CXCL12Gene Therapy Ameliorates Ischemia-Induced White Matter Injury in Mouse Brain

Abstract

Remyelination is an important repair process after ischemic stroke-induced white matter injury. It often fails because of the insufficient recruitment of oligodendrocyte progenitor cells (OPCs) to the demyelinated site or the inefficient differentiation of OPCs to oligodendrocytes. We investigated whether CXCL12 gene therapy promoted remyelination after middle cerebral artery occlusion in adult mice. The results showed that CXCL12 gene therapy at 1 week after ischemia could protect myelin sheath integrity in the perifocal region, increase the number of platelet-derived growth factor receptor-a (PDGFRa)-positive and PDGFRa/bromodeoxyuridine-double positive OPCs in the subventricular zone, and further enhance their migration to the ischemic lesion area. Coadministration of AMD3100, the antagonist for CXCL12 receptor CXCR4, eliminated the beneficial effect of CXCL12 on myelin sheath integrity and negatively influenced OPC proliferation and migration. At 5 weeks after ischemia, CXCR4 was found on the PDGFRa-and/or neuron/glia type 2 (NG2)-positive OPCs but not on the myelin basic protein-positive mature myelin sheaths, and CXCR7 was only expressed on the mature myelin sheath in the ischemic mouse brain. Our data indicated that CXCL12 gene therapy effectively protected white matter and promoted its repair after ischemic injury. The treatment at 1 week after ischemia is effective, suggesting that this strategy has a longer therapeutic time window than the treatments currently available. STEM CELLS TRANSLATIONAL MEDICINE 2015;4:1122-1130 SIGNIFICANCEThis study has demonstrated for the first time that CXCL12 gene therapy significantly ameliorates brain ischemia-induced white matter injury and promotes oligodendrocyte progenitor cell proliferation in the subventricular zone and migration to the perifocal area in the ischemic mouse brain. Additional data showed that CXCR4 receptor plays an important role during the proliferation and migration of oligodendrocyte progenitor cells, and CXCR7 might play a role during maturation. In contrast to many experimental studies that provide treatment before ischemic insult, CXCL12 gene therapy was performed 1 week after brain ischemia, which significantly prolonged the therapeutic time window of brain ischemia.

Roles of NG2‐glia in ischemic stroke

“…By overexpression of Netrin-1 or CXCL12 gene in OPCs, studies showed those factors promote OPCs proliferation, migration, axon remyelination, further facilitating white matter repair and remodeling, which provides a therapeutic perspective for targeting NG2-glia in ischemia. 62,63 These conclusions, however, need to be further confirmed in vivo. A recent study reported that NG2-glia can be reprogramed into both glutamatergic and GABAergic neurons after NeuroD1 expression in the brain, opening a completely new direction in the therapy of neurodegenerative diseases.…”

“…These alterations have direct and/or indirect effects on neurons and other glial cell populations during and after ischemia. By overexpression of Netrin‐1 or CXCL12 gene in OPCs, studies showed those factors promote OPCs proliferation, migration, axon remyelination, further facilitating white matter repair and remodeling, which provides a therapeutic perspective for targeting NG2‐glia in ischemia . These conclusions, however, need to be further confirmed in vivo.…”

Hypoxia Response Element-Regulated MMP-9 Promotes Neurological Recovery via Glial Scar Degradation and Angiogenesis in Delayed Stroke

“…Targeted genes were delivered to the ischemic area, which promoted focal angiogenesis, neurogenesis, and finally improved ischemic tissue metabolism and functional recovery. [2][3][4] Matrix metalloproteinase-9 (MMP-9) has been found to play dual roles after ischemia, with its detrimental upregulation in the acute phase but beneficial elevation in the delayed phase. 5,6 Because excessive MMP-9 expression could lead to brain edema and hemorrhagic transformation, approaches to modulate the MMP-9 expression level in the delayed phase of stroke may be attractive.…”

A promiscuous recognition mechanism between GPR17 and SDF-1: Molecular insights

“…Moreover, survival-supporting effects mediated via the second CXCL12 receptor, CXCR7, have been reported for neural progenitor cells [19]. Recently, a specific contribution of SDF-1 to the differentiation of oligodendrocyte precursor cells (OPCs), the myelin producing cells in the CNS, and remyelination after traumatic and inflammatory insults, via the chemokine receptors CXCR4 and CXCR7, have been demonstrated in vivo and in vitro [7,12,15,20,21]. This evidence supports the hypothesis that chemokine receptors participate in the inflammatory reactions during CNS diseases via specific mechanisms in addition to evoking leukocyte responses.…”