Neuregulin-1 promotes remyelination and fosters a pro-regenerative inflammatory response in focal demyelinating lesions of the spinal cord

Abstract

Oligodendroglial cell death and demyelination are hallmarks of neurotrauma and multiple sclerosis that cause axonal damage and functional impairments. Remyelination remains a challenge as the ability of endogenous precursor cells for oligodendrocyte replacement is hindered in the unfavorable milieu of demyelinating conditions. Here, in a rat model of lysolecithin lysophosphatidyl-choline (LPC)-induced focal demyelination, we report that Neuregulin-1 (Nrg-1), an important factor for oligodendrocytes and myelination, is dysregulated in demyelinating lesions and its bio-availability can promote oligodendrogenesis and remyelination. We delivered recombinant human Nrg-1β1 (rhNrg-1β1) intraspinally in the vicinity of LPC demyelinating lesion in a sustained manner using poly lactic-co-glycolic acid microcarriers. Availability of Nrg-1 promoted generation and maturation of new oligodendrocytes, and accelerated endogenous remyelination by both oligodendrocyte and Schwann cell populations in demyelinating foci. Importantly, Nrg-1 enhanced myelin thickness in newly remyelinated spinal cord axons. Our complementary in vitro studies also provided direct evidence that Nrg-1 significantly promotes maturation of new oligodendrocytes and facilitates their transition to a myelinating phenotype. Nrg-1 therapy remarkably attenuated the upregulated expression chondroitin sulfate proteoglycans (CSPGs) specific glycosaminoglycans in the extracellular matrix of demyelinating foci and promoted interleukin-10 (IL-10) production by immune cells. CSPGs and IL-10 are known to negatively and positively regulate remyelination, respectively. We found that Nrg-1 effects are mediated through ErbB2 and ErbB4 receptor activation. Our work provides novel evidence that dysregulated levels of Nrg-1 in demyelinating lesions of the spinal cord pose a challenge to endogenous remyelination, and appear to be an underlying cause of myelin thinning in newly remyelinated axons.

Main Points

Neuregulin-1 promotes remyelination in focal demyelinating lesions of spinal cord: We demonstrate that Neuregulin-1 (Nrg-1) is downregulated in lysolecithin induced focal demyelinating lesion of the spinal cord which could be an underlying cause of myelin thinning in remyelinated axons. Restoration of Nrg-1 levels in the demyelinated spinal cord lesions promoted generation and maturation of new oligodendrocytes. Nrg-1 therapy remarkably reduced the expression of oligodendrocyte inhibitory factor Chondroitin sulfate proteoglycans (CSPGs) and promoted a pro-regenerative inflammatory response characterized by induced interleukin-10 (IL-10) expression in LPC-demyelinating lesion. Importantly, Nrg-1 treatment accelerated endogenous remyelination by both oligodendrocyte and Schwann cell populations in LPC demyelinating foci resulting in significant improvement in myelin thickness in newly remyelinated spinal cord axons. Our complimentary in vitro assessments elucidated that Nrg-1 specifically mediates it effects through activation of ErbB2 and ErbB4 receptors. In conclusion, Nrg-1 promotes a pro-regenerative microenvironment that fosters oligodendrocyte replacement and enhances remyelination process in demyelinating lesions of the central nervous system.

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