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Advanced heart failure (AHF) represents an ominous stage of heart failure (HF), where the expected prognosis remains poor regardless of the improvement in medical knowledge. In this review, we summarize the definition, prognosis, physiopathology, and clinical/therapeutic management of the disease, focusing on the fast and timely referral of the patient to the AHF facilities. We provide an insight of the diagnostic and therapeutic ‘work up’ performed in an Italian AHF hub, implying a deep phenotypical patients characterization in order to evaluate candidacy to the therapeutic gold standards as heart transplantation (HTx) and left ventricular assist device (LVAD).

Even if immune checkpoint inhibitors have revolutionized the landscape of cancer therapy, their use may be complicated by immune-related adverse events. Among these, myocarditis is the most severe complication. The clinical suspicion often arises after clinical symptoms onset and increase in cardiac biomarkers or electrocardiographic manifestations. Echocardiography and cardiac magnetic resonance imaging are recommended for each patient. However, since they may be misleadingly normal, endomyocardial biopsy remains the gold standard for establishing the diagnosis. Until now, treatment has been based on glucocorticoids even if increasing interest has risen in other immunosuppressive agents. Although myocarditis currently imposes immunotherapy discontinuation, case reports have suggested a safety rechallenge in low-grade myocarditis paving the way for further studies to respond to this unmet clinical need.

Background no firm data exist regarding continuous intravenous inotropic infusion in outpatients with advanced heart failure (AHF). Methods We reviewed medical records of all inotrope dependent patients discharged from our institution on continuous home inotropes infusion for AHF after a hospitalization between 2014 and 2021. Indications for inotropic agents included bridge to transplant (BTT) or to candidacy (BTC) strategies or palliative care. We compared the number of hospitalizations the year before and the year after beginning the inotrope continuous infusion, assessing the main hospital diagnosis and the duration of hospital recovery in days, through hospital charts revision. Moreover, we used a linkert 7 item scale to assess quality of life (QoL) and, using peripheral blood sample, we esteemed the end organ damage trend evaluating NTproBNP, creatinine, blood urea nitrogen (BUN) and bilirubin. Results From 2014 to 2021, 27 patients (Median age 56 years (Q1-Q3 50-63 years), 74% male and 26% female) were dismissed with continuous inotrope infusion from our institution. The total number of days of hospital stay was 1591 the year before beginning inotropic support (average 58.93 ± 38.70 for patient), significantly different if compared with the post inotropes period (average 22,19 ± 36,84 days for patients, IC 95% 17,488-55,994 p < 0,001). Moreover, the number of hospitalizations per patient fell from 1.93 ± 0.997 to 0,93 ± 0,958 (IC 95% 0,522- 1,478, p < 0,001). After 6 months, 53% of the patients experienced an improvement in quality of life. Regarding end organ damage, while creatinine and BUN showed a significant reduction in the first month, with a trend to stability in the following period, bilirubin and NTproBNP significantly trended to reduction during the 6 month of monitoring. Conclusions In a real world population of contemporary AHF, continuous inotropes home infusion documented an improvement in hospitalization, QoL and end organ damage. We offer a practical guideline on initiation, selection and maintenance of chronic inotrope therapy in a population of challenging patients.

Aims There is still uncertainty on the management of patients with pheochromocytoma-induced CS (PICS), as only a few clinical cases have been reported. The aim of this study is to investigate the clinical presentation, management, and outcome of patients with PICS. Methods We collected retrospectively 18 patients without previously known pheochromocytoma with histologically proven PICS admitted to 8 European hospitals. Results Among the 18 patients with a mean age of 50 years, 50% were men. The main clinical features at presentation were pulmonary congestion (83%) and cyclic fluctuation of hypertension crises and hypotension (72%). On echocardiography, mean left ventricular ejection fraction (LVEF) was 25% with an atypical-Takotsubo pattern (basal/midventricular) in 50%. Laboratory exams showed increased inflammatory markers, in particular, the mean white blood count was 21.9*109/L. Inotropes/vasopressors were started in all patients and a temporary mechanical circulatory support (t-MCS) was required in 11 (61.1%) patients. All patients underwent surgical removal of the pheochromocytoma but 4 (22.2%) on t-MCS. Echocardiogram (16/17 patients) revealed a mean LVEF of 55% at discharge. Only one patient required heart transplantation (5.5%), and all patients were alive at a median follow-up of 679 days. Conclusions In patients with PICS, characteristically, an atypical Takotsubo pattern was observed in almost half of the cases. Although the use of exogenous catecholamine can be perceived as deleterious, we showed a fairly good mid-term prognosis with rapid improvement of LVEF in most, even if adrenalectomy often occurred on t-MCS.

Despite improvements in pharmacotherapy, morbidity and mortality rates in community-based populations with chronic heart failure still remain high. The increase in medical complexity among patients with heart failure may be reflected by an increase in concomitant non-cardiovascular comorbidities, which are recognized as independent prognostic factors in this population. Heart failure and chronic kidney disease share many risk factors, and often coexist. The presence of kidney failure is associated with incremented risk of cardiovascular and non-cardiovascular mortality in heart failure patients. Chronic kidney disease is also linked with underutilization of evidence-based heart failure therapy that may reduce morbidity and mortality. More targeted therapies would be important to improve the prognosis of patients with these diseases. In recent years, serum uric acid as a determinant of cardiovascular risk has gained interest. Epidemiological, experimental and clinical data show that patients with hyperuricaemia are at increased risk of cardiac, renal and vascular damage and cardiovascular events. Moreover, elevated serum uric acid predicts worse outcome in both acute and chronic heart failure. While studies have raised the possibility of preventing heart failure through the use of uric acid lowering agents, the literature is still inconclusive on whether the reduction in uric acid will result in a measurable clinical benefit. Available evidences suggest that chronic kidney disease and elevated uric acid could worsen heart failure patients’ prognosis. The aim of this review is to analyse a possible utilization of these comorbidities in risk stratification and as a therapeutic target to get a prognostic improvement in heart failure patients.

Axons in the adult mammalian central nervous system (CNS) fail to regenerate inside out due to intrinsic and extrinsic neuronal determinants. During CNS development, axon growth, synapse formation, and function are tightly regulated processes allowing immature neurons to effectively grow an axon, navigate toward target areas, form synaptic contacts and become part of information processing networks that control behavior in adulthood. Not only immature neurons are able to precisely control the expression of a plethora of genes necessary for axon extension and pathfinding, synapse formation and function, but also non-neuronal cells such as astrocytes and microglia actively participate in sculpting the nervous system through refinement, consolidation, and elimination of synaptic contacts. Recent evidence indicates that a balancing act between axon regeneration and synaptic function may be crucial for rebuilding functional neuronal circuits after CNS trauma and disease in adulthood. Here, we review the role of classical and new intrinsic and extrinsic neuronal determinants in the context of CNS development, injury, and disease. Moreover, we discuss strategies targeting neuronal and non-neuronal cell behaviors, either alone or in combination, to promote axon regeneration and neuronal circuit formation in adulthood.

Stroke causes devastating sensory-motor deficits and long-term disability due to disruption of descending motor pathways. Restoration of these functions enables independent living and therefore represents a high priority for those afflicted by stroke. Here, we report that daily administration of gabapentin, a clinically approved drug already used to treat various neurological disorders, promotes structural and functional plasticity of the corticospinal pathway after photothrombotic cortical stroke in adult mice. We found that gabapentin administration had no effects on vascular occlusion, haemodynamic changes nor survival of corticospinal neurons within the ipsilateral sensory-motor cortex in the acute stages of stroke. Instead, using a combination of tract tracing, electrical stimulation and functional connectivity mapping, we demonstrated that corticospinal axons originating from the contralateral side of the brain in mice administered gabapentin extend numerous collaterals, form new synaptic contacts and better integrate within spinal circuits that control forelimb muscles. Not only does gabapentin daily administration promote neuroplasticity, but it also dampens maladaptive plasticity by reducing the excitability of spinal motor circuitry. In turn, mice administered gabapentin starting 1 h or 1 day after stroke recovered skilled upper extremity function. Functional recovery persists even after stopping the treatment at 6 weeks following a stroke. Finally, chemogenetic silencing of cortical projections originating from the contralateral side of the brain transiently abrogated recovery in mice administered gabapentin, further supporting the conclusion that gabapentin-dependent reorganization of spared cortical pathways drives functional recovery after stroke. These observations highlight the strong potential for repurposing gabapentinoids as a promising treatment strategy for stroke repair.

Severe acute respiratory syndrome coronavirus 2 (SARS–CoV-2) is a worldwide health concern, and new treatment strategies are needed. Targeting inflammatory innate immunity pathways holds therapeutic promise, but effective molecular targets remain elusive. Here, we show that human caspase-4 (CASP4) and its mouse homolog, caspase-11 (CASP11), are up-regulated in SARS–CoV-2 infections and that CASP4 expression correlates with severity of SARS–CoV-2 infection in humans. SARS–CoV-2–infected Casp11−/− mice were protected from severe weight loss and lung pathology, including blood vessel damage, compared to wild-type (WT) mice and mice lacking the caspase downstream effector gasdermin-D (Gsdmd−/−). Notably, viral titers were similar regardless of CASP11 knockout. Global transcriptomics of SARS–CoV-2–infected WT, Casp11−/−, and Gsdmd−/− lungs identified restrained expression of inflammatory molecules and altered neutrophil gene signatures in Casp11−/− mice. We confirmed that protein levels of inflammatory mediators interleukin (IL)-1β, IL-6, and CXCL1, as well as neutrophil functions, were reduced in Casp11−/− lungs. Additionally, Casp11−/− lungs accumulated less von Willebrand factor, a marker for endothelial damage, but expressed more Kruppel-Like Factor 2, a transcription factor that maintains vascular integrity. Overall, our results demonstrate that CASP4/11 promotes detrimental SARS–CoV-2–induced inflammation and coagulopathy, largely independently of GSDMD, identifying CASP4/11 as a promising drug target for treatment and prevention of severe COVID-19.

SARS-CoV-2 is a worldwide health concern, and new treatment strategies are needed 1. Targeting inflammatory innate immunity pathways holds therapeutic promise, but effective molecular targets remain elusive. Here, we show that human caspase-4 (CASP4), and its mouse homologue, caspase-11 (CASP11), are upregulated in SARS-CoV-2 infections, and that CASP4 expression correlates with severity of SARS-CoV-2 infection in humans. SARS-CoV-2-infected Casp11-/- mice were protected from severe weight loss and lung pathology, including blood vessel damage, compared to wild-type (WT) and gasdermin-D knock out (Gsdmd-/-) mice. GSDMD is a downstream effector of CASP11 and CASP1. Notably, viral titers were similar in the three genotypes. Global transcriptomics of SARS-CoV-2-infected WT, Casp11-/- and Gsdmd-/- lungs identified restrained expression of inflammatory molecules and altered neutrophil gene signatures in Casp11-/- mice. We confirmed that protein levels of inflammatory mediators IL-1β, IL6, and CXCL1, and neutrophil functions, were reduced in Casp11-/- lungs. Additionally, Casp11-/- lungs accumulated less von Willebrand factor, a marker for endothelial damage, but expressed more Kruppel-Like Factor 2, a transcription factor that maintains vascular integrity. Overall, our results demonstrate that CASP4/11, promotes detrimental SARS-CoV-2-associated inflammation and coagulopathy, largely independently of GSDMD, identifying CASP4/11 as a promising drug target for treatment and prevention of severe COVID-19.

Monitoring oxygenation in vivo is critical to ensuring human health, particularly in the context of ‘silent’ hypoxia Utilizing blends of biodegradable polycaprolactone (PCL) and gelatine, we sought to develop an electrospun oxygen sensor that maintains the advantages of robust, phosphorescent oxygen-sensing chromophores while providing resorbable polymeric scaffolds benefiting from tailorable degradation times ranging from hours to weeks Electrospun sensors successfully provide accurate oxygen measurements for periods >1 month In vitro testing took place in a custom aqueous testing system over five weeks in 37°C phosphate-buffered saline (PBS);dissolved oxygen concentrations were maintained at 0–5% O2 where physoxia characteristic of the subdermal environment is defined as 2–5% O2 Excited state chromophore lifetime (τ) is quenched in the presence of dissolved diatomic oxygen and is influenced by characteristics of the surrounding matrix The observed final deoxygenated τ (τ0) values were split into 3 groups: polysulphone (PSU)-PCL (~397 µs) >75:25, 50:50 and 25:75 PCL:gelatine (~191–182 µs) > PCL, 10:90 PCL:gelatine, 1:99 crosslinked PCL:gelatine (~145–135 µs) Highly linear Stern–Volmer activity enabling accurate and precise calibration was observed even after 35 days of exposure;this proves that non-core–shell fibres consisting of blends of PCL and gelatine can yield predictable lifetime values for >30 days in vitro Scanning electron microscopy and mass loss data revealed that sensor degradation is highly tailorable, allowing for the fabrication of sensors engineered for a specific biomedical time frame In contrast, core–shell fibre sensors showed more variability in lifetime following internal degradation likely caused by caproic acid entrapment by the PCL ‘shell’ This work demonstrates that biodegradable and biocompatible optically monitored sensors can be fabricated to provide direct, accurate assessments of oxygenation, even as the sensor platform degrades in a controlled manner Such technologies have the potential to substantially change respiratory disease management

There is currently little information regarding the role of active smoking in predisposing to SARS-CoV-2 infection. This retrospective case series includes 441 patients with confirmed Covid-19, who were consecutively admitted between March 5 and March 31, 2020, at a tertiary referral center in Parma, Northern Italy, with laboratory-confirmed COVID-19. 273 (62%) patients were males. Median age was 71 y/o, 156 patients (35%) died during hospitalization and 285 (65%) were discharged because clinically healed. 21 patients (5%) were active smokers and 44 (10%) were ex-smokers, while 376 (85%) were non-smokers. Male sex, history of prior cardiovascular disease, D-dimer and C-reactive protein were significantly more prevalent or higher in the subgroup of 156 patients who died during hospital stay, compared with 285 patients discharged alive. Active smokers were only 21, this number corresponding to less than 5% prevalence of active smokers, which is disproportionately low compared with the 14.9% prevalence of smokers in the age-matched general Italian population (p

Coronary artery fistulas consist of a communication between a coronary artery and a cardiac chamber or major vessel. Coronary angiography showed an incidence of this condition in about 0.3–0.8% of ...

Axon regeneration failure causes neurological deficits and long-term disability after spinal cord injury (SCI). Here, we found that the α2δ2 subunit of voltage-gated calcium channels negatively regulates axon growth and regeneration of corticospinal neurons, the cells that originate the corticospinal tract. Increased α2δ2 expression in corticospinal neurons contributed to loss of corticospinal regrowth ability during postnatal development and after SCI. In contrast, α2δ2 pharmacological blockade through gabapentin administration promoted corticospinal structural plasticity and regeneration in adulthood. Using an optogenetic strategy combined with in vivo electrophysiological recording, we demonstrated that regenerating corticospinal axons functionally integrate into spinal circuits. Mice administered gabapentin recovered upper extremity function after cervical SCI. Importantly, such recovery relies on reorganization of the corticospinal pathway, as chemogenetic silencing of injured corticospinal neurons transiently abrogated recovery. Thus, targeting α2δ2 with a clinically relevant treatment strategy aids repair of motor circuits after SCI.

Axon regeneration and neuronal tissue repair varies across animal lineages as well as in the mammalian central and peripheral nervous systems. While the peripheral nervous system retains the ability to self-repair, the majority of axons in the adult mammalian central nervous system (CNS) fail to reactivate intrinsic growth programs after injury. Recent findings, however, suggest that long-distance axon regeneration, neuronal circuit assembly and recovery of functions in the adult mammalian CNS are possible. Here, we discuss our current knowledge of the cell signaling pathways and networks controlling axon regeneration. In addition, we outline a number of combinatorial strategies that include among others microtubule-based treatments to foster regeneration and functional connectivity after CNS trauma.

1-Deoxysphingolipids (deoxySLs) are atypical sphingolipids that are elevated in the plasma of patients with type 2 diabetes and hereditary sensory and autonomic neuropathy type 1 (HSAN1). Clinically, diabetic neuropathy and HSAN1 are very similar, suggesting the involvement of deoxySLs in the pathology of both diseases. However, very little is known about the biology of these lipids and the underlying pathomechanism. We synthesized an alkyne analog of 1-deoxysphinganine (doxSA), the metabolic precursor of all deoxySLs, to trace the metabolism and localization of deoxySLs. Our results indicate that the metabolism of these lipids is restricted to only some lipid species and that they are not converted to canonical sphingolipids or fatty acids. Furthermore, exogenously added alkyne-doxSA [(2S,3R)-2-aminooctadec-17-yn-3-ol] localized to mitochondria, causing mitochondrial fragmentation and dysfunction. The induced mitochondrial toxicity was also shown for natural doxSA, but not for sphinganine, and was rescued by inhibition of ceramide synthase activity. Our findings therefore indicate that mitochondrial enrichment of an N-acylated doxSA metabolite may contribute to the neurotoxicity seen in diabetic neuropathy and HSAN1. Hence, we provide a potential explanation for the characteristic vulnerability of peripheral nerves to elevated levels of deoxySLs. ispartof: Journal of Lipid Research vol:58 issue:1 pages:42-59 ispartof: location:United States status: published

Injuries to the adult CNS often result in permanent disabilities because neurons lose the ability to regenerate their axon during development. Here, whole transcriptome sequencing and bioinformatics analysis followed by gain- and loss-of-function experiments identified Cacna2d2, the gene encoding the Alpha2delta2 subunit of voltage-gated calcium channels (VGCCs), as a developmental switch that limits axon growth and regeneration. Cacna2d2 gene deletion or silencing promoted axon growth in vitro. In vivo, Alpha2delta2 pharmacological blockade through Pregabalin (PGB) administration enhanced axon regeneration in adult mice after spinal cord injury (SCI). As PGB is already an established treatment for a wide range of neurological disorders, our findings suggest that targeting Alpha2delta2 may be a novel treatment strategy to promote structural plasticity and regeneration following CNS trauma.

Injectable sensors can significantly improve the volume of critical biomedical information emerging from the human body in response to injury or disease. Optical oxygen sensors with rapid response times can be achieved by incorporating oxygen-sensitive luminescent molecules within polymeric matrices with suitably high surface area to volume ratios. In this work, electrospraying utilizes these advances to produce conveniently injectable, oxygen sensing particles made up of a core-shell polysulfone-polysulfone structure containing a phosphorescent oxygen-sensitive palladium porphyrin species within the core. Particle morphology is highly dependent on solvent identity and electrospraying parameters; DMF offers the best potential for the creation of uniform, sub-micron particles. Total internal reflection fluorescence (TIRF) microscopy confirms the existence of both core-shell structure and oxygen sensitivity. The dissolved oxygen response time is rapid (

Summary Injured axons fail to regenerate in the adult CNS, which contrasts with their vigorous growth during embryonic development. We explored the potential of re-initiating axon extension after injury by reactivating the molecular mechanisms that drive morphogenetic transformation of neurons during development. Genetic loss- and gain-of-function experiments followed by time-lapse microscopy, in vivo imaging, and whole-mount analysis show that axon regeneration is fueled by elevated actin turnover. Actin depolymerizing factor (ADF)/cofilin controls actin turnover to sustain axon regeneration after spinal cord injury through its actin-severing activity. This pinpoints ADF/cofilin as a key regulator of axon growth competence, irrespective of developmental stage. These findings reveal the central role of actin dynamics regulation in this process and elucidate a core mechanism underlying axon growth after CNS trauma. Thereby, neurons maintain the capacity to stimulate developmental programs during adult life, expanding their potential for plasticity. Thus, actin turnover is a key process for future regenerative interventions.

Trauma to the adult mammalian central nervous system (CNS) causes diffuse axonal injury that results in devastating long-term disabilities due to limited sprouting and axon regeneration failure. No therapeutic strategy that restores neurological function is currently available for individuals who have suffered damage to their spinal cords. The past few decades have witnessed major advances in the technology used to study CNS development, homeostasis, and disease. A better understanding of the cellular and molecular mechanisms underlying axonal growth and regeneration failure has allowed the development of several regenerative strategies that may change the way we treat spinal cord injury (SCI) in the near future. This chapter summarizes recent progress in spinal cord repair and regeneration, including combinatorial strategies promoting axonal sprouting, regeneration, formation, and consolidation of neuronal circuits as well as cellular replacement after injury.

Here we present a protocol for analyses of axon regeneration and density in unsectioned adult mouse spinal cord. This includes methods for injury and tracing of dorsal column sensory and corticospinal axons; clearing and staining of unsectioned spinal cord; visualization of axon degeneration and regeneration in cleared and uncleared specimens using two-photon microscopy; and either manual or semi-automatic analysis of axon density and regeneration in 3D space using Imaris and ImageJ software. This protocol can be used to elucidate the molecular and cellular mechanisms underlying nervous system degeneration and regeneration and to establish the therapeutic efficacy of candidate neuroregenerative treatments. Because tissue sectioning is not required, this protocol enables unambiguous evaluation of regeneration and greatly accelerates the speed at which analyses can be conducted. Surgical procedures take

© 2015 Elsevier Inc. Axon regeneration in the CNS requires reactivating injured neurons' intrinsic growth state and enabling growth in an inhibitory environment. Using an inbred mouse neuronal phenotypic screen, we find that CAST/Ei mouse adult dorsal root ganglion neurons extend axons more on CNS myelin than the other eight strains tested, especially when pre-injured. Injury-primed CAST/Ei neurons also regenerate markedly in the spinal cord and optic nerve more than those from C57BL/6 mice and show greater sprouting following ischemic stroke. Heritability estimates indicate that extended growth in CAST/Ei neurons on myelin is genetically determined, and two whole-genome expression screens yield the Activin transcript Inhba as most correlated with this ability. Inhibition of Activin signaling in CAST/Ei mice diminishes their CNS regenerative capacity, whereas its activation in C57BL/6 animals boosts regeneration. This screen demonstrates that mammalian CNS regeneration can occur and reveals a molecular pathway that contributes to this ability. Omura et al. screened for neuronal growth on myelin and find CAST/Ei inbred mice are uniquely able to regenerate axons in the injured CNS through Activin signaling. Enhancing Activin signaling confers a CNS-regenerative capacity in normally non-regenerative mouse strains.

Progress toward fixing a broken back? Axon regeneration after a spinal cord injury requires interference with neuronal mechanisms to promote axon extension and early suppression of scar formation. Microtubule stabilization could provide, in principle, a basis for such intervention. Ruschel et al. used animal models of spinal cord injury, time-lapse imaging in vivo, primary neuronal cultures, and behavioral studies to tackle this challenge (see the Perspective by Tran and Silver). They showed that epothilone B, a U.S. Food and Drug Administration–approved microtubule-stabilizing drug that can cross the blood-brain barrier, does promote functional axon regeneration, even after injury. Science , this issue p. 347 ; see also p. 285

Dual leucine zipper kinase (DLK), a mitogen-activated protein kinase kinase kinase, controls axon growth, apoptosis and neuron degeneration during neural development, as well as neurodegeneration after various insults to the adult nervous system. Interestingly, recent studies have also highlighted a role of DLK in promoting axon regeneration in diverse model systems. Invertebrates and vertebrates, cold- and warm-blooded animals, as well as central and peripheral mammalian nervous systems all differ in their ability to regenerate injured axons. Here, we discuss how DLK-dependent signalling regulates apparently contradictory functions during neural development and regeneration in different species. In addition, we outline strategies to fine-tune DLK function, either alone or together with other approaches, to promote axon regeneration in the adult mammalian central nervous system.

Acute spinal cord injury (SCI) causes systemic immunosuppression and life-threatening infections, thought to result from noradrenergic overactivation and excess glucocorticoid release via hypothalamus-pituitary-adrenal axis stimulation. Instead of consecutive hypothalamus-pituitary-adrenal axis activation, we report that acute SCI in mice induced suppression of serum norepinephrine and concomitant increase in cortisol, despite suppressed adrenocorticotropic hormone, indicating primary (adrenal) hypercortisolism. This neurogenic effect was more pronounced after high-thoracic level (Th1) SCI disconnecting adrenal gland innervation, compared with low-thoracic level (Th9) SCI. Prophylactic adrenalectomy completely prevented SCI-induced glucocorticoid excess and lymphocyte depletion but did not prevent pneumonia. When adrenalectomized mice were transplanted with denervated adrenal glands to restore physiologic glucocorticoid levels, the animals were completely protected from pneumonia. These findings identify a maladaptive sympathetic-neuroendocrine adrenal reflex mediating immunosuppression after SCI, implying that therapeutic normalization of the glucocorticoid and catecholamine imbalance in SCI patients could be a strategy to prevent detrimental infections.

The importance of genetic diversity in biological investigation has been recognized since the pioneering studies of Gregor Johann Mendel and Charles Darwin. Research in this area has been greatly informed recently by the publication of genomes from multiple species. Genes regulate and create every part and process in a living organism, react with the environment to create each living form and morph and mutate to determine the history and future of each species. The regenerative capacity of neurons differs profoundly between animal lineages and within the mammalian central and peripheral nervous systems. Here, we discuss research that suggests that genetic background contributes to the ability of injured axons to regenerate in the mammalian central nervous system (CNS), by controlling the regulation of specific signaling cascades. We detail the methods used to identify these pathways, which include among others Activin signaling and other TGF-β superfamily members. We discuss the potential of altering these pathways in patients with CNS damage and outline strategies to promote regeneration and repair by combinatorial manipulation of neuron-intrinsic and extrinsic determinants.

Failure of axon regeneration after central nervous system (CNS) injuries results in permanent functional deficits. Numerous studies in the past suggested that blocking extracellular inhibitory influences alone is insufficient to allow the majority of injured axons to regenerate, pointing to the importance of revisiting the hypothesis that diminished intrinsic regenerative ability critically underlies regeneration failure. Recent studies in different species and using different injury models have started to reveal important cellular and molecular mechanisms within neurons that govern axon regeneration. This review summarizes these observations and discusses possible strategies for stimulating axon regeneration and perhaps functional recovery after CNS injury.

Despite the essential role of the corticospinal tract (CST) in controlling voluntary movements, successful regeneration of large numbers of injured CST axons beyond a spinal cord lesion has never been achieved. Here we demonstrate a critical involvement of PTEN/mTOR in controlling the regenerative capacity of mouse corticospinal neurons. Upon the completion of development, the regrowth potential of CST axons lost and this is accompanied by a down-regulation of mTOR activity in corticospinal neurons. Axonal injury further diminishes neuronal mTOR activity in these neurons. Forced up-regulation of mTOR activity in corticospinal neurons by conditional deletion of PTEN, a negative regulator of mTOR, enhances compensatory sprouting of uninjured CST axons and even more strikingly, enables successful regeneration of a cohort of injured CST axons past a spinal cord lesion. Furthermore, these regenerating CST axons possess the ability to reform synapses in spinal segments distal to the injury. Thus, modulating neuronal intrinsic PTEN/mTOR activity represents a potential therapeutic strategy for promoting axon regeneration and functional repair after adult spinal cord injury.

Neuronal outgrowth is guided by both extrinsic and intrinsic factors, involving transcriptional regulation. The acetylation of histones and transcription factors, which facilitates promoter accessibility, ultimately promotes transcription, and depends on the balance between histone deacetylases (HDACs) and histone acetyltransferases (HATs) activities. However, a critical function for specific acetylation modifying enzymes in neuronal outgrowth has yet to be investigated. To address this issue, we have used an epigenetic approach to facilitate gene expression in neurons, by using specific HDAC inhibitors. Neurons treated with a combination of HDAC and transcription inhibitors display an acetylation and transcription-dependent increase in outgrowth and a reduction in growth cone collapse on both 'permissive' (poly-D-lysine, PDL) and 'non-permissive' substrates (myelin and chondroitin sulphate proteoglycans (CSPGs)). Next, we specifically show that the expression of the histone acetyltransferases CBP/p300 and P/CAF is repressed in neurons by inhibitory substrates, whereas it is triggered by HDAC inhibition on both permissive and inhibitory conditions. Gene silencing and gain of function experiments show that CBP/p300 and P/CAF are key players in neuronal outgrowth, acetylate histone H3 at K9-14 and the transcription factor p53, thereby initiating a pro-neuronal outgrowth transcriptional program. These findings contribute to the growing understanding of transcriptional regulation in neuronal outgrowth and may lay the molecular groundwork for the promotion of axonal regeneration after injury.

Functional recovery can occur after incomplete spinal cord injury. Takeoka et al. now report that such recovery relies on muscle spindle feedback that is necessary for neuronal circuit remodeling, suggesting novel targets to restore motor functions following spinal cord injuries.

Axonal regenerative failure is a major cause of neurological impairment following central nervous system (CNS) but not peripheral nervous system (PNS) injury. Notably, PNS injury triggers a coordinated regenerative gene expression programme. However, the molecular link between retrograde signalling and the regulation of this gene expression programme that leads to the differential regenerative capacity remains elusive. Here we show through systematic epigenetic studies that the histone acetyltransferase p300/CBP-associated factor (PCAF) promotes acetylation of histone 3 Lys 9 at the promoters of established key regeneration-associated genes following a peripheral but not a central axonal injury. Furthermore, we find that extracellular signal-regulated kinase (ERK)-mediated retrograde signalling is required for PCAF-dependent regenerative gene reprogramming. Finally, PCAF is necessary for conditioning-dependent axonal regeneration and also singularly promotes regeneration after spinal cord injury. Thus, we find a specific epigenetic mechanism that regulates axonal regeneration of CNS axons, suggesting novel targets for clinical application.

After central nervous system (CNS) injury, inhibitory factors in the lesion scar and poor axon growth potential prevent axon regeneration. Microtubule stabilization reduces scarring and promotes axon growth. However, the cellular mechanisms of this dual effect remain unclear. Here, delayed systemic administration of a blood-brain barrier-permeable microtubule-stabilizing drug, epothilone B (epoB), decreased scarring after rodent spinal cord injury (SCI) by abrogating polarization and directed migration of scar-forming fibroblasts. Conversely, epothilone B reactivated neuronal polarization by inducing concerted microtubule polymerization into the axon tip, which propelled axon growth through an inhibitory environment. Together, these drug-elicited effects promoted axon regeneration and improved motor function after SCI. With recent clinical approval, epothilones hold promise for clinical use after CNS injury.

The motor function of the spinal cord requires the computation of the local neuronal circuits within the same segments as well as the long-range coordination of different spinal levels. Implicated players in this process are the propriospinal neurons (PPNs) that project their axons across different levels of the spinal cord. However, their cellular, molecular, and functional properties remain unknown. Here we use a recombinant rabies virus-based method to label a specific type of long-projecting premotor PPNs in the mouse upper spinal cord that are monosynaptically connected to the motor neurons in the lumbar spinal cord. With a whole spinal cord imaging method, we find that these neurons are distributed along the entire length of the upper spinal cord with more in the lower thoracic levels. Among them, a subset of thoracic PPNs receive substantial numbers of sensory inputs, suggesting a function in coordinating the activity of trunk and hindlimb muscles. Although many PPNs in the cervical and thoracic spinal cord receive the synaptic inputs from corticospinal tract or serotonergic axons, limited bouton numbers suggested that these supraspinal inputs might not be major regulators of the PPNs in intact animals. Molecularly, these PPNs appear to be distinct from other known premotor interneurons, but some are derived from Chx10+ lineages. This study provides an anatomical basis for further exploring different functions of PPNs.

Axonal injury generates growth inert retraction bulbs with dynamic cytoskeletal properties that are severely compromised. Conversion of “frozen” retraction bulbs into actively progressing growth cones is a major aim in axon regeneration. Here we report that murine serum response factor (SRF), a gene regulator linked to the actin cytoskeleton, modulates growth cone actin dynamics during axon regeneration. In regeneration-competent facial motoneurons,Srfdeletion inhibited axonal regeneration. In wild-type mice after nerve injury, SRF translocated from the nucleus to the cytoplasm, suggesting a cytoplasmic SRF function in axonal regeneration. Indeed, adenoviral overexpression of cytoplasmic SRF (SRF-ΔNLS-GFP) stimulated axonal sprouting and facial nerve regenerationin vivo. In primary central and peripheral neurons, SRF-ΔNLS-GFP stimulated neurite outgrowth, branch formation, and growth cone morphology. Furthermore, we uncovered a link between SRF and the actin-severing factor cofilin during axonal regenerationin vivo. Facial nerve axotomy increased the total cofilin abundance and also nuclear localization of phosphorylated cofilin in a subpopulation of lesioned motoneurons. This cytoplasmic-to-nucleus translocation of P-cofilin upon axotomy was reduced in motoneurons expressing SRF-ΔNLS-GFP. Finally, we demonstrate that cytoplasmic SRF and cofilin formed a reciprocal regulatory unit. Overexpression of cytoplasmic SRF reduced cofilin phosphorylation and vice versa: overexpression of cofilin inhibited SRF phosphorylation. Therefore, a regulatory loop consisting of SRF and cofilin might take part in reactivating actin dynamics in growth-inert retraction bulbs and facilitating axon regeneration.