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Journal of Biomechanics Jan 2022Neurite extension is a dynamic process and is dependent on the microenvironment. The mechanical properties of the extracellular matrix (ECM), such as stiffness and...
Neurite extension is a dynamic process and is dependent on the microenvironment. The mechanical properties of the extracellular matrix (ECM), such as stiffness and topography influence the microenvironment and affects neurite extension; however, the mechanistic basis for this dynamic response of neurite extension remains elusive. In this study, we develop a computational model that predicts neurite extension dynamics process as the stiffness and patterned topography of ECM changes. The model includes the contribution of receptors integrin and neural cellular adhesion molecule toward the growth of neurite tip. We use non-linear finite element analysis (FEA) to model the neuronal cell, neurite, and the ECM, which is then coupled to the force-deformation receptor properties obtained from molecular dynamics simulations. Using an empirical relation, we develop a neurite extension algorithm that simulates the dynamic process of growth cone induced by growth cone extension, receptor density, and rupture. We investigate the dependence of neurite extension on ECM stiffness using three distinct materials, the effect of width and spacing of continuous (cylindrical) and discontinuous (pillar) patterned topography, as well as the topography steepness and stiffness gradient. We find that an increasing stiffness and width of patterned topography results in increased neurite extension, but the magnitude of the increase differs depending on the growth cone extension and receptor density between them. These findings will aid in vitro studies in determining an ECM with appropriate mechanical properties, such as stiffness and topography that will improve neurite extension, thus resulting in the formation of functional neurons.
Topics: Extracellular Matrix; Growth Cones; Integrins; Neurites; Neurons
PubMed: 34954524
DOI: 10.1016/j.jbiomech.2021.110897 -
Advanced Biology Jun 2022Dynamic extracellular environments profoundly affect the behavior and function of cells both biochemically and mechanically. Neurite initiation is the first step for...
Dynamic extracellular environments profoundly affect the behavior and function of cells both biochemically and mechanically. Neurite initiation is the first step for neurons to establish intricate neuronal networks. How such a process is modulated by mechanical factors is not fully understood. Particularly, it is unknown whether the molecular clutch model, which has been used to explain cell responses to matrix rigidity, also holds for neurite initiation. To study how mechanical properties modulate neurite initiation, substrates with various well-defined surface viscosities using supported lipid bilayers (SLBs) are synthesized. The results show that ligands with intermediate viscosity greatly maximize neurite initiation in primary neurons, while neurite initiation is drastically limited on substrates with higher or lower viscosity. Importantly, biochemical characterizations reveal altered focal adhesion and calpain activity are associated with distinct neurite initiation patterns. Collectively, these results indicate that neurite initiation is surface viscosity-dependent; there is an optimal range of surface viscosities to drive neurite initiation. Upon binding to ligands of varying viscosities, calpain activity is differentially triggered and leads to distinct levels of neurite outgrowth. These findings not only enhance the understanding of how extracellular environments regulate neurons, but also demonstrate the potential utility of SLBs for neural tissue engineering applications.
Topics: Calpain; Ligands; Lipid Bilayers; Neurites; Neurons; Viscosity
PubMed: 35362269
DOI: 10.1002/adbi.202101325 -
Neurochemical Research Jul 1996Molecules and activities which repulse growing neurites or induce growth cone collapse and long-lasting growth inhibition have been defined over the last 10 years.... (Review)
Review
Molecules and activities which repulse growing neurites or induce growth cone collapse and long-lasting growth inhibition have been defined over the last 10 years. Recently, specific guidance roles for developing axons and pathways could be associated with such repulsive effects. A high molecular weight membrane protein located in CNS myelin acts as potent neurite growth inhibitor and may play a role as a negative control element for sprouting, neurite growth and regeneration, and for the plasticity of the adult CNS. Interestingly, some guidance molecules can have positive, growth-promoting as well as negative, repulsive effects for specific types of neurons. These results underline the complex mechanisms involved in neurite guidance which depends on the interpretation of combinations of incoming signals by particular growth cones.
Topics: Animals; Growth Inhibitors; Nerve Regeneration; Neurites; Neuronal Plasticity
PubMed: 8873079
DOI: 10.1007/BF02532297 -
Current Pharmaceutical Design 2005Prominent among the several endogenous inhibitors known to limit recovery and plasticity after CNS injury are Nogo (neurite outgrowth inhibitor) and MAG (myelin... (Review)
Review
Prominent among the several endogenous inhibitors known to limit recovery and plasticity after CNS injury are Nogo (neurite outgrowth inhibitor) and MAG (myelin associated glycoprotein). The effects of these inhibitors on axonal regeneration can be reduced by administration of specific antagonists, some of which are commercially available for experimental investigation. There are three aspects of therapeutic manipulations: targeting the inhibitory proteins, antagonizing the known receptor, and inhibiting the intracellular signal transduction of these inhibitory molecules. Infusion of an antibody against Nogo improves behavioral deficits and enhances corticospinal tract regeneration in animals after stroke and spinal cord injury (SCI). Similarly, peripheral injection of a mouse monoclonal antibody directed against MAG results in dramatic preferential motor reinnervation in mice after transection of the femoral nerve, indicating that interference with the repellant function of MAG facilitates reinnervation of correct pathways by motor neurons. Further, antagonism of the Nogo receptor by the peptide NEP 1-40 (Nogo extracellular peptide residues 1-40) can promote axonal regeneration in rats after SCI. Blockade of signal transduction also can be effective. The p75 neurotrophin receptor probably represents the signaling part of the receptor complex for neurite growth inhibitors. There is evidence in vitro that the inhibitory actions of MAG and myelin are blocked if neurons are primed with a variety of neurotrophins. Thus, there are several therapeutic approaches to overcome the actions of endogenous neurite growth inhibitors so as to promote CNS regeneration.
Topics: Animals; Central Nervous System Diseases; Drug Delivery Systems; Growth Inhibitors; Humans; Nerve Regeneration; Neurites
PubMed: 15853681
DOI: 10.2174/1381612053507440 -
Biomedical Materials (Bristol, England) Dec 2022Neural networks have been culturedto investigate brain functions and diseases, clinical treatments for brain damage, and device development. However, it remains...
Neural networks have been culturedto investigate brain functions and diseases, clinical treatments for brain damage, and device development. However, it remains challenging to form complex neural network structures with desired orientations and connections. Here, we introduce a dynamic strategy by using diphenylalanine (FF) nanotubes for controlling physical patterns on a substrate to regulate neurite-growth orientation in cultivating neural networks. Parallel FF nanotube patterns guide neurons to develop neurites through the unidirectional FF nanotubes while restricting their polarization direction. Subsequently, the FF nanotubes disassemble and the restriction of neurites disappear, and secondary neurite development of the neural network occurs in other direction. Experiments were conducted that use the hippocampal neurons, and the results demonstrated that the cultured neural networks by using the proposed dynamic approach can form a significant cross-connected structure with substantially more lateral neural connections than static substrates. The proposed dynamic approach for neurite outgrowing enables the construction of oriented innervation and cross-connected neural networksand may explore the way for the bio-fabrication of highly complex structures in tissue engineering.
Topics: Neurites; Neurons; Nanotubes; Neuronal Outgrowth; Cells, Cultured
PubMed: 36541466
DOI: 10.1088/1748-605X/aca737 -
Progress in Brain Research 2005
Review
Topics: Animals; Humans; Models, Neurological; Neurites
PubMed: 15581698
DOI: 10.1016/S0079-6123(04)47006-X -
Cancer Science Sep 2007Wnt signaling consists of a highly conserved set of biochemical pathways that have a multitude of functions during embryonic development and in the adult. The Wnt... (Review)
Review
Wnt signaling consists of a highly conserved set of biochemical pathways that have a multitude of functions during embryonic development and in the adult. The Wnt proteins are extracellular agents that often act as gradient morphogens, indicating that their distribution in tissues is tightly controlled. This attribute is also characteristic of factors that regulate neurite outgrowth and guide axons precisely to their specific destinations. Several studies in various species now have established that Wnts and their receptors have an important role in axonal guidance. Different ligand/receptor combinations have been identified that mediate this activity in many of the experimental models. Clues about downstream effector molecules have come from in vitro systems. In this article, the authors review the results from many of these models, evaluate what is known about the associated signaling pathways and speculate about the direction of future research.
Topics: Animals; Cell Proliferation; Humans; Neurites; Neurons; Signal Transduction; Wnt Proteins
PubMed: 17627619
DOI: 10.1111/j.1349-7006.2007.00536.x -
Geriatrics & Gerontology International Mar 2016β-Amyloid (Aβ) oligomers may play an important role in the early pathogenesis of Alzheimer's disease: cognitive impairment caused by synaptic dysfunction. Dystrophic... (Review)
Review
β-Amyloid (Aβ) oligomers may play an important role in the early pathogenesis of Alzheimer's disease: cognitive impairment caused by synaptic dysfunction. Dystrophic neurites surrounding Aβ plaques, another pathological feature of Alzheimer's disease, are plaque-associated neuritic alterations preceding the appearance of synaptic loss. In the present review, we focus on the mechanism of dystrophic neurite formation by Aß oligomers, and discuss the neurotoxic role of Aβ-induced calsyntenin-3 in mediating dystrophic neurite formation.
Topics: Aged; Alzheimer Disease; Animals; Brain; Calcium-Binding Proteins; Humans; Membrane Proteins; Neurites
PubMed: 27018282
DOI: 10.1111/ggi.12737 -
Philosophical Transactions of the Royal... Feb 1999The extension of neurites is a major task of developing neurons, requiring a significant metabolic effort to sustain the increase in molecular synthesis necessary for... (Review)
Review
The extension of neurites is a major task of developing neurons, requiring a significant metabolic effort to sustain the increase in molecular synthesis necessary for plasma membrane expansion. In addition, neurite extension involves changes in the subsets of expressed proteins and reorganization of the cytomatrix. These phenomena are driven by environmental cues which activate signal transduction processes as well as by the intrinsic genetic program of the cell. The present review summarizes some of the most recent progress made in the elucidation of the molecular mechanisms underlying these processes.
Topics: Animals; Axons; Cell Compartmentation; Cell Differentiation; Cell Polarity; Cytoskeleton; Models, Neurological; Neurites; Signal Transduction
PubMed: 10212488
DOI: 10.1098/rstb.1999.0391 -
Critical Reviews in Toxicology 2008Numerous agents have demonstrated the potential to enhance neuronal repair following spinal cord or peripheral nerve injury using neurite outgrowth as a biomarker for... (Review)
Review
Numerous agents have demonstrated the potential to enhance neuronal repair following spinal cord or peripheral nerve injury using neurite outgrowth as a biomarker for axonal extension in primary cell cultures and neuronal cell lines. This article provides an assessment of the dose-response features of chemically induced neuronal outgrowth in a broad range of experimental models during normal developmental processes, following chemically induced neuronal damage or processes that simulate such damage. These findings indicate that endogenous and exogenous agents, independent of biological model, stimulate central and peripheral nervous system neuronal outgrowths in a biphasic manner consistent with the quantitative features of the hormetic dose-response model. These findings have important clinical implications as they define the plasticity of neurite outgrowth stimulatory responses with respect to the magnitude of enhancement and width of the possible therapeutic zone. The findings also display an essential role for hormetic dose-response relationships in normal neuronal-based developmental and tissue repair processes.
Topics: Animals; Cells, Cultured; Central Nervous System; Dose-Response Relationship, Drug; Humans; Models, Neurological; Nerve Growth Factors; Neurites; Neuroprotective Agents; Peripheral Nervous System; Rats
PubMed: 18432421
DOI: 10.1080/10408440801981981