Pigment Epithelium-Derived Factor Promotes Axon Regeneration and Functional Recovery After Spinal Cord Injury

Andrew R Stevens,Vasanthy Vigneswara,Umar Ahmed,Zubair Ahmed

doi:10.1007/s12035-019-1614-2

Andrew R Stevens, Vasanthy Vigneswara + Show 2 more

Open Access

https://doi.org/10.1007/s12035-019-1614-2

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Abstract

Although neurons in the adult mammalian CNS are inherently incapable of regeneration after injury, we previously showed that exogenous delivery of pigment epithelium-derived factor (PEDF), a 50-kDa neurotrophic factor (NTF), promoted adult retinal ganglion cell neuroprotection and axon regeneration. Here, we show that PEDF and other elements of the PEDF pathway are highly upregulated in dorsal root ganglion neurons (DRGN) from regenerating dorsal column (DC) injury paradigms when compared with non-regenerating DC injury models. Exogenous PEDF was neuroprotective to adult DRGN and disinhibited neurite outgrowth, whilst overexpression of PEDF after DC injury in vivo promoted significant DC axon regeneration with enhanced electrophysiological, sensory, and locomotor function. Our findings reveal that PEDF is a novel NTF for adult DRGN and may represent a therapeutically useful factor to promote functional recovery after spinal cord injury.

Highlights

Injury to the central nervous system (CNS) is a considerable cause of morbidity and mortality in modern populations
We show that Pigment epithelium-derived factor (PEDF) is activated in regenerating models of dorsal column (DC) injury, promotes dorsal root ganglion neurons (DRGN) survival and neurite outgrowth in a serum-withdrawal model in vitro, promotes DC axon regeneration and improved functional recovery in vivo, and causes the release of several Trkdependent neurotrophic factors (NTF) that account for some of its survival/neurite-growth promoting effects
Three NTF were highly upregulated, including glialderived neurotrophic factor (GDNF; 5.04-fold), nerve growth factor (NGF; 4.32-fold) and brain-derived neurotrophic factor (BDNF; 4.25-fold) (Fig. 1c). These results suggest that PEDF and other pathway molecules were positively correlated with DC axon regeneration

Summary

Introduction

Injury to the central nervous system (CNS) is a considerable cause of morbidity and mortality in modern populations. Neuronal cells lost through injury are not replaced, and axons do not regenerate; the damage acquired causes a permanent functional deficit. Whilst spinal cord injury (SCI) presents a pertinent clinical problem, no regenerative therapy is available which offers an adequate level of functional recovery [1]. PEDF has been noted for its neuroprotective activity throughout the CNS [2, 3]. More recently PEDF has been shown to be both neuroprotective and axogenic in adult retinal ganglion cells after optic nerve crush injury [5, 6]. We asked the question as to whether PEDF is neuroprotective and axogenic to spinal neurons

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