Special Issue "Axon Regeneration"

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cells of the Nervous System".

Deadline for manuscript submissions: closed (30 April 2021).

Special Issue Editor

Dr. Antón Barreiro-Iglesias
E-Mail Website
Guest Editor
Department of Functional Biology, CIBUS, Faculty of Biology, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain
Interests: spinal cord injury; axon regeneration; neuronal regeneration; neurotransmitters; lampreys; zebrafish; neuropeptides; spinal cord; notch; prostanoids

Special Issue Information

Axon regeneration is a fundamental process for recovery after disease or traumatic injuries in the nervous system. In the central nervous system of mammals, neurons only regenerate in the embryonic or neonatal periods. By contrast, axon regeneration occurs spontaneously in the peripheral nervous system of adult individuals. Additionally, non-mammalian species show spontaneous axon regeneration after central nervous systems injuries. It is of crucial importance to understand the intrinsic and extrinsic molecular pathways limiting or promoting axon regeneration in those different contexts. This will provide key knowledge for the development of new therapies to promote repair and neurological recovery after disease or injury.

The aim of this Special Issue is to compile recent advances in our understanding of axon regeneration. Submissions of original studies and reviews on axon regeneration in mammalian models of degenerative and traumatic injuries are welcomed, as well as research in other vertebrate and invertebrate models of regeneration. Another important aspect related to axon regrowth is the re-establishment of proper neuronal connections to achieve functional recovery; therefore, research on this area is also welcomed. This is a timely Special Issue given recent methodological developments such as single cell sequencing, CRISPR/Cas genetic manipulations, optogenetics or whole-tissue imaging, which are increasing exponentially our understanding of axon regeneration.

Dr. Antón Barreiro-Iglesias
Guest Editor

Manuscript Submission Information

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Keywords

  • axon regeneration
  • traumatic brain injury
  • spinal cord injury
  • neurogenerative diseases
  • ischemia
  • axon growth
  • axon guidance
  • animal models
  • spontaneous regeneration
  • synaptogenesis

Published Papers (10 papers)

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Research

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Article
MMP2 Modulates Inflammatory Response during Axonal Regeneration in the Murine Visual System
Cells 2021, 10(7), 1672; https://doi.org/10.3390/cells10071672 - 02 Jul 2021
Viewed by 676
Abstract
Neuroinflammation has been put forward as a mechanism triggering axonal regrowth in the mammalian central nervous system (CNS), yet little is known about the underlying cellular and molecular players connecting these two processes. In this study, we provide evidence that MMP2 is an [...] Read more.
Neuroinflammation has been put forward as a mechanism triggering axonal regrowth in the mammalian central nervous system (CNS), yet little is known about the underlying cellular and molecular players connecting these two processes. In this study, we provide evidence that MMP2 is an essential factor linking inflammation to axonal regeneration by using an in vivo mouse model of inflammation-induced axonal regeneration in the optic nerve. We show that infiltrating myeloid cells abundantly express MMP2 and that MMP2 deficiency results in reduced long-distance axonal regeneration. However, this phenotype can be rescued by restoring MMP2 expression in myeloid cells via a heterologous bone marrow transplantation. Furthermore, while MMP2 deficiency does not affect the number of infiltrating myeloid cells, it does determine the coordinated expression of pro- and anti-inflammatory molecules. Altogether, in addition to its role in axonal regeneration via resolution of the glial scar, here, we reveal a new mechanism via which MMP2 facilitates axonal regeneration, namely orchestrating the expression of pro- and anti-inflammatory molecules by infiltrating innate immune cells. Full article
(This article belongs to the Special Issue Axon Regeneration)
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Article
Age-Dependent Decline in Neuron Growth Potential and Mitochondria Functions in Cortical Neurons
Cells 2021, 10(7), 1625; https://doi.org/10.3390/cells10071625 - 29 Jun 2021
Viewed by 898
Abstract
The age of incidence of spinal cord injury (SCI) and the average age of people living with SCI is continuously increasing. However, SCI is extensively modeled in young adult animals, hampering translation of research to clinical applications. While there has been significant progress [...] Read more.
The age of incidence of spinal cord injury (SCI) and the average age of people living with SCI is continuously increasing. However, SCI is extensively modeled in young adult animals, hampering translation of research to clinical applications. While there has been significant progress in manipulating axon growth after injury, the impact of aging is still unknown. Mitochondria are essential to successful neurite and axon growth, while aging is associated with a decline in mitochondrial functions. Using isolation and culture of adult cortical neurons, we analyzed mitochondrial changes in 2-, 6-, 12- and 18-month-old mice. We observed reduced neurite growth in older neurons. Older neurons also showed dysfunctional respiration, reduced membrane potential, and altered mitochondrial membrane transport proteins; however, mitochondrial DNA (mtDNA) abundance and cellular ATP were increased. Taken together, these data suggest that dysfunctional mitochondria in older neurons may be associated with the age-dependent reduction in neurite growth. Both normal aging and traumatic injury are associated with mitochondrial dysfunction, posing a challenge for an aging SCI population as the two elements can combine to worsen injury outcomes. The results of this study highlight this as an area of great interest in CNS trauma. Full article
(This article belongs to the Special Issue Axon Regeneration)
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Article
Exercise Ameliorates Spinal Cord Injury by Changing DNA Methylation
Cells 2021, 10(1), 143; https://doi.org/10.3390/cells10010143 - 12 Jan 2021
Viewed by 968
Abstract
Exercise training is a traditional method to maximize remaining function in patients with spinal cord injury (SCI), but the exact mechanism by which exercise promotes recovery after SCI has not been identified; whether exercise truly has a beneficial effect on SCI also remains [...] Read more.
Exercise training is a traditional method to maximize remaining function in patients with spinal cord injury (SCI), but the exact mechanism by which exercise promotes recovery after SCI has not been identified; whether exercise truly has a beneficial effect on SCI also remains unclear. Previously, we showed that epigenetic changes in the brain motor cortex occur after SCI and that a treatment leading to epigenetic modulation effectively promotes functional recovery after SCI. We aimed to determine how exercise induces functional improvement in rats subjected to SCI and whether epigenetic changes are engaged in the effects of exercise. A spinal cord contusion model was established in rats, which were then subjected to treadmill exercise for 12 weeks. We found that the size of the lesion cavity and the number of macrophages were decreased more in the exercise group than in the control group after 12 weeks of injury. Immunofluorescence and DNA dot blot analysis revealed that levels of 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) in the brain motor cortex were increased after exercise. Accordingly, the expression of ten-eleven translocation (Tet) family members (Tet1, Tet2, and Tet3) in the brain motor cortex also elevated. However, no macrophage polarization was induced by exercise. Locomotor function, including Basso, Beattie, and Bresnahan (BBB) and ladder scores, also improved in the exercise group compared to the control group. We concluded that treadmill exercise facilitates functional recovery in rats with SCI, and mechanistically epigenetic changes in the brain motor cortex may contribute to exercise-induced improvements. Full article
(This article belongs to the Special Issue Axon Regeneration)
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Article
Intravital Assessment of Cells Responses to Conducting Polymer-Coated Carbon Microfibres for Bridging Spinal Cord Injury
Cells 2021, 10(1), 73; https://doi.org/10.3390/cells10010073 - 05 Jan 2021
Cited by 1 | Viewed by 1449
Abstract
The extension of the lesion following spinal cord injury (SCI) poses a major challenge for regenerating axons, which must grow across several centimetres of damaged tissue in the absence of ordered guidance cues. Biofunctionalized electroconducting microfibres (MFs) that provide biochemical signals, as well [...] Read more.
The extension of the lesion following spinal cord injury (SCI) poses a major challenge for regenerating axons, which must grow across several centimetres of damaged tissue in the absence of ordered guidance cues. Biofunctionalized electroconducting microfibres (MFs) that provide biochemical signals, as well as electrical and mechanical cues, offer a promising therapeutic approach to help axons overcome this blind journey. We used poly(3,4-ethylenedioxythiophene)-coated carbon MFs functionalized with cell adhesion molecules and growth factors to bridge the spinal cord after a partial unilateral dorsal quadrant lesion (PUDQL) in mice and followed cellular responses by intravital two-photon (2P) imaging through a spinal glass window. Thy1-CFP//LysM-EGFP//CD11c-EYFP triple transgenic reporter animals allowed real time simultaneous monitoring of axons, myeloid cells and microglial cells in the vicinity of the implanted MFs. MF biocompatibility was confirmed by the absence of inflammatory storm after implantation. We found that the sprouting of sensory axons was significantly accelerated by the implantation of functionalized MFs after PUDQL. Their implantation produced better axon alignment compared to random and misrouted axon regeneration that occurred in the absence of MF, with a most striking effect occurring two months after injury. Importantly, we observed differences in the intensity and composition of the innate immune response in comparison to PUDQL-only animals. A significant decrease of immune cell density was found in MF-implanted mice one month after lesion along with a higher ratio of monocyte-derived dendritic cells whose differentiation was accelerated. Therefore, functionalized carbon MFs promote the beneficial immune responses required for neural tissue repair, providing an encouraging strategy for SCI management. Full article
(This article belongs to the Special Issue Axon Regeneration)
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Article
Source of Early Regenerating Axons in Lamprey Spinal Cord Revealed by Wholemount Optical Clearing with BABB
Cells 2020, 9(11), 2427; https://doi.org/10.3390/cells9112427 - 06 Nov 2020
Cited by 1 | Viewed by 593
Abstract
Many studies of axon regeneration in the lamprey focus on 18 pairs of large identified reticulospinal (RS) neurons, whose regenerative abilities have been individually quantified. Their axons retract during the first 2 weeks after transection (TX), and many grow back to the site [...] Read more.
Many studies of axon regeneration in the lamprey focus on 18 pairs of large identified reticulospinal (RS) neurons, whose regenerative abilities have been individually quantified. Their axons retract during the first 2 weeks after transection (TX), and many grow back to the site of injury by 4 weeks. However, locomotor movements begin before 4 weeks and the lesion is invaded by axons as early as 2 weeks post-TX. The origins of these early regenerating axons are unknown. Their identification could be facilitated by studies in central nervous system (CNS) wholemounts, particularly if spatial resolution and examination by confocal microscopy were not limited by light scattering. We have used benzyl alcohol/benzyl benzoate (BABB) clearing to enhance the resolution of neuronal perikarya and regenerated axons by confocal microscopy in lamprey CNS wholemounts, and to assess axon regeneration by retrograde and anterograde labeling with fluorescent dye applied to a second TX caudal or rostral to the original lesion, respectively. We found that over 50% of the early regenerating axons belonged to small neurons in the brainstem. Some propriospinal neurons located close to the TX also contributed to early regeneration. The number of early regenerating propriospinal neurons decreased with distance from the original lesion. Descending axons from the brainstem were labeled anterogradely by application of tracer to a second TX close to the spinal–medullary junction. This limited contamination of the data by regenerating spinal axons whose cell bodies are located rostral or caudal to the TX and confirmed the regeneration of many small RS axons as early as 2 weeks post-TX. Compared with the behavior of axotomized giant axons, the early regenerating axons were of small caliber and showed little retraction, probably because they resealed rapidly after injury. Full article
(This article belongs to the Special Issue Axon Regeneration)
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Review

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Review
Know How to Regrow—Axon Regeneration in the Zebrafish Spinal Cord
Cells 2021, 10(6), 1404; https://doi.org/10.3390/cells10061404 - 06 Jun 2021
Cited by 1 | Viewed by 1219
Abstract
The capacity for long-distance axon regeneration and functional recovery after spinal cord injury is poor in mammals but remarkable in some vertebrates, including fish and salamanders. The cellular and molecular basis of this interspecies difference is beginning to emerge. This includes the identification [...] Read more.
The capacity for long-distance axon regeneration and functional recovery after spinal cord injury is poor in mammals but remarkable in some vertebrates, including fish and salamanders. The cellular and molecular basis of this interspecies difference is beginning to emerge. This includes the identification of target cells that react to the injury and the cues directing their pro-regenerative responses. Among existing models of successful spinal cord regeneration, the zebrafish is arguably the most understood at a mechanistic level to date. Here, we review the spinal cord injury paradigms used in zebrafish, and summarize the breadth of neuron-intrinsic and -extrinsic factors that have been identified to play pivotal roles in the ability of zebrafish to regenerate central nervous system axons and recover function. Full article
(This article belongs to the Special Issue Axon Regeneration)
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Review
EFA6 in Axon Regeneration, as a Microtubule Regulator and as a Guanine Nucleotide Exchange Factor
Cells 2021, 10(6), 1325; https://doi.org/10.3390/cells10061325 - 26 May 2021
Viewed by 929
Abstract
Axon regeneration after injury is a conserved biological process that involves a large number of molecular pathways, including rapid calcium influx at injury sites, retrograde injury signaling, epigenetic transition, transcriptional reprogramming, polarized transport, and cytoskeleton reorganization. Despite the numerous efforts devoted to understanding [...] Read more.
Axon regeneration after injury is a conserved biological process that involves a large number of molecular pathways, including rapid calcium influx at injury sites, retrograde injury signaling, epigenetic transition, transcriptional reprogramming, polarized transport, and cytoskeleton reorganization. Despite the numerous efforts devoted to understanding the underlying cellular and molecular mechanisms of axon regeneration, the search continues for effective target molecules for improving axon regeneration. Although there have been significant historical efforts towards characterizing pro-regenerative factors involved in axon regeneration, the pursuit of intrinsic inhibitors is relatively recent. EFA6 (exchange factor for ARF6) has been demonstrated to inhibit axon regeneration in different organisms. EFA6 inhibition could be a promising therapeutic strategy to promote axon regeneration and functional recovery after axon injury. This review summarizes the inhibitory role on axon regeneration through regulating microtubule dynamics and through affecting ARF6 (ADP-ribosylation factor 6) GTPase-mediated integrin transport. Full article
(This article belongs to the Special Issue Axon Regeneration)
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Review
The Role of Lipids, Lipid Metabolism and Ectopic Lipid Accumulation in Axon Growth, Regeneration and Repair after CNS Injury and Disease
Cells 2021, 10(5), 1078; https://doi.org/10.3390/cells10051078 - 01 May 2021
Viewed by 1171
Abstract
Axons in the adult mammalian nervous system can extend over formidable distances, up to one meter or more in humans. During development, axonal and dendritic growth requires continuous addition of new membrane. Of the three major kinds of membrane lipids, phospholipids are the [...] Read more.
Axons in the adult mammalian nervous system can extend over formidable distances, up to one meter or more in humans. During development, axonal and dendritic growth requires continuous addition of new membrane. Of the three major kinds of membrane lipids, phospholipids are the most abundant in all cell membranes, including neurons. Not only immature axons, but also severed axons in the adult require large amounts of lipids for axon regeneration to occur. Lipids also serve as energy storage, signaling molecules and they contribute to tissue physiology, as demonstrated by a variety of metabolic disorders in which harmful amounts of lipids accumulate in various tissues through the body. Detrimental changes in lipid metabolism and excess accumulation of lipids contribute to a lack of axon regeneration, poor neurological outcome and complications after a variety of central nervous system (CNS) trauma including brain and spinal cord injury. Recent evidence indicates that rewiring lipid metabolism can be manipulated for therapeutic gain, as it favors conditions for axon regeneration and CNS repair. Here, we review the role of lipids, lipid metabolism and ectopic lipid accumulation in axon growth, regeneration and CNS repair. In addition, we outline molecular and pharmacological strategies to fine-tune lipid composition and energy metabolism in neurons and non-neuronal cells that can be exploited to improve neurological recovery after CNS trauma and disease. Full article
(This article belongs to the Special Issue Axon Regeneration)
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Review
Zebrafish Models of Autosomal Recessive Ataxias
Cells 2021, 10(4), 836; https://doi.org/10.3390/cells10040836 - 08 Apr 2021
Cited by 2 | Viewed by 752
Abstract
Autosomal recessive ataxias are much less well studied than autosomal dominant ataxias and there are no clearly defined systems to classify them. Autosomal recessive ataxias, which are characterized by neuronal and multisystemic features, have significant overlapping symptoms with other complex multisystemic recessive disorders. [...] Read more.
Autosomal recessive ataxias are much less well studied than autosomal dominant ataxias and there are no clearly defined systems to classify them. Autosomal recessive ataxias, which are characterized by neuronal and multisystemic features, have significant overlapping symptoms with other complex multisystemic recessive disorders. The generation of animal models of neurodegenerative disorders increases our knowledge of their cellular and molecular mechanisms and helps in the search for new therapies. Among animal models, the zebrafish, which shares 70% of its genome with humans, offer the advantages of being small in size and demonstrating rapid development, making them optimal for high throughput drug and genetic screening. Furthermore, embryo and larval transparency allows to visualize cellular processes and central nervous system development in vivo. In this review, we discuss the contributions of zebrafish models to the study of autosomal recessive ataxias characteristic phenotypes, behavior, and gene function, in addition to commenting on possible treatments found in these models. Most of the zebrafish models generated to date recapitulate the main features of recessive ataxias. Full article
(This article belongs to the Special Issue Axon Regeneration)
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Review
Zebrafish Models of Autosomal Dominant Ataxias
Cells 2021, 10(2), 421; https://doi.org/10.3390/cells10020421 - 17 Feb 2021
Cited by 2 | Viewed by 1023
Abstract
Hereditary dominant ataxias are a heterogeneous group of neurodegenerative conditions causing cerebellar dysfunction and characterized by progressive motor incoordination. Despite many efforts put into the study of these diseases, there are no effective treatments yet. Zebrafish models are widely used to characterize neuronal [...] Read more.
Hereditary dominant ataxias are a heterogeneous group of neurodegenerative conditions causing cerebellar dysfunction and characterized by progressive motor incoordination. Despite many efforts put into the study of these diseases, there are no effective treatments yet. Zebrafish models are widely used to characterize neuronal disorders due to its conserved vertebrate genetics that easily support genetic edition and their optic transparency that allows observing the intact CNS and its connections. In addition, its small size and external fertilization help to develop high throughput assays of candidate drugs. Here, we discuss the contributions of zebrafish models to the study of dominant ataxias defining phenotypes, genetic function, behavior and possible treatments. In addition, we review the zebrafish models created for X-linked repeat expansion diseases X-fragile/fragile-X tremor ataxia. Most of the models reviewed here presented neuronal damage and locomotor deficits. However, there is a generalized lack of zebrafish adult heterozygous models and there are no knock-in zebrafish models available for these diseases. The models created for dominant ataxias helped to elucidate gene function and mechanisms that cause neuronal damage. In the future, the application of new genetic edition techniques would help to develop more accurate zebrafish models of dominant ataxias. Full article
(This article belongs to the Special Issue Axon Regeneration)
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