Search Results (397)

Background: Lower phylogenetic species are known to rebuild cut-off caudal parts with regeneration of the central nervous system (CNS). In contrast, CNS regeneration in higher vertebrates is often attributed to immaturity, although this has never been conclusively demonstrated. The emergence of stem cells and their effective medical applications has intensified research into spinal cord regeneration. However, despite these advances, the impact of clinical trials involving spinal cord-injured (SCI) patients remains disappointingly low. Long-distance regeneration has yet to be proven. Methods: Our study involved a microsurgical dorsal myelotomy in fetal rats. The development of pioneering long primary afferent axons during early gestation was examined long after birth. Results: A single cut triggered the intrinsic ability of the dorsal root ganglion (DRG) neurons to reprogram. Susceptibility to hypoxia caused the axons to stop developing. However, the residual axonal outgrowth sheds light on the intriguing temporal and spatial events that reveal long-distance CNS regeneration. The altered phenotypes displayed axons of varying lengths and different features, which remained visible throughout life. The previously designed developmental blueprint was crucial for interpreting these enigmatic features. Conclusions: This research into immaturity enabled the exploration of the previously impenetrable domain of early life and the identification of a potential missing link in CNS regeneration research. Central axon regeneration appeared to occur much faster than is generally believed. The paradigm provides a challenging approach for exhaustive intrauterine reprogramming. When the results demonstrate pre-clinical effectiveness in CNS regeneration research, the transformational impact may ultimately lead to improved outcomes for patients with spinal cord injuries. Full article

Neuronal proteins synthesized locally in axons and dendrites contribute to growth, plasticity, survival, and retrograde signaling underlying these cellular processes. Advances in molecular tools to profile localized mRNAs, along with single-molecule detection approaches for RNAs and proteins, have significantly expanded our understanding of the diverse proteins produced in subcellular compartments. These investigations have also uncovered key molecular mechanisms that regulate mRNA transport, storage, stability, and translation within neurons. The long distances that axons extend render their processes vulnerable, especially when injury necessitates regeneration to restore connectivity. Localized mRNA translation in axons helps initiate and sustain axon regeneration in the peripheral nervous system and promotes axon growth in the central nervous system. Recent and ongoing studies suggest that axonal RNA transport, storage, and stability mechanisms represent promising targets for enhancing regenerative capacity. Here, we summarize critical post-transcriptional regulatory mechanisms, emphasizing translation in the axonal compartment and highlighting potential strategies for the development of new regeneration-promoting therapeutics. Full article

Bioactive materials have recently shown potential in nerve repair and regeneration by promoting the growth of new cells, tissue repair, and restoring nerve function. These natural, synthetic, and hybrid materials offer a biomimetic structure, enhance cell attachment, and release bioactive molecules that promote the axonal extension of severed nerves. Scaffold-based preclinical studies have shown promising results on enhancing nerve repair; however, they are limited by the immune response and fabrication, scalability, and cost. Nevertheless, advances in manufacturing, including 3D bioprinting, and other strategies, such as gene editing by CRISPR, will overcome these shortcomings. The opportunity for the development of individualized approaches and specific treatment plans for each patient will also increase the effectiveness of bioactive materials for the treatment of nerve injuries. Combining bioactive materials with the neural interface can develop new reliable therapeutic solutions, particularly for neuroprosthetics. Finally, it is essential to stress a multidisciplinary focus, and future studies are needed to enhance the potential of bioactive materials for patients with nerve injuries and the field of regenerative medicine. Full article

Schwann cells (SCs) play a crucial role in peripheral nerve repair by supporting axonal regeneration and remyelination. While extensive research has been conducted using rodent SCs, increasing attention is being directed toward human SCs due to species-specific differences in phenotypical and functional properties, and accessibility of human SCs derived from diverse sources. A major challenge in translating SC-based therapies for nerve repair lies in the inability to replicate human SC myelination in vitro, posing a significant obstacle to drug discovery and preclinical research. In this study, we compared the myelination capacity of human, rodent, and porcine SCs in various co-culture conditions, including species-matched and cross-species neuronal environments in a serum-free medium. Our results confirmed that rodent and porcine SCs readily myelinate neurites under standard culture conditions after treatment with ascorbic acid for two weeks, whereas human SCs, at least within the four-week observation period, failed to show myelin staining in all co-cultures. Furthermore, we investigated whether cell culture manipulation impairs human SC myelination by transplanting freshly harvested and predegenerated human nerve segments into NOD-SCID mice for four weeks. Despite supporting host axonal regeneration into the grafts, human SCs exhibited very limited myelination, suggesting an intrinsic species-specific restriction rather than a cell culture-induced defect. These observations suggest fundamental differences between human and rodent SCs and highlight the need for human-specific models and protocols to advance our understanding of SC myelination. Full article

Extracellular vesicles (EVs) are bilayer lipid membrane particles that are released by every cell type. These secretions are further classified as exosomes, ectosomes, and microvesicles. They contain biomolecules (RNAs, proteins, metabolites, and lipids) with the ability to modulate various biological processes and have been shown to play a role in intercellular communication and cellular rejuvenation. Various studies suggest exosomes and/or microvesicles as a potential platform for drug delivery. EVs may deliver lipids and nucleotides directly to an injury site in an axon, promoting growth cone stabilization and membrane expansion as well as repair, thus positively modulating adult axon regeneration. In this review, we will provide a perspective on the metabolite composition of EVs in adult axonal regeneration relevant to the central nervous system (CNS), specifically that pertaining to the optic nerve. We will present an overview of the methods for isolation, enrichment, omics data analysis and quantification of extracellular vesicles with the goal of providing direction for future studies relevant to axon regeneration. We will also include current resources for multi-omics data integration relevant to extracellular vesicles from diverse cell types. Full article

Background: Numerous experimental studies aim to improve outcomes of peripheral nerve repair following trauma. This study evaluates the efficacy of the human epineural patch (hEP) compared to the human amniotic membrane (hAM) in promoting nerve regeneration following sciatic nerve crush injury. Methods: Thirty-six athymic nude rats were divided into three groups (n = 12 per group) following nerve crush: (1) an unprotected injury site; (2) crush injury wrapped with hEP; and (3) crush injury wrapped with hAM. Animals were assessed over 6 or 12 weeks post-injury. Evaluations included motor recovery (Toe-Spread test), sensory recovery (Pinprick test), muscle denervation atrophy (the gastrocnemius muscle index (GMI)), histomorphometry (myelin thickness, axonal density, fiber diameter, and percentage of myelinated fibers), and immunofluorescence (GFAP, Laminin B, NGF, S-100, VEGF, vWF, HLA-DR, and HLA-I) assessments. Results: The hEP group showed superior motor recovery, axonal density and higher GMI values compared to the hAM and control groups. The increased expression of neurogenic and angiogenic markers highlighted its neuroregenerative potential. Negligible HLA-DR and HLA-I expression confirmed the lack of hEP and hAM immunogenicity. Conclusions: The application of hEP following sciatic nerve crush injury facilitated nerve regeneration, improved functional outcomes, and offered a viable alternative to hAM. Structural stability and the regenerative capacity position hEP as a new, promising off-the-shelf product for nerve regeneration. Full article

Traumatic injuries to the peripheral (PNS) and central nervous systems (CNS) trigger distinct regenerative responses, with the PNS displaying limited regenerative capacity and the CNS remaining largely refractory. Recent research highlights the role of epigenetic modifications, particularly histone acetylation, in modulating the gene expression programs that drive axonal regeneration. This review synthesizes current findings on post-translational histone modifications, focusing on histone acetyltransferases (HATs), histone deacetylases (HDACs), and epigenetic readers, in addition to their impact on neuronal and non-neuronal cells following injury. While HATs like p300/CBP and PCAF promote the expression of regeneration-associated genes, HDAC inhibition has been shown to facilitate neurite outgrowth, neuroprotection, and functional recovery in both PNS and CNS models. However, HDAC3, HDAC5, and HDAC6 demonstrate context- and cell-type-specific roles in both promoting and limiting regenerative processes. The review also highlights cell-specific findings that have been scarcely covered in the previous literature. Thus, the immunomodulatory roles of epigenetic regulators in microglia and macrophages, their involvement in remyelination via Schwann cells and oligodendrocytes, and their impact on astrocyte function are within the scope of this review. Closely considering cell-context specificity is critical, as some targets can exert opposite effects depending on the cell type involved. This represents a major challenge for current pharmacological therapies, which often lack precision. This complexity underscores the need to develop strategies that allow for cell-specific delivery or target regulators with converging beneficial effects across cell types. Such approaches may enhance regenerative outcomes after CNS or PNS injury. Full article

Neurotrophic factor 3 (NT-3), a potent neurotrophin, promotes neuronal survival and axonal regeneration while demonstrating a unique capacity to induce lineage-specific differentiation of pluripotent stem cells into functional neurons, underscoring its therapeutic potential in neural repair. Despite these advantages, the large-scale production of recombinant human NT-3 with preserved structure integrity and functional bioactivity remains a critical challenge. This study takes advantage of the silk gland bioreactor of silkworms for the recombinant expression of human NT-3 protein on a large scale. Our findings reveal that NT-3 was successfully expressed in the middle silk gland of silkworms and secreted into the silk fibers, achieving a yield of up to 0.5 mg of bioactive NT-3 per gram of cocoon weight. The engineered NT-3-functionalized silk material demonstrates no cytotoxicity and significantly enhanced the proliferation, migration, and differentiation of neural cells compared to natural silk protein. Importantly, this functionalized material also promotes neurite outgrowth in HT-22 cells. These results collectively underscore the high bioactivity of the recombinant human NT-3 protein produced in the silkworm silk gland. The ongoing fabrication of NT-3-incorporated silk-based materials holds considerable promise for advancing tissue engineering and nerve regeneration applications. Full article

Adenylyl cyclases (ACs) are key regulators of cyclic adenosine monophosphate (cAMP) signaling—a pathway critical for neuroregeneration, synaptic plasticity, and neuronal survival. In both the central and peripheral nervous systems, injury-induced activation of ACs promotes axonal outgrowth and functional recovery through the stimulation of protein kinase A (PKA), exchange proteins directly activated by cAMP (Epac), and cAMP-response element-binding protein (CREB). Among the various AC isoforms, calcium-sensitive AC1, AC8, and AC5, as well as bicarbonate-responsive soluble AC (sAC), have emerged as crucial mediators of neuroplasticity and axon regeneration. These isoforms coordinate diverse cellular responses—including gene transcription, cytoskeletal remodeling, and neurotransmitter release—to metabolic, synaptic, and injury-related signals. Dysregulation of AC activity has been implicated in the pathophysiology of neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease, and amyotrophic lateral sclerosis, as well as in chronic pain syndromes. Pharmacological modulation of cAMP levels through AC activation, phosphodiesterase (PDE) inhibition, or pituitary adenylyl cyclase-activating polypeptide (PACAP) receptor signaling has shown therapeutic promise in preclinical models by enhancing neurogenesis, remyelination, and synaptic repair. Conversely, targeted inhibition of specific AC isoforms, particularly AC1, has demonstrated efficacy in reducing maladaptive plasticity and neuropathic pain. This review highlights the diverse roles of ACs in neuronal function and injury response and discusses emerging strategies for their therapeutic targeting. Full article

Peripheral nerve injuries (PNIs) present a significant clinical challenge due to the inherently limited regenerative capacity of the adult nervous system. Conventional therapeutic strategies, such as nerve autografting and systemic pharmacological interventions, are often limited by donor site morbidity, restricted graft availability, and suboptimal drug bioavailability. In this context, gelatin-based hydrogels have emerged as a promising class of biomaterials due to their excellent biocompatibility, biodegradability, and structural similarity to the native extracellular matrix. These hydrogels could offer a highly tunable platform capable of supporting cellular adhesion, promoting axonal elongation, and enabling localized and sustained release of therapeutic agents. This narrative review synthesizes recent advances in the application of gelatin-based hydrogels for peripheral nerve regeneration, with a particular focus on their use as delivery vehicles for neurotrophic factors, stem cells, and pharmacologically active compounds. Additionally, this review provides a foundation for extending our ongoing preclinical study, evaluating the neuroregenerative effects of alpha-lipoic acid, B-complex vitamins, and a deproteinized hemoderivative in a murine PNI model. Although systemic administration has demonstrated promising neuroprotective effects, limitations related to local drug availability and off-target exposure highlight the need for site-specific delivery strategies. In this regard, gelatin hydrogels might represent an excellent candidate for localized, controlled drug delivery. The review concludes by discussing formulation techniques, manufacturing considerations, biological performance, and key translational and regulatory aspects. Full article

Multiple sclerosis (MS) is a multifaceted inflammatory, demyelinating, and neurodegenerative disease typified by lesions with distinct hallmarks in the central nervous system. Dysregulation of micro-environmental factors, including extracellular matrix (ECM) remodelling and glial cell activation, has a decisive effect on lesion development and disease progression. Understanding the biological and pathological features of lesions would aid in prognosis and personalised treatment decision making. Positron emission tomography (PET) is an imaging technique that uses radio-labelled tracers to detect specific biological phenomena. Recent PET hardware developments enable high-resolution, quantitative imaging, which may allow biological characterisation of relatively small MS lesions. PET may complement MRI by offering objective, quantitative insights into lesion characteristics, including myelin density, inflammation and axonal integrity. Moreover, PET may provide information on lesion traits supporting decision making on upcoming therapeutic strategies for progressive MS, such as the availability of oligodendrocyte progenitor cells and ECM composition that affect remyelination and/or axon regeneration. This review explores the cellular and molecular ECM signatures and neuropathological processes of white matter MS lesions, discusses current and potential novel PET targets that may help characterise MS lesions in vivo, and addresses the potential of PET as a decision tool for selection and evaluation of therapeutic strategies, with a focus on remyelination. Full article

The central nervous system (CNS) is highly susceptible to damage due to its limited ability to regenerate. Injuries to the CNS, whether from trauma, ischemia, or neurodegenerative diseases, disrupt both cellular and vascular structures, leading to immediate (primary) and subsequent (secondary) damage. Primary damage involves the physical disruption of cells and blood vessels, weakening the blood–brain barrier (BBB) and triggering excitotoxicity and calcium overload. Secondary damage develops over hours to days and is marked by ionic imbalance, mitochondrial dysfunction, oxidative stress, and chronic inflammation, which further aggravates tissue damage. Inflammation plays a dual role: acute inflammation helps in repair, while chronic inflammation accelerates neurodegeneration. Microglia and astrocytes play key roles in this inflammatory response, with M1-like microglia promoting pro-inflammatory responses and M2-like microglia supporting anti-inflammatory and repair processes. Neurodegenerative diseases are characterized by the accumulation of misfolded proteins such as Tau, amyloid-beta, TDP-43, and α-synuclein, which impair cellular function and lead to neuronal loss. Neurodegenerative diseases are characterized by the accumulation of misfolded proteins and influenced by genetic risk factors (e.g., APOE4, TARDBP). Despite the CNS’s limited regenerative abilities, processes like synaptogenesis, neurogenesis, axonal regeneration, and remyelination offer potential for recovery. Therapeutic approaches aim to target inflammatory pathways, enhance repair mechanisms, and develop neuroprotective treatments to counter excitotoxicity, oxidative stress, and apoptosis. Advances in stem cell therapy, gene therapy, and personalized medicine hold promise for improving outcomes. Future research should focus on combining strategies, utilizing advanced technologies, and conducting translational studies to bridge the gap between preclinical research and clinical application. By better understanding and leveraging the complex processes of CNS injury and repair, researchers hope to develop effective therapies to restore function and enhance the quality of life for individuals with CNS disorders. Full article

Laser-generated structures have a huge potential to induce an alignment of biological cells, which may be important for various fields in medicine and biotechnology. We describe the formation of fs-laser-induced micro- and nanostructures for achieving the directed growth of Schwann cells, a type of glial cell that can support the regeneration of nerve pathways by guiding the neuronal axons in the direction of their alignment. Polymer surfaces, i.e., polycarbonate (PC) or cellulose acetate butyrate (CAB), were exposed to the beam of a 1040 nm Yb-based amplified fs-laser system with a pulse length of about 350 fs. With appropriate parameters, the laser exposure resulted in a surface topography with oriented micro-grooves, which, for PC, were covered with nano-ripples. Schwann cell growth on these substrates was inspected after 3 to 5 days of cultivation by means of scanning electron microscopy (SEM). We show that Schwann cells can grow in a certain direction, predetermined by micro-groove or nano-ripple orientation. In contrast, cells cultivated on randomly oriented nanofibers or unstructured surfaces show an omnidirectional growth behavior. This method may be used in the future to produce nerve conduits for the treatment of injuries to the peripheral nervous system. Full article

The diverse methylation modifications of DNA, histones and RNA have emerged as pivotal regulatory mechanisms of gene expression in multiple biological processes at the epigenetic level. They function by coordinating gene expression through impacting gene transcription, mRNA processing and maturation, protein translation and metabolism. Changes in methylation profiles of nucleic acids and histones have been observed in many different types neural injuries in both the central nervous system and the peripheral nervous system, such as 5-methylcytosine in DNA, N6-methyladenosine in RNA and methylation of lysine residues in various histones. Importantly, altering these modifications plays key roles in regulation of neural injury and repair. In this review, we highlight recent research advances of the methylation-related epigenetic modifications in multiple aspects of neural injury and regeneration, including neural protection, axon regeneration, microenvironment modulation and neural functional recovery. We also discuss the current unsolved problems in the field and propose potential future research directions. Full article

The skin is the body’s largest organ. It serves various functions, including protection and metabolism. Due to its structure and location, it is more vulnerable to external physical and chemical damage than internal organs. Additionally, certain endogenous diseases can cause pathological changes to appear on the skin and nerves. When skin tissue breaks down or sustains severe trauma, the cells, blood vessels, and nerves across all layers can suffer varying degrees of damage. This often results in pain, itching, sensory disturbances, and other discomforts, causing significant distress to patients. Stem-cell-derived exosome therapy has emerged as a promising treatment for skin injuries due to its safety, non-toxicity, and precision medicine benefits. Research has shown that stem-cell-derived exosomes regulate nerve cells by mediating MicroRNA (miRNA) transport and expression between cells, promoting axon growth. This exosome-driven miRNA exchange serves as a vital mode of intercellular communication, playing a crucial role in nervous system repair. Nerves play a critical role in skin wound healing and tissue regeneration, with sensory and autonomic nerves influencing key skin functions such as inflammation, immune defense, apoptosis, proliferation, and wound repair. Exosomes may aid in treating cutaneous nerve injuries by directly or indirectly promoting axon regeneration, nerve cell proliferation, and the release of protective neurofactors. Full article