Explore the vast range of titles available.

: Autophagy in Schwann cells (SCs) is crucial for myelin debris degradation and clearance following peripheral nerve injury (PNI). Nerve growth factor (NGF) plays an important role in reconstructing peripheral nerve fibers and promoting axonal regeneration. However, it remains unclear if NGF effect in enhancing nerve regeneration is mediated through autophagic clearance of myelin debris in SCs. : , free NGF solution plus with/without pharmacological inhibitors were administered to a rat sciatic nerve crush injury model. , the primary Schwann cells (SCs) and its cell line were cultured in normal medium containing NGF, their capable of swallowing or clearing degenerated myelin was evaluated through supplement of homogenized myelin fractions. : Administration of exogenous NGF could activate autophagy in dedifferentiated SCs, accelerate myelin debris clearance and phagocytosis, as well as promote axon and myelin regeneration at early stage of PNI. These NGF effects were effectively blocked by autophagy inhibitors. In addition, inhibition of the p75 kD neurotrophin receptor (p75 ) signal or inactivation of the AMP-activated protein kinase (AMPK) also inhibited the NGF effect as well. : NGF effect on promoting early nerve regeneration is closely associated with its accelerating autophagic clearance of myelin debris in SCs, which probably regulated by the p75 /AMPK/mTOR axis. Our studies thus provide strong support that NGF may serve as a powerful pharmacological therapy for peripheral nerve injuries.

The great plasticity of Schwann cells (SCs), the myelinating glia of the peripheral nervous system (PNS), is a critical feature in the context of peripheral nerve regeneration following traumatic injuries and peripheral neuropathies. After a nerve damage, SCs are rapidly activated by injury-induced signals and respond by entering the repair program. During the repair program, SCs undergo dynamic cell reprogramming and morphogenic changes aimed at promoting nerve regeneration and functional recovery. SCs convert into a repair phenotype, activate negative regulators of myelination and demyelinate the damaged nerve. Moreover, they express many genes typical of their immature state as well as numerous de-novo genes. These genes modulate and drive the regeneration process by promoting neuronal survival, damaged axon disintegration, myelin clearance, axonal regrowth and guidance to their former target, and by finally remyelinating the regenerated axon. Many signaling pathways, transcriptional regulators and epigenetic mechanisms regulate these events. In this review, we discuss the main steps of the repair program with a particular focus on the molecular mechanisms that regulate SC plasticity following peripheral nerve injury.

Traumatic peripheral nerve lesions affect hundreds of thousands of patients every year; their consequences are life-altering and often devastating and cause alterations in movement and sensitivity. Spontaneous peripheral nerve recovery is often inadequate. In this context, nowadays, cell therapy represents one of the most innovative approaches in the field of nerve repair therapies. The purpose of this systematic review is to discuss the features of different types of mesenchymal stem cells (MSCs) relevant for peripheral nerve regeneration after nerve injury. The published literature was reviewed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A combination of the keywords “nerve regeneration”, “stem cells”, “peripheral nerve injury”, “rat”, and “human” were used. Additionally, a “MeSH” research was performed in PubMed using the terms “stem cells” and “nerve regeneration”. The characteristics of the most widely used MSCs, their paracrine potential, targeted stimulation, and differentiation potentials into Schwann-like and neuronal-like cells are described in this paper. Considering their ability to support and stimulate axonal growth, their remarkable paracrine activity, their presumed differentiation potential, their extremely low immunogenicity, and their high survival rate after transplantation, ADSCs appear to be the most suitable and promising MSCs for the recovery of peripheral nerve lesion. Clinical considerations are finally reported.

Significance Peripheral nerve injury is a major neurological disorder that can cause multiple motor and sensory disturbances. In this study we found that VEGF-B can be used as a previously unidentified therapeutic for treating peripheral nerve injury. We demonstrated that VEGF-B stimulated nerve regeneration and enhanced the recovery of both tissue sensation and the ability of nerves to enhance healing of innervated tissue. The physiologic relevance of VEGF-B is demonstrated by our findings showing that mice lacking VEGF-B have impaired nerve regeneration and that nerve injury resulted in increased endogenous expression of VEGF-B. We discover that VEGF-B induces strong elongation and branching of neurons and requires specific transmembrane receptors as well as activation of a complex intracellular signaling. VEGF-B primarily provides neuroprotection and improves survival in CNS-derived neurons. However, its actions on the peripheral nervous system have been less characterized. We examined whether VEGF-B mediates peripheral nerve repair. We found that VEGF-B induced extensive neurite growth and branching in trigeminal ganglia neurons in a manner that required selective activation of transmembrane receptors and was distinct from VEGF-A–induced neuronal growth. VEGF-B–induced neurite elongation required PI3K and Notch signaling. In vivo, VEGF-B is required for normal nerve regeneration: mice lacking VEGF-B showed impaired nerve repair with concomitant impaired trophic function. VEGF-B treatment increased nerve regeneration, sensation recovery, and trophic functions of injured corneal peripheral nerves in VEGF-B–deficient and wild-type animals, without affecting uninjured nerves. These selective effects of VEGF-B on injured nerves and its lack of angiogenic activity makes VEGF-B a suitable therapeutic target to treat nerve injury.

Peripheral nerve injury is a complex condition with a variety of signs and symptoms such as numbness, tingling, jabbing, throbbing, burning or sharp pain. Peripheral nerves are fragile in nature and can easily get damaged due to acute compression or trauma which may lead to the sensory and motor functions deficits and even lifelong disability. After lesion, the neuronal cell body becomes disconnected from the axon's distal portion to the injury site leading to the axonal degeneration and dismantlement of neuromuscular junctions of targeted muscles. In spite of extensive research on this aspect, complete functional recovery still remains a challenge to be resolved. This review highlights detailed pathophysiological events after an injury to a peripheral nerve and the associated factors that can either hinder or promote the regenerative machinery. In addition, it throws light on the available therapeutic strategies including supporting therapies, surgical and non-surgical interventions to ameliorate the axonal regeneration, neuronal survival, and reinnervation of peripheral targets. Despite the availability of various treatment options, we are still lacking the optimal treatments for a perfect and complete functional regain. The need for the present age is to discover or design such potent compounds that would be able to execute the complete functional retrieval. In this regard, plant-derived compounds are getting more attention and several recent reports validate their remedial effects. A plethora of plants and plant-derived phytochemicals have been suggested with curative effects against a number of diseases in general and neuronal injury in particular. They can be a ray of hope for the suffering individuals.

Injured peripheral nerves but not central nerves have the capacity to regenerate and reinnervate their target organs. After the two most severe peripheral nerve injuries of six types, crush and transection injuries, nerve fibers distal to the injury site undergo Wallerian degeneration. The denervated Schwann cells (SCs) proliferate, elongate and line the endoneurial tubes to guide and support regenerating axons. The axons emerge from the stump of the viable nerve attached to the neuronal soma. The SCs downregulate myelin-associated genes and concurrently, upregulate growth-associated genes that include neurotrophic factors as do the injured neurons. However, the gene expression is transient and progressively fails to support axon regeneration within the SC-containing endoneurial tubes. Moreover, despite some preference of regenerating motor and sensory axons to “find” their appropriate pathways, the axons fail to enter their original endoneurial tubes and to reinnervate original target organs, obstacles to functional recovery that confront nerve surgeons. Several surgical manipulations in clinical use, including nerve and tendon transfers, the potential for brief low-frequency electrical stimulation proximal to nerve repair, and local FK506 application to accelerate axon outgrowth, are encouraging as is the continuing research to elucidate the molecular basis of nerve regeneration.

Vascularization is an important factor in nerve graft survival and function. The specific molecular regulations and patterns of angiogenesis following peripheral nerve injury are in a broad complex of pathways. This review aims to summarize current knowledge on the role of vascularization in nerve regeneration, including the key regulation molecules, and mechanisms and patterns of revascularization after nerve injury. Angiogenesis, the maturation of pre-existing vessels into new areas, is stimulated through angiogenic factors such as vascular endothelial growth factor and precedes the repair of damaged nerves. Vascular endothelial growth factor administration to nerves has demonstrated to increase revascularization after injury in basic science research. In the clinical setting, vascularized nerve grafts could be used in the reconstruction of large segmental peripheral nerve injuries. Vascularized nerve grafts are postulated to accelerate revascularization and enhance nerve regeneration by providing an optimal nutritional environment, especially in scarred beds, and decrease fibroblast infiltration. This could improve functional recovery after nerve grafting, however, conclusive evidence of the superiority of vascularized nerve grafts is lacking in human studies. A well-designed randomized controlled trial comparing vascularized nerve grafts to non-vascularized nerve grafts involving patients with similar injuries, nerve graft repair and follow-up times is necessary to demonstrate the efficacy of vascularized nerve grafts. Due to technical challenges, composite transfer of a nerve graft along with its adipose tissue has been proposed to provide a healthy tissue bed. Basic science research has shown that a vascularized fascial flap containing adipose tissue and a vascular bundle improves revascularization through excreted angiogenic factors, provided by the stem cells in the adipose tissue as well as by the blood supply and environmental support. While it was previously believed that revascularization occurred from both nerve ends, recent studies propose that revascularization occurs primarily from the proximal nerve coaptation. Fascial flaps or vascularized nerve grafts have limited applicability and future directions could lead towards off-the-shelf alternatives to autografting, such as biodegradable nerve scaffolds which include capillary-like networks to enable vascularization and avoid graft necrosis and ischemia.

Resident and inflammatory macrophages are essential effectors of the innate immune system. These cells provide innate immune defenses and regulate tissue and organ homeostasis. In addition to their roles in diseases such as cancer, obesity and osteoarthritis, they play vital roles in tissue repair and disease rehabilitation. Macrophages and other inflammatory cells are recruited to tissue injury sites where they promote changes in the microenvironment. Among the inflammatory cell types, only macrophages have both pro-inflammatory (M1) and anti-inflammatory (M2) actions, and M2 macrophages have four subtypes. The co-action of M1 and M2 subtypes can create a favorable microenvironment, releasing cytokines for damaged tissue repair. In this review, we discuss the activation of macrophages and their roles in severe peripheral nerve injury. We also describe the therapeutic potential of macrophages in nerve tissue engineering treatment and highlight approaches for enhancing M2 cell-mediated nerve repair and regeneration.

The nervous system is a crucial component of the body and damages to this system, either by of injury or disease, can result in serious or potentially lethal consequences. Restoring the damaged nervous system is a great challenge due to the complex physiology system and limited regenerative capacity. Polymers, either synthetic or natural in origin, have been extensively evaluated as a solution for restoring functions in damaged neural tissues. Polymers offer a wide range of versatility, in particular regarding shape and mechanical characteristics, and their biocompatibility is unmatched by other biomaterials, such as metals and ceramics. Several studies have shown that polymers can be shaped into suitable support structures, including nerve conduits, scaffolds, and electrospun matrices, capable of improving the regeneration of damaged neural tissues. In general, natural polymers offer the advantage of better biocompatibility and bioactivity, while synthetic or non-natural polymers have better mechanical properties and structural stability. Often, combinations of the two allow for the development of polymeric conduits able to mimic the native physiological environment of healthy neural tissues and, consequently, regulate cell behaviour and support the regeneration of injured nervous tissues. Currently, most of neural tissue engineering applications are in pre-clinical study, in particular for use in the central nervous system, however collagen polymer conduits aimed at regeneration of peripheral nerves have already been successfully tested in clinical trials. This review highlights different types of natural and synthetic polymers used in neural tissue engineering and their advantages and disadvantages for neural regeneration.

The peripheral nervous system (PNS) has remarkable regenerative abilities after injury. Successful PNS regeneration relies on both injured axons and non-neuronal cells, including Schwann cells and immune cells. Macrophages are the most notable immune cells that play key roles in PNS injury and repair. Upon peripheral nerve injury, a large number of macrophages are accumulated at the injury sites, where they not only contribute to Wallerian degeneration, but also are educated by the local microenvironment and polarized to an anti-inflammatory phenotype (M2), thus contributing to axonal regeneration. Significant progress has been made in understanding how macrophages are educated and polarized in the injured microenvironment as well as how they contribute to axonal regeneration. Following the discussion on the main properties of macrophages and their phenotypes, in this review, we will summarize the current knowledge regarding the mechanisms of macrophage infiltration after PNS injury. Moreover, we will discuss the recent findings elucidating how macrophages are polarized to M2 phenotype in the injured PNS microenvironment, as well as the role and underlying mechanisms of macrophages in peripheral nerve injury, Wallerian degeneration and regeneration. Furthermore, we will highlight the potential application by targeting macrophages in treating peripheral nerve injury and peripheral neuropathies.