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Microtubules are highly polar structures and are characterized by high anisotropy and stiffness. In neurons, they play a key role in the directional transport of vesicles and organelles. In the neuronal projections called axons, they form parallel bundles, mostly oriented with the plus-end towards the axonal termination. Their physico-chemical properties have recently attracted attention as a potential candidate in sensing, processing and transducing physical signals generated by mechanical forces. Here, we discuss the main evidence supporting the role of microtubules as a signal hub for axon growth in response to a traction force. Applying a tension to the axon appears to stabilize the microtubules, which, in turn, coordinate a modulation of axonal transport, local translation and their cross-talk. We speculate on the possible mechanisms modulating microtubule dynamics under tension, based on evidence collected in neuronal and non-neuronal cell types. However, the fundamental question of the causal relationship between these mechanisms is still elusive because the mechano-sensitive element in this chain has not yet been identified., (© 2023 the author(s), published by De Gruyter, Berlin/Boston.)

The axon is a sophisticated macromolecular machine composed of interrelated parts that transmit signals like spur gears transfer motion between parallel shafts. The growth cone is a fine sensor that integrates mechanical and chemical cues and transduces these signals through the generation of a traction force that pushes the tip and pulls the axon shaft forward. The axon shaft, in turn, senses this pulling force and transduces this signal in an orchestrated response, coordinating cytoskeleton remodeling and intercalated mass addition to sustain and support the advancing of the tip. Extensive research suggests that the direct application of active force is per se a powerful inducer of axon growth, potentially bypassing the contribution of the growth cone. This review provides a critical perspective on current knowledge of how the force is a messenger of axon growth and its mode of action for controlling navigation, including aspects that remain unclear. It also focuses on novel approaches and tools designed to mechanically manipulate axons, and discusses their implications in terms of potential novel therapies for re-wiring the nervous system., Competing Interests: Declaration of Interest None., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Mechanical force is crucial in guiding axon outgrowth before and after synapse formation. This process is referred to as "stretch growth." However, how neurons transduce mechanical input into signaling pathways remains poorly understood. Another open question is how stretch growth is coupled in time with the intercalated addition of new mass along the entire axon. Here, we demonstrate that active mechanical force generated by magnetic nano-pulling induces remodeling of the axonal cytoskeleton. Specifically, the increase in the axonal density of microtubules induced by nano-pulling leads to an accumulation of organelles and signaling vesicles, which, in turn, promotes local translation by increasing the probability of assembly of the "translation factories." Modulation of axonal transport and local translation sustains enhanced axon outgrowth and synapse maturation., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

New strategies to promote neuronal regeneration should aim to increase the speed of axonal elongation. Biochemical signaling is a key factor in axon growth, but recent discoveries have shown that mechanical force, through a process referred to as stretch growth, can significantly influence the elongation rate. Here, we develop a method to apply forces to primary hippocampal neurons from mice using magnetic microposts that actuate in response to an external magnetic field. Neurons are cultured onto these microposts and subjected to an average displacement of 0.2 μm at a frequency of 5 Hz. We find that the mechanical stimulation promotes an increase in the length of the axons compared to control conditions. In addition, there is an increase in the density of microtubules and in the amount of cisternae of the endoplasmic reticulum, providing evidence that stretch growth is accompanied by a mass addition to the neurite. Together, these results indicate that magnetically-actuated microposts can accelerate the rate of axon growth, paving the way for future applications in neuronal regeneration. VIDEO ABSTRACT., (Copyright © 2021 Biophysical Society. Published by Elsevier Inc. All rights reserved.)

Magnetosomes are membrane-enclosed iron oxide crystals biosynthesized by magnetotactic bacteria. As the biomineralization of bacterial magnetosomes can be genetically controlled, they have become promising nanomaterials for bionanotechnological applications. In the present paper, we explore a novel application of magnetosomes as nanotool for manipulating axonal outgrowth via stretch-growth (SG). SG refers to the process of stimulation of axonal outgrowth through the application of mechanical forces. Thanks to their superior magnetic properties, magnetosomes have been used to magnetize mouse hippocampal neurons in order to stretch axons under the application of magnetic fields. We found that magnetosomes are avidly internalized by cells. They adhere to the cell membrane, are quickly internalized, and slowly degrade after a few days from the internalization process. Our data show that bacterial magnetosomes are more efficient than synthetic iron oxide nanoparticles in stimulating axonal outgrowth via SG.

Introduction: Axonal plasticity is strongly related to neuronal development as well as regeneration. It was recently demonstrated that active mechanical tension, intended as an extrinsic factor, is a valid contribution to the modulation of axonal plasticity. Methods: In previous publications, our team validated a the "nano-pulling" method used to apply mechanical forces to developing axons of isolated primary neurons using magnetic nanoparticles (MNP) actuated by static magnetic fields. This method was found to promote axon growth and synaptic maturation. Here, we explore the use of nano-pulling as an extrinsic factor to promote axon regeneration in a neuronal tissue explant. Results: Whole dorsal root ganglia (DRG) were thus dissected from a mouse spinal cord, incubated with MNPs, and then stretched. We found that particles were able to penetrate the ganglion and thus become localised both in the somas and in sprouting axons. Our results highlight that nano-pulling doubles the regeneration rate, and this is accompanied by an increase in the arborizing capacity of axons, an accumulation of cellular organelles related to mass addition (endoplasmic reticulum and mitochondria) and pre-synaptic proteins with respect to spontaneous regeneration. In line with the previous results on isolated hippocampal neurons, we observed that this process is coupled to an increase in the density of stable microtubules and activation of local translation. Discussion: Our data demonstrate that nano-pulling enhances axon regeneration in whole spinal ganglia exposed to MNPs and external magnetic fields. These preliminary data represent an encouraging starting point for proposing nano-pulling as a biophysical tool for the design of novel therapies based on the use of force as an extrinsic factor for promoting nerve regeneration. [ABSTRACT FROM AUTHOR]

Microtubules are highly polar structures and are characterized by high anisotropy and stiffness. In neurons, they play a key role in the directional transport of vesicles and organelles. In the neuronal projections called axons, they form parallel bundles, mostly oriented with the plus-end towards the axonal termination. Their physico-chemical properties have recently attracted attention as a potential candidate in sensing, processing and transducing physical signals generated by mechanical forces. Here, we discuss the main evidence supporting the role of microtubules as a signal hub for axon growth in response to a traction force. Applying a tension to the axon appears to stabilize the microtubules, which, in turn, coordinate a modulation of axonal transport, local translation and their cross-talk. We speculate on the possible mechanisms modulating microtubule dynamics under tension, based on evidence collected in neuronal and non-neuronal cell types. However, the fundamental question of the causal relationship between these mechanisms is still elusive because the mechano-sensitive element in this chain has not yet been identified. [ABSTRACT FROM AUTHOR]

This document is an editorial published in the journal Frontiers in Molecular Neuroscience. It discusses the role of mechanical forces in axonal mechanics and nerve regeneration. The editorial highlights the importance of understanding the biophysical environment and axonal mechanics in promoting axon regeneration post-injury. It presents several studies that explore the effects of mechanical forces on axonal growth and repair, including the role of microtubules and the actin cytoskeleton. The editorial suggests that the future of nerve repair lies in the integration of chemical signaling and biophysical stimuli. [Extracted from the article]

As olfactory receptor axons grow from the peripheral to the central nervous system (CNS) aided by olfactory ensheathing cells (OECs), the transplantation of OECs has been suggested as a plausible therapy for spinal cord lesions. The problem with this hypothesis is that OECs do not represent a single homogeneous entity, but, instead, a functionally heterogeneous population that exhibits a variety of responses, including adhesion and repulsion during cell-matrix interactions. Some studies report that the migratory properties of OECs are compromised by inhibitory molecules and potentiated by chemical gradients. In this paper, we report a system based on modified OECs carrying magnetic nanoparticles as a proof of concept experiment enabling specific studies aimed at exploring the potential of OECs in the treatment of spinal cord injuries. Our studies have confirmed that magnetized OECs (i) survive well without exhibiting stress-associated cellular responses; (ii) in vitro, their migration can be modulated by magnetic fields; and (iii) their transplantation in organotypic slices of spinal cord and peripheral nerve showed positive integration in the model. Altogether, these findings indicate the therapeutic potential of magnetized OECs for CNS injuries. [ABSTRACT FROM AUTHOR]