The role of CXCR4 signaling in the migration of transplanted oligodendrocyte progenitors into the cerebral white matter

Abstract

Enhancing the ability of either endogenous or transplanted oligodendrocyte progenitors (OPs) to engage in myelination may constitute a novel therapeutic approach to demyelinating diseases of the brain. It is known that in adults neural progenitors situated in the subventricular zone of the lateral ventricle (SVZ) are capable of generating OPs which can migrate into white matter tracts such as the corpus callosum (CC). We observed that progenitor cells in the SVZ of adult mice expressed CXCR4 chemokine receptors and that the chemokine SDF-1/CXCL12 was expressed in the CC. We therefore investigated the role of chemokine signaling in regulating the migration of OPs into the CC following their transplantation into the lateral ventricle. We established OP cell cultures from Olig2-EGFP mouse brains. These cells expressed a variety of chemokine receptors, including CXCR4 receptors. Olig2-EGFP OPs differentiated into CNPase-expressing oligodendrocytes in culture. To study the migratory capacity of Olig2-EGFP OPs in vivo, we transplanted them into the lateral ventricles of mice. Donor cells migrated into the CC and differentiated into mature oligodendrocytes. This migration was enhanced in animals with Experimental Autoimmune Encephalomyelitis (EAE). Inhibition of CXCR4 receptor expression in OPs using shRNA inhibited the migration of transplanted OPs into the white matter suggesting that their directed migration is regulated by CXCR4 signaling. These findings indicate that CXCR4 mediated signaling is important in guiding the migration of transplanted OPs in the context of inflammatory demyelinating brain disease.

Integrin/Chemokine Receptor Interactions in the Pathogenesis of Experimental Autoimmune Encephalomyelitis

“…In addition to regulating the movement of leukocytes, chemokines also control the migration of neural stem cells both during development and in the context of brain disease, where they help to target the migration of neural stem cells to damaged areas of the brain so that they can participate in repair related functions. Hence, interference with chemokine signaling in the brain may have important consequences for both the influx of leukocytes (McCandless et al 2008) and for the migration of OPs during EAE (Banisadr et al 2011). …”

“…We have recently shown that chemokines, and SDF-1 in particular, are upregulated in the brain during neuroinflammation and are key factors in regulating the migration of OPs to demyelinated regions in the brains of mice with EAE (Banisadr et al 2011) where OPs can potentially induce remyelination.…”

Mechanisms of cell–cell interaction in oligodendrogenesis and remyelination after stroke

“…Activation of the CXCL12/CXCR7 pathway may also promote oligodendroglial maturation and remyelination in a mouse model of experimental autoimmune encephalomyelitis (EAE) (Gottle et al, 2010). In the EAE model, transplanted OPCs migrated into the injured white matter and differentiated into mature oligodendrocytes via the CXCL12/CXCR4 signaling pathway (Banisadr et al, 2011). Although CXCL12 plays a key role in white matter pathology after stroke, the underlying mechanisms of CXCL12 on oligodendrogenesis after stroke are still largely unknown.…”

Chemokines and chemokine receptors in the pathogenesis of multiple sclerosis

“…Takođe, u životinjskom modelu demijelinizacije indukovane kuprizonom (specifični helator jona bakra), inhibicija CXCR4 ili utišavanje transkripcije gena za CXCR4 izazvalo je poremećaj diferencijacije prekursora oligodendrocita, onemogućavajući proces remijelinizacije (42). Potvrđena je uloga signalizacije preko CXCR4 i u stimulisanju migracije i aktivnosti prekursora oligodendrocita i prekursora neurona u mozgu životinja sa EAE (43,44,45).…”

“…Opadanje nivoa liganda za CXCR3 (CXCL10) detektovano je u serumu pacijenata nakon intravenskog davanja metilprednizolona (91 hemokinom CXCL10 indukovanu migraciju efektorskih CD4+ T-limfocita, in vitro (92). In vitro analizom perifernih T-limfocita kod obolelih od MS utvrđeno je da tretman metilprednizolonom inhibira migraciju ovih ćelija ka CCL19, dok značajno stimuliše njihovu migraciju ka CXCL12 (93), što ukazuje na pokazane protektivne efekte CXCL12 u patogenezi MS (41,43,44,45). Interferon-β je godinama poznat kao efikasan imunomodulatorni agens za lečenje pacijenata s relapsno-remitentnom MS (94).…”