Comparing natural hydrogels to self-assembling peptides in spinal cord injury treatment: a systematic review

Background: In many cases, central nervous system (CNS) injury is unchanging due to the absence of neuronal regeneration and repair capabilities. In recent years, regenerative medicine, and especially hydrogels, has reached a significant amount of attention for their promising results for the treatment of spinal cord injury (SCI) currently considered permanent. Hydrogels are categorized based on their foundation: synthetic, natural, and combination. The objective of this study was to compare the properties and efficacy of commonly used hydrogels, like collagen, and other natural peptides with synthetic self-assembling peptide hydrogels in the treatment of SCI. Methods: Articles were searched in PubMed, Scopus, Web of Science, and Embase. All studies from 1985 until January 2020 were included in the primary search. Eligible articles were included based on the following criteria: administering hydrogels (both natural and synthetic) for SCI treatment, solely focusing on spinal cord injury treatment, and published in a peer-reviewed journal. Data on axonal regeneration, revascularization, elasticity, drug delivery efficacy, and porosity were extracted. Results: A total of 24 articles were included for full-text review and data extraction. There was only one experimental study comparing collagen I (natural hydrogel) and polyethylene glycol (PEG) in an in vitro setting. The included study suggested the behavior of cells with PEG is more expectable in the injury site, which makes it a more reliable scaffold for neurites. Conclusions: There is limited research comparing and evaluating both types of natural and self-assembling peptides (SAPs) in the same animal or in vitro study, despite its importance. Although we assume that the remodeling of natural scaffolds may lead to a stable hydrogel, there was not a definitive conclusion that synthetic hydrogels are more beneficial than natural hydrogels in neuronal regeneration.

Neurorestorative Roles of Microgliosis and Astrogliosis in Neuroinflammation and Neurodegeneration

The pathophysiological processes involved in neurodegenerative diseases have not been clearly defined. Nevertheless, a significant aspect of the proof focuses directly on the function of several mechanisms of inflammation. The immune system is represented in the central nervous system by the microglial cell capable of detecting harmful or foreign pathogens, and thus initiates self-activation and neuro-inflammatory processes via phagocytosis and cytokines release, to maintain the cellular microenvironment. Then, microglial cells can spawn an emphasis on persistent inflammation that sometimes precedes or promote the neurodegenerative processes. Hence, the neuro-inflammatory micro-environment turns toxic and damaging to the neuronal cell, leading to degeneration and release of several factors which trigger an inflammatory reaction of the microglia, activating the neurodegenerative cycle. The biomechanical properties of the brain, neuronal regeneration, and plasticity can be modified by reactive gliosis. Defining the inception and development of reactive microgliosis and astrogliosis is vital for better clinical treatments design.

Diamond Concept as Principle for the Development of Spinal Cord Scaffold: A Literature Review

INTRODUCTION: Spinal cord injury (SCI) has been bringing detrimental impacts on the affected individuals. However, not only that, it also brings a tremendous effect on the socioeconomic and health-care system. Treatment regimen and strategy for SCI patient have been under further research. DISCUSSION: The main obstacles of regeneration on neuronal structure are the neuroinflammatory process and poor debris clearance, causing a longer healing process and an extensive inflammation process due to this particular inflammatory process. To resolve all of the mentioned significant issues in SCIs neuronal regeneration, a comprehensive model is necessary to analyze each step of progressive condition in SCI. In this review, we would like to redefine a comprehensive concept of the “Diamond Concept” from previously used in fracture management to SCI management, which consists of cellular platform, cellular inductivity, cellular conductivity, and material integrity. The scaffolding treatment strategy for SCI has been widely proposed due to its flexibility. It enables the physician to combine another treatment method such as neuroprotective or neuroregenerative or both in one intervention. CONCLUSION: Diamond concept perspective in the implementation of scaffolding could be advantageous to increase the outcome of SCI treatment.

Danzhi Xiaoyao Powder Promotes Neuronal Regeneration by Downregulating Notch Signaling Pathway in the Treatment of Generalized Anxiety Disorder

Background: Generalized anxiety disorder (GAD) is one of the most common types of anxiety disorders with unclear pathogenesis. Our team’s previous research found that extensive neuronal apoptosis and neuronal regeneration disorders occur in the hippocampus of GAD rats. Danzhi Xiaoyao (DZXYS) Powder can improve the anxiety behavior of rats, but its molecular mechanism is not well understood.Objective: This paper discusses whether the pathogenesis of GAD is related to the abnormal expression of Notch signal pathway, and whether the anti-anxiety effect of DZXYS promotes nerve regeneration in the hippocampus by regulating the Notch signaling pathway.Methods: The animal model of GAD was developed by the chronic restraint stress and uncertain empty bottle stimulation method. After the model was successfully established, the rats in the model preparation group were divided into the buspirone, DZXYS, DZXYS + DAPT, and model groups, and were administered the corresponding drug intervention. The changes in body weight and food intake of rats were continuously monitored throughout the process. The changes in anxiety behavior of rats were measured by open field experiment and elevated plus-maze test, and morphological changes and regeneration of neurons in the rat hippocampus were observed by HE staining and double immunofluorescence staining. Changes in the expression of key targets of the Notch signaling pathway in the hippocampus were monitored by real-time fluorescence quantitative PCR and western blotting.Results: In this study, we verified that the GAD model was stable and reliable, and found that the key targets of the Notch signaling pathway (Notch1, Hes1, Hes5, etc.) in the hippocampus of GAD rats were significantly upregulated, leading to the increased proliferation of neural stem cells in the hippocampus and increased differentiation into astrocytes, resulting in neuronal regeneration. DZXYS intervention in GAD rats can improve appetite, promote weight growth, and significantly reverse the anxiety behavior of GAD rats, which can inhibit the upregulation of key targets of the Notch signaling pathway, promote the differentiation of neural stem cells in the hippocampus into neurons, and inhibit their differentiation into astrocytes, thus alleviating anxiety behavior.Conclusion: The occurrence of GAD is closely related to the upregulation of the Notch signaling pathway, which hinders the regeneration of normal neurons in the hippocampus, while DZXYS can downregulate the Notch signaling pathway and promote neuronal regeneration in the hippocampus, thereby relieving anxiety behavior.

Semaphorin signaling restricts neuronal regeneration in C. elegans

Extracellular signaling proteins serve as neuronal growth cone guidance molecules during development and are well positioned to be involved in neuronal regeneration and recovery from injury. Semaphorins and their receptors, the plexins, are a family of conserved proteins involved in development that, in the nervous system, are axonal guidance cues mediating axon pathfinding and synapse formation. The Caenorhabditis elegans genome encodes for three semaphorins and two plexin receptors: the transmembrane semaphorins, SMP-1 and SMP-2, signal through their receptor, PLX-1, while the secreted semaphorin, MAB-20, signals through PLX-2. Here, we determined the neuronal morphology and locomotion behavior of knockout animals missing each of the semaphorins and plexins; we described the expression pattern of all plexins in the nervous system of C. elegans; and we evaluated their effect on the regeneration of motoneuron neurites and the recovery of locomotion behavior following precise laser microsurgery.

The MicroRNA miR-18a Links Proliferation and Inflammation During Photoreceptor Regeneration in the Injured Zebrafish Retina

In mammals, photoreceptor loss causes permanent blindness, but in zebrafish (Danio rerio), photoreceptor loss reprograms Müller glia to function as stem cells, producing progenitors that fully regenerate photoreceptors. MicroRNAs (miRNAs) regulate neurogenesis in the CNS, but the roles of miRNAs in injury-induced neuronal regeneration are largely unknown. In the embryonic zebrafish retina, miRNA miR-18a regulates photoreceptor differentiation. The purpose of the current study was to determine in zebrafish the function of miR-18a during injury-induced photoreceptor regeneration. RT-qPCR, in-situ hybridization and immunohistochemistry showed that miR-18a expression increases throughout the retina by 1-day post-injury (dpi) and increases through 5 dpi. To test miR-18a function during photoreceptor regeneration, we used homozygous miR-18a mutants (miR-18ami5012), and knocked down miR-18a with morpholino oligonucleotides. During photoreceptor regeneration, miR-18ami5012 retinas have fewer mature photoreceptors than WT at 7 and 10 dpi, but there is no difference at 14 dpi, indicating that photoreceptor regeneration is delayed. Labeling dividing cells with bromodeoxyuridine (BrdU) showed that at 7 and 10 dpi, there are excess Müller glia-derived progenitors in both mutants and morphants, indicating that miR-18a negatively regulates injury-induced proliferation. Tracing BrdU-labeled cells showed that in miR-18ami5012 retinas excess progenitors migrate to other retinal layers in addition to the photoreceptor layer. Inflammation is critical for photoreceptor regeneration, and RT-qPCR showed that in miR-18ami5012 retinas, inflammatory gene expression and microglia activation are prolonged. Suppressing inflammation with dexamethasone rescues the miR-18ami5012 phenotype. Together, these data show that during photoreceptor regeneration in zebrafish, miR-18a regulates proliferation and photoreceptor regeneration by regulating the inflammatory response.

Contralateral Axon Sprouting but Not Ipsilateral Regeneration Is Responsible for Spontaneous Locomotor Recovery Post Spinal Cord Hemisection

Spinal cord injury (SCI) usually results in permanent functional impairment and is considered a worldwide medical problem. However, both motor and sensory functions can spontaneously recover to varying extents in humans and animals with incomplete SCI. This study observed a significant spontaneous hindlimb locomotor recovery in Sprague-Dawley rats at four weeks after post-right-side spinal cord hemisection at thoracic 8 (T8). To verify whether the above spontaneous recovery derives from the ipsilateral axonal or neuronal regeneration to reconnect the lesion site, we resected either the scar tissue or right side T7 spinal cord at five weeks post-T8 hemisected injury. The results showed that the spontaneously achieved right hindlimb locomotor function had little change after resection. Furthermore, when T7 left hemisection was performed five weeks after the initial injury, the spontaneously achieved right hindlimb locomotor function was dramatically abolished. A similar result could also be observed when T7 transection was performed after the initial hemisection. The results indicated that it might be the contralateral axonal remolding rather than the ipsilateral axonal or neuronal regeneration beyond the lesion site responsible for the spontaneous hindlimb locomotor recovery. The immunostaining analyses and corticospinal tracts (CSTs) tracing results confirmed this hypothesis. We detected no substantial neuronal and CST regeneration throughout the lesion site; however, significantly more CST fibers were observed to sprout from the contralateral side at the lumbar 4 (L4) spinal cord in the hemisection model rats than in intact ones. In conclusion, this study verified that contralateral CST sprouting, but not ipsilateral CST or neuronal regeneration, is primarily responsible for the spontaneous locomotor recovery in hemisection SCI rats.

Guided Axon Outgrowth of Neurons by Real-Time Femtosecond Laser Penetration on a 4 μm Thick Thin-Glass Sheet

Transplantation of scaffold-embedded guided neurons has been reported to increase neuronal regeneration following brain injury. However, precise axonal integration between host and transplant neurons to form functional synapses remains a major problem. This study aims to develop a real-time femtosecond (fs) laser penetration on a 4 μm thick thin-glass sheet to promote guided axon outgrowth influenced by molecular gradients in a microfluidic device. The device enables the introduction of the guidance molecule (i.e., netrin-1), neuronal culture, and manipulation by fs laser. After fabricating multiple micro-holes on the thin-glass sheet using fs laser, netrin-1 gradients with radial concentrations are generated in the chamber, affecting axon outgrowth and guidance. A majority of axons (~92%) experiences guided outgrowth with positive angular changes towards netrin-1 gradients. These results demonstrate the capability of the precise and real-time manipulation system based on a fs laser and a microfluidic device to control the growth of neurons.