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Progress in Neurobiology Aug 2023Myelin improves axonal conduction velocity and is essential for nerve development and regeneration. In peripheral nerves, Schwann cells depend on bidirectional...
Myelin improves axonal conduction velocity and is essential for nerve development and regeneration. In peripheral nerves, Schwann cells depend on bidirectional mechanical and biochemical signaling to form the myelin sheath but the mechanism underlying this process is not understood. Rho GTPases are integrators of "outside-in" signaling that link cytoskeletal dynamics with cellular architecture to regulate morphology and adhesion. Using Schwann cell-specific gene inactivation in the mouse, we discovered that RhoA promotes the initiation of myelination, and is required to both drive and terminate myelin growth at different stages of peripheral myelination, suggesting developmentally-specific modes of action. In Schwann cells, RhoA targets actin filament turnover, via Cofilin 1, actomyosin contractility and cortical actin-membrane attachments. This mechanism couples actin cortex mechanics with the molecular organization of the cell boundary to target specific signaling networks that regulate axon-Schwann cell interaction/adhesion and myelin growth. This work shows that RhoA is a key component of a biomechanical response required to control Schwann cell state transitions for proper myelination of peripheral nerves.
Topics: Mice; Animals; Actins; Schwann Cells; Myelin Sheath; Peripheral Nerves; Axons
PubMed: 37315917
DOI: 10.1016/j.pneurobio.2023.102481 -
Journal of Neuroinflammation Mar 2021Following peripheral nerve injury, multiple cell types, including axons, Schwann cells, and macrophages, coordinate to promote nerve regeneration. However, this capacity... (Review)
Review
Following peripheral nerve injury, multiple cell types, including axons, Schwann cells, and macrophages, coordinate to promote nerve regeneration. However, this capacity for repair is limited, particularly in older populations, and current treatments are insufficient. A critical component of the regeneration response is the network of cell-to-cell signaling in the injured nerve microenvironment. Sheddases are expressed in the peripheral nerve and play a role in the regulation if this cell-to-cell signaling through cleavage of transmembrane proteins, enabling the regulation of multiple pathways through cis- and trans-cellular regulatory mechanisms. Enhanced axonal regeneration has been observed in mice with deletion of the sheddase beta-secretase (BACE1), a transmembrane aspartyl protease that has been studied in the context of Alzheimer's disease. BACE1 knockout (KO) mice display enhanced macrophage recruitment and activity following nerve injury, although it is unclear whether this plays a role in driving the enhanced axonal regeneration. Further, it is unknown by what mechanism(s) BACE1 increases macrophage recruitment and activity. BACE1 has many substrates, several of which are known to have immunomodulatory activity. This review will discuss current knowledge of the role of BACE1 and other sheddases in peripheral nerve regeneration and outline known immunomodulatory BACE1 substrates and what potential roles they could play in peripheral nerve regeneration. Currently, the literature suggests that BACE1 and substrates that are expressed by neurons and Schwann cells are likely to be more important for this process than those expressed by macrophages. More broadly, BACE1 may play a role as an effector of immunomodulation beyond the peripheral nerve.
Topics: Amyloid Precursor Protein Secretases; Animals; Aspartic Acid Endopeptidases; Humans; Macrophages; Nerve Regeneration; Peripheral Nerve Injuries; Peripheral Nerves
PubMed: 33722254
DOI: 10.1186/s12974-021-02121-2 -
International Journal of Molecular... Jul 2021Peripheral nerves are highly susceptible to injuries induced from everyday activities such as falling or work and sport accidents as well as more severe incidents such... (Review)
Review
Peripheral nerves are highly susceptible to injuries induced from everyday activities such as falling or work and sport accidents as well as more severe incidents such as car and motorcycle accidents. Many efforts have been made to improve nerve regeneration, but a satisfactory outcome is still unachieved, highlighting the need for easy to apply supportive strategies for stimulating nerve growth and functional recovery. Recent focus has been made on the effect of the consumed diet and its relation to healthy and well-functioning body systems. Normally, a balanced, healthy daily diet should provide our body with all the needed nutritional elements for maintaining correct function. The health of the central and peripheral nervous system is largely dependent on balanced nutrients supply. While already addressed in many reviews with different focus, we comprehensively review here the possible role of different nutrients in maintaining a healthy peripheral nervous system and their possible role in supporting the process of peripheral nerve regeneration. In fact, many dietary supplements have already demonstrated an important role in peripheral nerve development and regeneration; thus, a tailored dietary plan supplied to a patient following nerve injury could play a non-negotiable role in accelerating and promoting the process of nerve regeneration.
Topics: Animals; Diet; Humans; Nerve Regeneration; Nutrients; Peripheral Nerve Injuries; Peripheral Nerves; Recovery of Function
PubMed: 34299037
DOI: 10.3390/ijms22147417 -
International Journal of Molecular... Nov 2022Common mechanisms of peripheral axon regeneration are recruited following diverse forms of damage to peripheral nerve axons. Whether the injury is traumatic or disease... (Review)
Review
Common mechanisms of peripheral axon regeneration are recruited following diverse forms of damage to peripheral nerve axons. Whether the injury is traumatic or disease related neuropathy, reconnection of axons to their targets is required to restore function. Supporting peripheral axon regrowth, while not yet available in clinics, might be accomplished from several directions focusing on one or more of the complex stages of regrowth. Direct axon support, with follow on participation of supporting Schwann cells is one approach, emphasized in this review. However alternative approaches might include direct support of Schwann cells that instruct axons to regrow, manipulation of the inflammatory milieu to prevent ongoing bystander axon damage, or use of inflammatory cytokines as growth factors. Axons may be supported by a growing list of growth factors, extending well beyond the classical neurotrophin family. The understanding of growth factor roles continues to expand but their impact experimentally and in humans has faced serious limitations. The downstream signaling pathways that impact neuron growth have been exploited less frequently in regeneration models and rarely in human work, despite their promise and potency. Here we review the major regenerative signaling cascades that are known to influence adult peripheral axon regeneration. Within these pathways there are major checkpoints or roadblocks that normally check unwanted growth, but are an impediment to robust growth after injury. Several molecular roadblocks, overlapping with tumour suppressor systems in oncology, operate at the level of the perikarya. They have impacts on overall neuron plasticity and growth. A second approach targets proteins that largely operate at growth cones. Addressing both sites might offer synergistic benefits to regrowing neurons. This review emphasizes intrinsic aspects of adult peripheral axon regeneration, emphasizing several molecular barriers to regrowth that have been studied in our laboratory.
Topics: Adult; Humans; Axons; Nerve Regeneration; Schwann Cells; Neurons; Peripheral Nerves; Peripheral Nerve Injuries
PubMed: 36362354
DOI: 10.3390/ijms232113566 -
Peripheral Nerve Regeneration Using a Nerve Conduit with Olfactory Ensheathing Cells in a Rat Model.Tissue Engineering and Regenerative... Jun 2021Autologous nerve grafts are the gold standard treatment for peripheral nerve injury treatment. However, this procedure cannot avoid sacrificing other nerves as a major...
BACKGROUND
Autologous nerve grafts are the gold standard treatment for peripheral nerve injury treatment. However, this procedure cannot avoid sacrificing other nerves as a major limitation. The aim of the present study was to evaluate the potential of olfactory ensheathing cells (OECs) embedded in a nerve conduit.
METHODS
A 10-mm segment of the sciatic nerve was resected in 21 rats, and the nerve injury was repaired with one of the following (n = 7 per group): autologous nerve graft, poly (ε-caprolactone) (PCL) conduit and OECs, and PCL conduit only. The consequent effect on nerve regeneration was measured based on the nerve conduction velocity (NCV), amplitude of the compound muscle action potential (ACMAP), wet muscle weight, histomorphometric analysis, and nerve density quantification.
RESULTS
Histomorphometric analysis revealed nerve regeneration and angiogenesis in all groups. However, there were significant differences (p < 0.05) in the ACMAP nerve regeneration rate of the gastrocnemius and tibialis anterior muscles between the autologous graft (37.9 ± 14.3% and 39.1% ± 20.4%) and PCL only (17.8 ± 8.6% and 13.6 ± 5.8%) groups, and between the PCL only and PCL + OECs (46.3 ± 20.0% and 34.5 ± 14.6%) groups, with no differences between the autologous nerve and PCL + OEC groups (p > 0.05). No significant results in NCV, wet muscle weight, and nerve density quantification were observed among the 3 groups.
CONCLUSION
A PCL conduit with OECs enhances the regeneration of injured peripheral nerves, offering a good alternative to autologous nerve grafts.
Topics: Animals; Nerve Regeneration; Nerve Tissue; Rats; Rats, Sprague-Dawley; Sciatic Nerve; Tissue Scaffolds
PubMed: 33515167
DOI: 10.1007/s13770-020-00326-9 -
Experimental Neurology Jun 2020A highly regulated endoneurial microenvironment is required for normal axonal function in peripheral nerves and nerve roots, which structurally consist of an outer... (Review)
Review
A highly regulated endoneurial microenvironment is required for normal axonal function in peripheral nerves and nerve roots, which structurally consist of an outer collagenous epineurium, inner perineurium consisting of multiple concentric layers of specialized epithelioid myofibroblasts that surround the innermost endoneurium, which consists of myelinated and unmyelinated axons embedded in a looser mesh of collagen fibers. Endoneurial homeostasis is achieved by tight junction-forming endoneurial microvessels that control ion, solute, water, nutrient, macromolecule and leukocyte influx and efflux between the bloodstream and endoneurium, and the innermost layers of the perineurium that control interstitial fluid component flux between the freely permeable epineurium and endoneurium. Strictly speaking, endoneurial microvascular endothelium should be considered the blood-nerve barrier (BNB) due to direct communication with circulating blood. The mammalian BNB is considered the second most restrictive vascular system after the blood-brain barrier (BBB) based on classic in situ permeability studies. Structural alterations in endoneurial microvessels or interactions with hematogenous leukocytes have been described in several human peripheral neuropathies; however major advances in BNB biology in health and disease have been limited over the past 50 years. Guided by transcriptome and proteome studies of normal and pathologic human peripheral nerves, purified primary and immortalized human endoneurial endothelial cells that form the BNB and leukocytes from patients with well-characterized peripheral neuropathies, validated by in situ or ex vivo protein expression studies, data are emerging on the molecular and functional characteristics of the human BNB in health and in specific peripheral neuropathies, as well as chronic neuropathic pain. These early advancements have the potential to not only increase our understanding of how the BNB works and adapts or fails to adapt to varying insult, but provide insights relevant to pathogenic leukocyte trafficking, with translational potential and specific therapeutic application for chronic peripheral neuropathies and neuropathic pain.
Topics: Blood-Nerve Barrier; Homeostasis; Humans; Peripheral Nerves; Peripheral Nervous System Diseases
PubMed: 32142802
DOI: 10.1016/j.expneurol.2020.113272 -
Nature Neuroscience Feb 2022The peripheral nerve contains diverse cell types that support its proper function and maintenance. In this study, we analyzed multiple peripheral nerves using...
The peripheral nerve contains diverse cell types that support its proper function and maintenance. In this study, we analyzed multiple peripheral nerves using single-nuclei RNA sequencing, which allowed us to circumvent difficulties encountered in analyzing cells with complex morphologies via conventional single-cell methods. The resultant mouse peripheral nerve cell atlas highlights a diversity of cell types, including multiple subtypes of Schwann cells (SCs), immune cells and stromal cells. We identified a distinct myelinating SC subtype that expresses Cldn14, Adamtsl1 and Pmp2 and preferentially ensheathes motor axons. The number of these motor-associated Pmp2 SCs is reduced in both an amyotrophic lateral sclerosis (ALS) SOD1 mouse model and human ALS nerve samples. Our findings reveal the diversity of SCs and other cell types in peripheral nerve and serve as a reference for future studies of nerve biology and disease.
Topics: Amyotrophic Lateral Sclerosis; Animals; Disease Models, Animal; Mice; Mice, Transgenic; Neuroglia; Peripheral Nerves; Schwann Cells; Superoxide Dismutase
PubMed: 35115729
DOI: 10.1038/s41593-021-01005-1 -
Anesthesiology Jun 2022
Topics: Analgesia; Catheters; Humans; Nerve Block; Pain, Postoperative; Peripheral Nerves
PubMed: 35472131
DOI: 10.1097/ALN.0000000000004219 -
Anaesthesia Jan 2021With the widespread use of ultrasound for localising nerves during peripheral nerve blockade, the value of electrical nerve stimulation of evoked motor responses has... (Review)
Review
With the widespread use of ultrasound for localising nerves during peripheral nerve blockade, the value of electrical nerve stimulation of evoked motor responses has been questioned. Studies continue to show that, compared with nerve stimulation, ultrasound guidance alone leads to: significantly improved block success; decreased need for rescue analgesia; decreased procedural pain; and lower rates of vascular puncture. Nerve stimulation combined with ultrasound does also not appear to improve block success rates, apart from those blocks where the nerves are challenging to view, such as the obturator nerve. The role of nerve stimulation has changed in the last 15 years from a technique to locate nerves to that of an adjunct to ultrasound. Nerve stimulation can serve as a monitor against needle-nerve contact and may be useful in avoiding nerves that are in the needle trajectory during specific ultrasound guided techniques. Nerve stimulation is also a useful adjunct in teaching novices ultrasound-guided regional anaesthesia, especially when the position and or appearance of nerves may be variable. In this review, the changing role of nerve stimulation in contemporary regional anaesthetic practice is presented and discussed.
Topics: Anesthesia, Conduction; Electric Stimulation; Humans; Nerve Block; Peripheral Nerves; Ultrasonography, Interventional
PubMed: 33426665
DOI: 10.1111/anae.15257 -
Journal of Neuroinflammation Apr 2022Macrophages are present in all mammalian tissues and coexist with various cell types in order to respond to different environmental cues. However, the role of these... (Review)
Review
Macrophages are present in all mammalian tissues and coexist with various cell types in order to respond to different environmental cues. However, the role of these cells has been underestimated in the context of peripheral nerve damage. More importantly, macrophages display divergent characteristics, associated with their origin, and in response to the modulatory effects of their microenvironment. Interestingly, the advent of new techniques such as fate mapping and single-cell transcriptomics and their synergistic use has helped characterize in detail the origin and fate of tissue-resident macrophages in the peripheral nervous system (PNS). Furthermore, these techniques have allowed a better understanding of their functions from simple homeostatic supervisors to chief regulators in peripheral neuropathies. In this review, we summarize the latest knowledge about macrophage ontogeny, function and tissue identity, with a particular focus on PNS-associated cells, as well as their interaction with reactive oxygen species under physiological and pathological conditions. We then revisit the process of Wallerian degeneration, describing the events accompanying axon degeneration, Schwann cell activation and most importantly, macrophage recruitment to the site of injury. Finally, we review these processes in light of internal and external insults to peripheral nerves leading to peripheral neuropathies, the involvement of macrophages and the potential benefit of the targeting of specific macrophages for the alleviation of functional defects in the PNS.
Topics: Animals; Macrophages; Mammals; Peripheral Nerve Injuries; Peripheral Nerves; Schwann Cells; Wallerian Degeneration
PubMed: 35429971
DOI: 10.1186/s12974-022-02454-6