Differentiation of oligodendroglial precursor cells (OPCs), a crucial prerequisite for central nervous system (CNS) remyelination in diseases such asMultiple Sclerosis (MS), is modulated by a multitude of extrinsic and intrinsic factors. In a previous study we revealed that the chemokine CXCL12 stimulates rodent OPC differentiation via activation of its receptor CXCR7. We could now demonstrate that CXCR7 is also expressed on NogoA- and Nkx2.2-positive oligodendroglial cells in human MS brains and that stimulation of cultured primary fetal human OPCs with CXCL12 promotes their differentiation as measured by surface marker expression and morphologic complexity. Pharmacological inhibition of CXCR7 effectively blocks these CXCL12-dependent effects. Our findings therefore suggest that a specific activation of CXCR7 could provide a means to promote oligodendroglial differentiation facilitating endogenous remyelination activities.
The stromal cell-derived factor 1 (SDF-1) also known as C-X-C motif chemokine 12 (CXCL12) is a chemokine protein. Stromal cell-derived factors 1-alpha and 1-beta are small cytokines that belong to the chemokine family, members of which activate leukocytes and are often induced by proinflammatory stimuli such as lipopolysaccharide, TNF, or IL1. This acts via CXCR-4, but there is also activity with CXCR-7
It is also interesting that we also have this paper implicaing the CXCL12 pathway in oligodendrocyte function
Zilkha-Falb R, Kaushansky N, Kawakami N, Ben-Nun A.Post-CNS-inflammation expression of CXCL12 promotes the endogenous myelin/neuronal repair capacity following spontaneous recovery from multiple sclerosis-like disease. J Neuroinflammation. 2016;13(1):7.
METHODS: CNS tissue sections from mice with different clinical EAE phases or following spontaneous recovery and in vitro differentiated adult neural stem cell cultures were analyzed by immunofluorescent staining and confocal imaging for detecting and enumerating neuronal progenitor cells (NPCs) and oligodendrocyte precursor cells (OPCs) and for expression of CXCL12.
RESULTS:Our expression dynamics analysis of CXCL12 in the CNS with EAE progression revealed elevated CXCL12 expression in the DG and CC, which persistently increases following spontaneous recovery even though CNS inflammation has subsided. Correspondingly, the numbers of NPCs and OPCs in the DG and CC, respectively, of EAE-recovered mice increased compared to that of naïve mice (NPCs, p < 0.0001; OPCs, p < 0.00001) or mice with active disease (OPCs, p < 0.0005). Notably, about 30 % of the NPCs and unexpectedly also OPCs (~50 %) express CXCL12, and their numbers in DG and CC, respectively, are higher in EAE-recovered mice compared with naïve mice and also compared with mice with ongoing clinical EAE (CXCL12+ NPCs, p < 0.005; CXCL12+ OPCs, p < 0.0005). Moreover, a significant proportion (>20 %) of the CXCL12+ NPCs and OPCs co-express the CXCL12 receptor, CXCR4, and their numbers significantly increase with recovery from EAE not only relative to naïve mice (p < 0.0002) but also to mice with ongoing EAE (p < 0.004).
CONCLUSIONS: These data link CXCL12 expression in the DG and CC of EAE-recovering mice to the promotion of neuro/oligodendrogenesis generating CXCR4+ CXCL12+ neuronal and oligodendrocyte progenitor cells endowed with intrinsic neuro/oligondendroglial differentiation potential. These findings highlight the post-CNS-inflammation role of CXCL12 in augmenting the endogenous myelin/neuronal repair capacity in MS-like disease, likely via CXCL12/CXCR4 autocrine signaling.