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Nerve bundle formation during the promotion of peripheral nerve regeneration: collagen VI-neural cell adhesion molecule 1 interaction.

ABSTRACT: The formation of nerve bundles, which is partially regulated by neural cell adhesion molecule 1 (NCAM1), is important for neural network organization during peripheral nerve regeneration. However, little is known about how the extracellular matrix (ECM) microenvironment affects this process. Here, we seeded dorsal root ganglion tissue blocks on different ECM substrates of peripheral nerve ECM-derived matrix-gel, Matrigel, laminin 521, collagen I, and collagen IV, and observed well-aligned axon bundles growing in the peripheral nerve ECM-derived environment. We confirmed that NCAM1 is necessary but not sufficient to trigger this phenomenon. A protein interaction assay identified collagen VI as an extracellular partner of NCAM1 in the regulation of axonal fasciculation. Collagen VI interacted with NCAM1 by directly binding to the FNIII domain, thereby increasing the stability of NCAM1 at the axolemma. Our in vivo experiments on a rat sciatic nerve defect model also demonstrated orderly nerve bundle regeneration with improved projection accuracy and functional recovery after treatment with 10 mg/mL Matrigel and 20 μg/mL collagen VI. These findings suggest that the collagen VI-NCAM1 pathway plays a regulatory role in nerve bundle formation. This study was approved by the Animal Ethics Committee of Guangzhou Medical University (approval No. GY2019048) on April 30, 2019.

SUBMITTER: Sun JH

PROVIDER: S-EPMC8552870 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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Nerve bundle formation during the promotion of peripheral nerve regeneration: collagen VI-neural cell adhesion molecule 1 interaction.

Sun Jia-Hui JH Huang Ming M Fang Zhou Z Li Tian-Xiao TX Wu Ting-Ting TT Chen Yi Y Quan Da-Ping DP Xu Ying-Ying YY Wang Yu-Ming YM Yang Yi Y Zou Jian-Long JL

Neural regeneration research 20220501 5

The formation of nerve bundles, which is partially regulated by neural cell adhesion molecule 1 (NCAM1), is important for neural network organization during peripheral nerve regeneration. However, little is known about how the extracellular matrix (ECM) microenvironment affects this process. Here, we seeded dorsal root ganglion tissue blocks on different ECM substrates of peripheral nerve ECM-derived matrix-gel, Matrigel, laminin 521, collagen I, and collagen IV, and observed well-aligned axon b ...[more]

PMID: 34558529

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Project description:Peripheral nerve injury accounts for roughly 2.8% of all trauma patients with an annual cost of 7 billion USD in the U.S. alone. Current treatment options rely on surgical intervention with the use of an autograft, despite associated shortcomings. Engineered nerve guidance conduits, stem cell therapies, and transient electrical stimulation have reported to increase speeds of functional recovery. As an alternative to the conduction effects of electrical stimulation, we have designed and optimized a nerve guidance conduit with aligned microchannels for the sustained release of a small molecule drug that promotes nerve impulse conduction. A biodegradable chitosan structure reinforced with drug-loaded halloysite nanotubes (HNT) was formed into a foam-like conduit with interconnected, longitudinally-aligned pores with an average pore size of 59.3 ± 14.2 μm. The aligned composite with HNTs produced anisotropic mechanical behavior with a Young's modulus of 0.33 ± 0.1 MPa, very similar to that of native peripheral nerve. This manuscript reports on the sustained delivery of 4-Aminopyridine (4AP, molecular weight 94.1146 g/mol), a potassium-channel blocker as a growth factor alternative to enhance the rate of nerve regeneration. The conduit formulation released a total of 30 ± 2% of the encapsulated 4AP in the first 7 days. Human Schwann cells showed elevated expression of key proteins such as nerve growth factor, myelin protein zero, and brain derived neurotrophic factor in a 4AP dose dependent manner. Preliminary in vivo studies in a critical-sized sciatic nerve defect in Wistar rats confirmed conduit suturability and strength to withstand ambulatory forces over 4 weeks of their implantation. Histological evaluations suggest conduit biocompatibility and Schwann cell infiltration and organization within the conduit and lumen. These nerve guidance conduits and 4AP sustained delivery may serve as an attractive strategy for nerve repair and regeneration.

Project description:JOURNAL/nrgr/04.03/01300535-202501000-00035/figure1/v/2024-05-14T021156Z/r/image-tiff Our previous study found that rat bone marrow-derived neural crest cells (acting as Schwann cell progenitors) have the potential to promote long-distance nerve repair. Cell-based therapy can enhance peripheral nerve repair and regeneration through paracrine bioactive factors and intercellular communication. Nevertheless, the complex contributions of various types of soluble cytokines and extracellular vesicle cargos to the secretome remain unclear. To investigate the role of the secretome and extracellular vesicles in repairing damaged peripheral nerves, we collected conditioned culture medium from hypoxia-pretreated neural crest cells, and found that it significantly promoted the repair of sensory neurons damaged by oxygen-glucose deprivation. The mRNA expression of trophic factors was highly expressed in hypoxia-pretreated neural crest cells. We performed RNA sequencing and bioinformatics analysis and found that miR-21-5p was enriched in hypoxia-pretreated extracellular vesicles of neural crest cells. Subsequently, to further clarify the role of hypoxia-pretreated neural crest cell extracellular vesicles rich in miR-21-5p in axonal growth and regeneration of sensory neurons, we used a microfluidic axonal dissociation model of sensory neurons in vitro, and found that hypoxia-pretreated neural crest cell extracellular vesicles promoted axonal growth and regeneration of sensory neurons, which was greatly dependent on loaded miR-21-5p. Finally, we constructed a miR-21-5p-loaded neural conduit to repair the sciatic nerve defect in rats and found that the motor and sensory functions of injured rat hind limb, as well as muscle tissue morphology of the hind limbs, were obviously restored. These findings suggest that hypoxia-pretreated neural crest extracellular vesicles are natural nanoparticles rich in miRNA-21-5p. miRNA-21-5p is one of the main contributors to promoting nerve regeneration by the neural crest cell secretome. This helps to explain the mechanism of action of the secretome and extracellular vesicles of neural crest cells in repairing damaged peripheral nerves, and also promotes the application of miR-21-5p in tissue engineering regeneration medicine.

Project description:BackgroundSchwann cell-like cells (SCLCs), differentiated from mesenchymal stem cells, have shown promising outcomes in the treatment of peripheral nerve injuries in preclinical studies. However, certain clinical obstacles limit their application. Hence, the primary aim of this study was to investigate the role of exosomes derived from SCLCs (SCLCs-exo) in peripheral nerve regeneration.MethodsSCLCs were differentiated from human amniotic mesenchymal stem cells (hAMSCs) in vitro and validated by immunofluorescence, real-time quantitative PCR and western blot analysis. Exosomes derived from hAMSCs (hAMSCs-exo) and SCLCs were isolated by ultracentrifugation and validated by nanoparticle tracking analysis, WB analysis and electron microscopy. A prefabricated nerve graft was used to deliver hAMSCs-exo or SCLCs-exo in an injured sciatic nerve rat model. The effects of hAMSCs-exo or SCLCs-exo on rat peripheral nerve injury (PNI) regeneration were determined based on the recovery of neurological function and histomorphometric variation. The effects of hAMSCs-exo or SCLCs-exo on Schwann cells were also determined via cell proliferation and migration assessment.ResultsSCLCs significantly expressed the Schwann cell markers glial fibrillary acidic protein and S100. Compared to hAMSCs-exo, SCLCs-exo significantly enhanced motor function recovery, attenuated gastrocnemius muscle atrophy and facilitated axonal regrowth, myelin formation and angiogenesis in the rat model. Furthermore, hAMSCs-exo and SCLCs-exo were efficiently absorbed by Schwann cells. However, compared to hAMSCs-exo, SCLCs-exo significantly promoted the proliferation and migration of Schwann cells. SCLCs-exo also significantly upregulated the expression of a glial cell-derived neurotrophic factor, myelin positive regulators (SRY-box transcription factor 10, early growth response protein 2 and organic cation/carnitine transporter 6) and myelin proteins (myelin basic protein and myelin protein zero) in Schwann cells.ConclusionsThese findings suggest that SCLCs-exo can more efficiently promote PNI regeneration than hAMSCs-exo and are a potentially novel therapeutic approach for treating PNI.

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Nerve bundle formation during the promotion of peripheral nerve regeneration: collagen VI-neural cell adhesion molecule 1 interaction.

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Nerve bundle formation during the promotion of peripheral nerve regeneration: collagen VI-neural cell adhesion molecule 1 interaction.

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