebral Unilateral Hypoxia-Ischemia

Zhu¹,

Xu²,

Wang³

et al. 2014

Neonatology

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Background: Recombinant human erythropoietin (rh-EPO) has been used as a drug to treat premature infant anemia for over a decade. In addition to its erythropoietic effect, rh-EPO has also been reported to have protective effects against brain injury. Objectives: Our aim was to evaluate the levels of angiogenesis-related cells (CD34+ cells) and angiogenic factors (vascular endothelial growth factor, VEGF, and angiopoietin-1, Ang-1) in a neonatal rat model of cerebral unilateral hypoxia-ischemia (HI) and to identify the effects of rh-EPO on angiogenic responses. Methods: Postnatal day 3 (PD3) rats underwent permanent ligation of the right common carotid artery followed by 6% O₂ for 4 h (HI) or sham operation and normoxic exposure (sham). Immediately after HI, the rats received a single intraperitoneal injection of rh-EPO (5 U/g) or saline. Angiogenesis-related cells (CD34+ cells) and angiogenic factors (VEGF and Ang-1) were examined on PD5, 7, 10 and 14. Results: Compared with the sham rats, the number of CD34+ cells in HI rats increased from PD5 to 7 but decreased from PD10 to 14. VEGF and Ang-1 mRNA levels both increased from PD5 to 14. CD34+ cells, VEGF and Ang-1 were all upregulated in rh-EPO-treated rats compared with HI rats. Conclusions: In the present study, we show the angiogenic effects of rh-EPO in a rat model of neonatal cerebral unilateral HI. Our results highlight the powerful therapeutic potential of rh-EPO treatment of HI premature brain for the enhancement of angiogenic responses.

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Endogenous erythropoietin from astrocyte protects the oligodendrocyte precursor cell against hypoxic and reoxygenation injury

Cited by 59 publications

References 66 publications

Erythropoietin (EPO) Increases Myelin Gene Expression in CG4 Oligodendrocyte Cells through the Classical EPO Receptor

Erythropoietin (EPO) Increases Myelin Gene Expression in CG4 Oligodendrocyte Cells through the Classical EPO Receptor

Potential interactions between pericytes and oligodendrocyte precursor cells in perivascular regions of cerebral white matter

Recombinant Human Erythropoietin Augments Angiogenic Responses in a Neonatal Rat Model of Cerebral Unilateral Hypoxia-Ischemia

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