Enhancing the Regeneration of Neurons in the Central Nervous System
Summary and Keywords
Injured axons fail to regenerate in the adult mammalian central nervous system, representing a major barrier for effective neural repair. Both extrinsic inhibitory environments and neuron-intrinsic mechanisms contribute to such regeneration failure. In the past decade, there has been an explosion in our understanding of neuronal injury responses and regeneration regulations. As a result, several strategies have been developed to promote axon regeneration with the potential of restoring functions after injury. This article will highlight these new developments, with an emphasis on cellular and molecular mechanisms from a neuron-centric perspective, and discuss the challenges to be addressed toward developing effective functional restoration strategies.
In the adult mammalian central nervous system (CNS), spontaneous regeneration usually does not occur (Byrne & Hammarlund, 2017; Hilton & Bradke, 2017; Rasmussen & Sagasti, 2017). Although much progress has been made on deciphering this lack of regenerative ability, there is still no effective neural repair strategy for CNS injuries such as spinal cord injury, traumatic brain injury, or stroke. One underlying cause is the extraordinary complexity of interconnected cellular and molecular injury responses that involve different neuronal compartments. In general, axonal injury elicits an injury signal that propagates from the site of injury to the cell body of the neuron. Such signals often trigger a set of homeostatic adaptations. In some cases, axon insults could lead to cell death. However, preventing neuronal death after a CNS insult is not sufficient to promote axonal regeneration. For regrowing axons, the inhibitory injury site is often a tremendous hurdle. Even if this is overcome, they will face further challenges in finding their way to their appropriate targets. Following this chronology of events from the injury to the functional connection of regenerating axons (Figure 1), we will go through the current understanding of the mechanisms of axonal regeneration from a neuron-centric perspective. Readers are referred to recent reviews that focus on neuron-extrinsic influences (Geoffroy & Zheng, 2014; Silver, Schwab, & Popovich, 2015).
Neurons have a unique morphology with a cell body or soma and elaborated processes including both axons and dendrites. In humans, axons could project up to one meter from their cell bodies. Such structural properties require a tight regulation of the intra-cellular communication between different subcellular compartments. For the interaction between axon and soma, the cell body adjusts the gene expression programs based on information received from the axons. Conversely, the axon needs to know how the cell body is adapting to a situation such as injury. While the injury responses have been mainly studied in more permissive systems such as peripheral sensory neurons (Lieberman, 1971) and C. elegans neurons (Hammarlund & Jin, 2014; Yanik et al., 2004), the mechanisms of the generation and propagation of injury signals appear to be conserved in CNS (Bradke, Fawcett, & Spira, 2012; He & Jin, 2016).
Upon an axotomy, three sequential steps, probably to some extent overlapping, have been proposed as a model for injury site–soma communication (Abe & Cavalli, 2008). First, the breakage of the axonal membrane induces a disruption of membrane potential. Second, the normal flux of retrograde transport is interrupted. Finally, signaling molecules will be actively transported from the injury site to the neuron soma with axonal transport machinery (Ambron & Walters, 1996; Rishal & Fainzilber, 2013). Among these, a key event is the locally activated kinases which phosphorylate a variety of substrates and trigger the retrograde transport (Cavalli, 2005; Hanz et al., 2003; Lindwall & Kanje, 2005; Perlson et al., 2005; Sung, Chiu, & Ambron, 2006; Yudin et al., 2008).
Conducted on C. elegans beta spectrin mutant (unc-70) whose axons break because of locomotion-induced mechanical stress, an elegant RNAi screen revealed a key sensor of axon injury called the dual leucine-zipper kinase (DLK) (Hammarlund, Nix, Hauth, Jorgensen, & Bastiani, 2009). DLK was also independently identified as a crucial axon regeneration regulator (Yan, Wu, Chisholm, & Jin, 2009). As a MAP kinase kinase kinase (MAPKKK), DLK is locally activated by axonal insults in a calcium-dependent manner and activates its substrates MAP kinase kinase MKK-4 and in turn the MAP kinase PMK-3, therefore triggering the signaling cascade. These activated signaling components are retrogradely transported back to the cell bodies to initiate regenerative programs. Indeed, DLK knock-down or knock-out inhibits axonal regeneration and its over-expression improves growth cone initiation. Interestingly, it appears that the DLK effect on axonal regeneration was linked to its capacity to stabilize CCAAT-enhancer-binding protein 1 (CEBP-1) mRNA to ensure local translation in axons (Yan et al., 2009). In Drosophila, the deletion of the actin and microtubule protein binding spectraplakin short stop (Shot) activates the early injury response protein DLK (Valakh, Walker, Skeath, & DiAntonio, 2013), consistent with the notion of DLK as an axonal sensor for injury and disorganization. Importantly, the role of DLK is conserved in mammals in both PNS (peripheral nervous system) (Shin et al., 2012) and CNS (Watkins et al., 2013).
Similar to the DLK/MAP pathway, cytokine-dependent Janus kinase (JAK)/Signal transducer and activator of transcription (STAT) signaling is another avenue to relay injury signals to the cell body (Sun & He, 2010). In this case, the signal, cytokines, such as leukemia inhibitory factor (LIF) (Banner & Patterson, 1994; Sun & Zigmond, 1996), interleukin-6 (IL6) (Fregnan, Muratori, Simões, Giacobini-Robecchi, & Raimondo, 2012; Yang, Wen, Ou, Cui, & Fan, 2012), and ciliary neurotrophic factor (CNTF) (Park et al., 2009; Smith et al., 2009), could be released from neighboring cells after injury, and activate neuronal signaling in a non-cell autonomous way. Specifically, they will interact with their specific receptors on neuronal surface and activate JAK kinases and phosphorylated signal transducer and activator of transcription 3 (STAT3) will be transported to the nucleus (Curtis et al., 1993, 1994; O’Brien & Nathanson, 2007).
For all aspects of injury responses, calcium entry triggered by axonal injury is pivotal. It has been well studied in all species that a calcium wave propagates from the injury site and contributes to other key cellular regeneration events including the activation of pro-regenerative signaling pathways, cytoskeletal remodeling, and growth cone formation (Chierzi, Ratto, Verma, & Fawcett, 2005; Ghosh-Roy, Wu, Goncharov, Jin, & Chisholm, 2010; Gitler & Spira, 1998; Sun et al., 2014). In C. elegans, the extent of regeneration is positively correlated with the amplitude of the initial calcium wave (Ghosh-Roy et al., 2010) and internal calcium release from the endoplasmic reticulum is necessary for axonal regeneration (Sun et al., 2014). However, calcium overload could cause neuronal death (Pivovarova & Andrews, 2010) and therefore its entrance and release in the axons need to be tightly regulated. For example, after a spinal cord contusion, the better the axons mitigate the influx of calcium, the less probability they have to be affected by axonal degeneration (Williams et al., 2014). Interestingly, deletion of the gene encoding the Alpha2delta2 subunit of voltage-gated calcium channels (VGCCs) promotes axonal growth in vitro and dorsal column sensory axon regeneration after spinal cord injury (Tedeschi et al., 2016). Along the same line, calcium channel inhibitors prevent injury-induced intra-axonal calcium increase and attenuate axonal degeneration in retinal ganglion cells (RGCs) (Knöferle et al., 2010) and promote limited axonal regeneration in vivo (Ribas, Koch, Michel, Bähr, & Lingor, 2016). As many cellular events are tightly regulated by calcium, future studies should monitor calcium dynamics with high temporal and spatial resolution and assess their specific outcomes.
With incoming injury signals, an injured neuron has to make a decision to either initiate or abort axonal regrowth, which involves a number of molecular and cellular responses in both axonal and soma compartments. This is influenced by the axonal immediate environment in which reactive glial/fibrotic scars and myelin debris could inhibit or support axon regeneration (He & Koprivica, 2004; Yiu, 2003; Yiu & He, 2006). On the other hand, the other contributing factor is the intrinsic regenerative ability associated with individual neurons (He & Jin, 2016). Deciphering this regenerative growth program is currently under intense investigation.
As an essential step for axon growth, a lesioned axonal tip needs to be reorganized and reform the growth cone (Bradke et al., 2012). Although the morphology of regenerated growth cones could be very different from their counterparts during early development, the basic function is the same: as a leading driving force for axonal extension. In the CNS, injured axons often form retraction bulbs with disorganized microtubules and accumulation of mitochondria (Ertürk, Hellal, Enes, & Bradke, 2007), an indicator of regenerative failure. In this regard, the stabilization of microtubules and actins appears to be necessary for growth cone reformation (Bradke et al., 2012) and this appears to be evolutionarily conserved in different species (Chen et al., 2011; Ertürk et al., 2007; Nawabi et al., 2015; Ruschel et al., 2015). Importantly, microtubule-stabilizing compounds such as taxol, epothilone B and D, widely used for cancer chemotherapy, have been shown to promote axon regeneration and some degree of functional recovery in spinal cord injury models (Hellal et al., 2011; Ruschel & Bradke, 2018; Ruschel et al., 2015; Sandner et al., 2018). Interestingly, microtubule stabilizing agents have dual effects on axons (intrinsic) and scar tissues (extrinsic). In addition to the axonal terminal, many types of CNS axons exhibit an injury-induced retrograde retraction with disruption of the f-actin and microtubules cytoskeleton away from the injury site (Chen et al., 2011, 2015; Erez & Spira, 2008). Thus, preserving the cytoskeleton along the axonal shaft is also important for the regeneration process.
Recent studies have begun to reveal molecular mechanisms for such cytoskeleton regulation in injured axons and their correlation with axon regeneration. Besides the well-characterized role of calcium (Bradke et al., 2012), several other molecules have been implicated in regulating cytoskeleton stabilization and growth cone reformation after axonal injury. For example, injury down-regulates the expression of the members of the doublecortin-like kinases family (DCLK1/2, DCX), which all have the ability to bind microtubules and actin. Forced expression of these molecules promotes growth cone formation and axonal regeneration in RGCs, for which both functional domains for binding microtubules and actin are required to work together. Intriguingly, other types of microtubule-binding proteins such as EB3 and Tau fail to mimic the effects of DCX members (Nawabi et al., 2015). These examples place the cytoskeleton at the center of the mechanisms that promote growth cone formation and the subsequent regeneration.
In addition to cytoskeleton, the subcellular organelles also need to reorganize and adapt to injury-induced alterations in injured axons. Being at the crossroads of many of these axonal adaptations to injury, it is possible that mitochondria play an important role in the initiation of axonal regeneration. Some of the most important second messengers such as calcium and reactive oxygen species are mainly derived from mitochondria. Additionally, growth cone formation, microtubule dynamics, and phosphorylation by kinases require a large amount of ATP. Recent studies in different models have begun to reveal the role of mitochondria in axonal regeneration (Cartoni et al., 2016; Han, Baig, & Hammarlund, 2016; Zhou et al., 2016). Of note, in RGCs, increasing mitochondrial transport by over-expression of the mammalian-specific Armadillo repeat-containing X-linked protein 1 (Armcx1) leads to a high level of short-distance regeneration but a weaker effect for long-distance extension (Cartoni et al., 2016), suggesting a preferential involvement in the initiation phase of regeneration. However, how mitochondria regulate other functions requires further investigation.
Sustaining Axonal Re-Regrowth
Similar to the initiation, sustained growth requires the localized actions in the lesioned axons. However, continuous axon extension faces additional challenges to synthesize more building blocks and transport them to the correct locations. Toward the completion of neural development, mature neurons need to switch from axon-growth mode to dendrite/synapse growth mode. Thus, de novo axon growth programs need to be activated to coordinate the actions between the soma and the axonal process. Recent studies have begun to reveal the genetic programs of axon regeneration.
An important realization is that axon regeneration could be activated by inflammation that occurs in the vicinity of injured neurons. For example, a lens injury prior to optic nerve crush resulted in a significant increase in axonal regeneration (Fischer, Pavlidis, & Thanos, 2000; Mansour-Robaey, Clarke, Wang, Bray, & Aguayo, 1994). Subsequent studies of the mechanism revealed that the lens injury induces an inflammatory response that leads to the infiltration and activation of macrophages, Müller cells, and increased expression of the growth-associated protein GAP-43 (Leon, Yin, Nguyen, Irwin, & Benowitz, 2000; Yin et al., 2003). Similarly, inducing inflammation via intravitreal injection of zymosan, a yeast wall component, also promotes axonal regeneration, suggesting direct links between inflammation, innate-immune response, and axonal regeneration (Kurimoto et al., 2010; Yin et al., 2006, 2009). Interestingly, whereas both injection of zymosan and the bacterial cell wall component lipopolysaccharide (LPS) induces similar inflammatory response, axonal regeneration was only observed in the zymosan-treated group and this effect is abolished in mouse after deletion of the receptor dectin-1 (Baldwin, Carbajal, Segal, & Giger, 2015). However, inflammation is a double-edged sword with both reparative and pathological properties (Gensel et al., 2015) and challenges remain to find approaches to fine-tune these processes.
In further support of regenerative growth as a neuronal response to inflammation and stresses, genetic studies revealed that the suppressor of cytokine signaling 3 (SOCS3) (Baker, Akhtar, & Benveniste, 2009), an important regulator of the inflammatory and immune response in CNS, acts as a negative regulator of axonal regeneration (Smith et al., 2009). Induced by cytokine-activated JAK/STAT pathways, SOCS3 acts as a negative regulator of this pathway, preventing the over-activation of inflammatory responses. Releasing this inhibition promotes STAT3 responsive genes, including many pro-regenerative ones, leading to axonal regeneration (Smith et al., 2009).
The archetype of the intrinsic and cell-autonomous regenerative program regulator is the phosphatase and tensin homolog (PTEN), a negative regulator of the mTOR pathway. PTEN is a phosphatase that converts, via inhibition of the phosphoinositide 3-kinases (PI3K), phosphatidylinositol trisphosphate (PIP3) to phosphatidylinositol bisphosphate (PIP2) (Knafo & Esteban, 2017; Worby & Dixon, 2014). The role of the mTOR pathway in cellular growth has been extensively described (Mathieu Laplante, 2012). Correlated with development-dependent decline of axon growth ability, the activation level of this pathway is gradually decreased (Park et al., 2008). Remarkably, increasing the mTOR pathway via PTEN inhibition results in profound increases of neuronal survival and axonal regeneration after optic nerve crush. This effect appears to be conserved in other neuronal types in rodents (Liu et al., 2010) and across different species (Byrne et al., 2014; Hu, 2015). Increasing this pathway via specific deletion of the tuberous sclerosis protein 1 (TSC1) gene also increases axonal regeneration of RGCs, although to a lesser extent, underscoring the central role played by mTOR as well as other related pathways in adult regeneration of CNS neurons (Park et al., 2008). Despite aging-dependent decrease (Geoffroy, Hilton, Tetzlaff, & Zheng, 2016), deleting PTEN up to 12 months post-injury still promotes injured corticospinal axons to regenerate albeit at a reduced speed (Du et al., 2015). It is important to note that mTOR regulates a general growth pathway and uncontrolled over-activation could lead to side effects. Indeed, long-term deletion of PTEN in the sensorimotor cortex leads to an increase in the cortical thickness and a disruption of cortical lamination (Gutilla, Buyukozturk, & Steward, 2016).
Because of limited numbers and distances of axon regeneration observed in individual manipulations, it is conceivable that an individual signaling pathway acts on certain populations of neurons and/or certain aspects of regenerative mechanisms. In this regard, PTEN deletion selectively promotes the regeneration from a specific type of RGCs, alpha-RGCs (Duan et al., 2015). Thus, co-manipulations of these pathways may maximize their regenerative effects. Indeed, a number of manipulations have been shown to exhibit synergistic effects with PTEN deletion/inhibition. For example, co-deleted PTEN and SOCS3 resulted in much-increased extents of axonal regrowth. The synergistic effects were characterized by transcriptome analysis, which showed that co-deleting PTEN and SOCS3 triggered the up-regulation of a specific set of genes whose expression was unchanged in single knock-outs (Sun et al., 2012). Similar additive or synergistic effects have been documented for other manipulations with PTEN deletion (see, e.g., Norsworthy et al., 2017; Luo et al., 2016; Bei et al., 2016; Cartoni et al., 2016; Belin et al., 2015; Nawabi et al., 2015; de Lima et al., 2012; Sun et al., 2012; Kurimoto et al., 2010).
Different axon growth ability in immature and mature neurons has provided mechanistic insights into the mechanisms of axon regeneration. Another transcriptional repressor for axonal growth and regeneration, the krüppel-like factor-4 (KLF4), was discovered when comparing gene expression patterns of RGCs at different developmental stages (Moore et al., 2009). KLF4 knock-out increases axonal outgrowth of RGCs in culture and promotes axonal regeneration after optic nerve crush. The effects of KLF family members appear to be conserved in other species, as these molecules have been shown to regulate axon regeneration in both mammals and zebra fish (Moore et al., 2009; Veldman, Bemben, Thompson, & Goldman, 2007). On the other hand, Sox11, a transcription factor involved in axon growth during development (Chang et al., 2017), recently has been shown to promote axon regeneration after optic nerve injury (Norsworthy et al., 2017). Intriguingly, in contrast to PTEN deletion that promotes axon regeneration from alpha-RGCs (Duan et al., 2015), Sox11 kills most alpha-RGCs and promotes the regeneration from other types (Norsworthy et al., 2017). These results revealed unexpected cell type specificity in regulating axon regeneration, which should be a focus of the next frontier of axon regeneration research.
Reaching the Targets and Beyond
To restore function, regenerated axons need to establish functional connection in the targets. So far, most of our knowledge on this issue comes from the optic nerve crush model in mice. In this model, regenerating axons are initially confined within injured optic nerves for about 2 millimeters. However, at the chiasm, a classical model of choice points for retinal axons during development (Petros, Rebsam, & Mason, 2008; Sitko, Kuwajima, & Mason, 2018; Wang, Marcucci, Cerullo, & Mason, 2016), regenerating axons have to make choices, either stopping growing, continuing growing with or without crossing to the contralateral side of the optic tract, or even toward contralateral optic nerves. Robust axon regeneration observed with different combinatorial treatments offered opportunities of assessing their projection patterns. While some studies suggested precise targeting (de Lima et al., 2012; Lim et al., 2016), others found that many axons make mistakes at the chiasm and over-shoot or completely miss their original target after crossing the chiasm (Belin et al., 2015; Luo et al., 2013). Such projection errors are not restricted to regenerating axons from RGCs, as similar mistargeting has been observed in regenerating axons in peripheral nerves (Kelamangalath et al., 2015) and in C. elegans (Gabel, Antoine, Chuang, Samuel, & Chang, 2008; Wu et al., 2007). Thus, guiding regenerating axons to appropriate targets remains an important challenge.
On the other hand, once reaching the targets, regenerating axons are able to make functional synapses, but surprisingly, fail to be myelinated (Bei et al., 2016). As a result, even when regenerated axons had made functional synapses in the target, the mice failed to recover their visual acuity unless they were treated with voltage-gated potassium channel blockers that restore conduction (Bei et al., 2016). These results revealed another barrier for functional restoration: the re-myelination of regenerating axons. Thus, further studies are needed to understand the mechanisms by which regenerated axons fail to be myelinated, which could provide insights into ways to overcome this and other possible hurdles for functional recovery.
Extensive studies in the past decade led to unprecedented progress in our understanding of the cellular and molecular mechanisms of axon regeneration in different models. Some of these findings showed clear translational potential. For example, clinically used microtubule-stabilizing compounds are promising to promote axon regeneration and functional recovery. Similarly, based on mTOR effects on axon regeneration, more translational approaches could be devised. For example, osteopontin was discovered to possess the ability to sensitize neuronal responses to IGF1 and BDNF, resulting in axon regrowth and functional recovery (Duan et al., 2015). However, even with the best combinations, only subsets of injured axons are able to regenerate for relatively short distances. A possible reason is that different types of neurons have distinct abilities to respond to individual treatments. Thus, understanding the molecular basis for these different types of neurons should be extremely informative.
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