Complement Protein C1q Modulates Neurite Outgrowth<i>In Vitro</i>and Spinal Cord Axon Regeneration<i>In Vivo</i>

Peterson, Sheri L.; Nguyen, Hal X.; Méndez, Oscar; Anderson, Aileen J.

doi:10.1523/jneurosci.4473-12.2015

Cited by 46 publications

(63 citation statements)

References 91 publications

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“…Moreover, matricellular proteins like MMP2, TIMP, GDNF, PDGF, IGFBPs, THBS and complement factor C1R have been reported to promote neurite extension, adhesion, branching and differentiation as well as protection from neurotoxicity69707172. Also found unique in SF secretion, PRDX1, coding for antioxidant enzyme, has been reported in neuroprotection against oxidative stress73.…”

Section: Discussionmentioning

confidence: 99%

Nerve regeneration by human corneal stromal keratocytes and stromal fibroblasts

Yam

Williams

Setiawan

et al. 2017

Sci Rep

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Laser refractive surgeries reshape corneal stroma to correct refractive errors, but unavoidably affect corneal nerves. Slow nerve regeneration and atypical neurite morphology cause desensitization and neuro-epitheliopathy. Following injury, surviving corneal stromal keratocytes (CSKs) are activated to stromal fibroblasts (SFs). How these two different cell types influence nerve regeneration is elusive. Our study evaluated the neuro-regulatory effects of human SFs versus CSKs derived from the same corneal stroma using an in vitro chick dorsal root ganglion model. The neurite growth was assessed by a validated concentric circle intersection count method. Serum-free conditioned media (CM) from SFs promoted neurite growth dose-dependently, compared to that from CSKs. We detected neurotrophic and pro-inflammatory factors (interleukin-8, interleukin-15, monocyte chemoattractant protein-1, eotaxin, RANTES) in SFCM by Bio-Plex Human Cytokine assay. More than 130 proteins in SFCM and 49 in CSKCM were identified by nanoLC-MS/MS. Proteins uniquely present in SFCM had reported neuro-regulatory activities and were predicted to regulate neurogenesis, focal adhesion and wound healing. Conclusively, this was the first study showing a physiological relationship between nerve growth and the metabolically active SFs versus quiescent CSKs from the same cornea source. The dose-dependent effect on neurite growth indicated that nerve regeneration could be influenced by SF density.

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Section: Discussionmentioning

confidence: 99%

Nerve regeneration by human corneal stromal keratocytes and stromal fibroblasts

Yam

Williams

Setiawan

et al. 2017

Sci Rep

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“…Extending the model to several days will also be informative for testing the long-term prognosis and suitability of different therapeutic targets. For example it is known that C1q plays a role in neurite outgrowth and regeneration [ 26 ]; therefore timing of therapy may be crucial.…”

Section: Discussionmentioning

confidence: 99%

C1q-targeted inhibition of the classical complement pathway prevents injury in a novel mouse model of acute motor axonal neuropathy

McGonigal

Cunningham

Yao

et al. 2016

acta neuropathol commun

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IntroductionGuillain-Barré syndrome (GBS) is an autoimmune disease that results in acute paralysis through inflammatory attack on peripheral nerves, and currently has limited, non-specific treatment options. The pathogenesis of the acute motor axonal neuropathy (AMAN) variant is mediated by complement-fixing anti-ganglioside antibodies that directly bind and injure the axon at sites of vulnerability such as nodes of Ranvier and nerve terminals. Consequently, the complement cascade is an attractive target to reduce disease severity. Recently, C5 complement component inhibitors that block the formation of the membrane attack complex and subsequent downstream injury have been shown to be efficacious in an in vivo anti-GQ1b antibody-mediated mouse model of the GBS variant Miller Fisher syndrome (MFS). However, since gangliosides are widely expressed in neurons and glial cells, injury in this model was not targeted exclusively to the axon and there are currently no pure mouse models for AMAN. Additionally, C5 inhibition does not prevent the production of early complement fragments such as C3a and C3b that can be deleterious via their known role in immune cell and macrophage recruitment to sites of neuronal damage.Results and ConclusionsIn this study, we first developed a new in vivo transgenic mouse model of AMAN using mice that express complex gangliosides exclusively in neurons, thereby enabling specific targeting of axons with anti-ganglioside antibodies. Secondly, we have evaluated the efficacy of a novel anti-C1q antibody (M1) that blocks initiation of the classical complement cascade, in both the newly developed anti-GM1 antibody-mediated AMAN model and our established MFS model in vivo. Anti-C1q monoclonal antibody treatment attenuated complement cascade activation and deposition, reduced immune cell recruitment and axonal injury, in both mouse models of GBS, along with improvement in respiratory function. These results demonstrate that neutralising C1q function attenuates injury with a consequent neuroprotective effect in acute GBS models and promises to be a useful new target for human therapy.

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“…VGF has been shown to enhance dendritic growth of multipolar stellate neurons, but not cortical pyramidal neurons [49] and to promote neurite outgrowth of PC12 cells [50]. Although the receptor for the TLQP-62 peptide derived from VGF has not been confirmed, two putative receptors for TLQP-21 have been reported [51,52] and one of them, Complement Protein C1q, has been shown to modulate neurite outgrowth in spinal cord neurons [53]. However, the effects of TLQP-62 on the morphology and maturation of primary hippocampal neurons has not been examined.…”

Section: Introductionmentioning

confidence: 99%

Neuropeptide VGF Promotes Maturation of Hippocampal Dendrites That Is Reduced by Single Nucleotide Polymorphisms

Behnke

Cheedalla

Bhatt

et al. 2017

IJMS

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The neuropeptide VGF (non-acronymic) is induced by brain-derived neurotrophic factor and promotes hippocampal neurogenesis, as well as synaptic activity. However, morphological changes induced by VGF have not been elucidated. Developing hippocampal neurons were exposed to VGF through bath application or virus-mediated expression in vitro. VGF-derived peptide, TLQP-62, enhanced dendritic branching, and outgrowth. Furthermore, VGF increased dendritic spine density and the proportion of immature spines. Spine formation was associated with increased synaptic protein expression and co-localization of pre- and postsynaptic markers. Three non-synonymous single nucleotide polymorphisms (SNPs) were selected in human VGF gene. Transfection of N2a cells with plasmids containing these SNPs revealed no relative change in protein expression levels and normal protein size, except for a truncated protein from the premature stop codon, E525X. All three SNPs resulted in a lower proportion of N2a cells bearing neurites relative to wild-type VGF. Furthermore, all three mutations reduced the total length of dendrites in developing hippocampal neurons. Taken together, our results suggest VGF enhances dendritic maturation and that these effects can be altered by common mutations in the VGF gene. The findings may have implications for people suffering from psychiatric disease or other conditions who may have altered VGF levels.

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Complement Protein C1q Modulates Neurite OutgrowthIn Vitroand Spinal Cord Axon RegenerationIn Vivo

Cited by 46 publications

References 91 publications

Nerve regeneration by human corneal stromal keratocytes and stromal fibroblasts

Nerve regeneration by human corneal stromal keratocytes and stromal fibroblasts

C1q-targeted inhibition of the classical complement pathway prevents injury in a novel mouse model of acute motor axonal neuropathy

Neuropeptide VGF Promotes Maturation of Hippocampal Dendrites That Is Reduced by Single Nucleotide Polymorphisms

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