Manipulation of Axonal Outgrowth via Exogenous Low Forces

Abstract

Neurons are mechanosensitive cells. The role of mechanical force in the process of neurite initiation, elongation and sprouting; nerve fasciculation; and neuron maturation continues to attract considerable interest among scientists. Force is an endogenous signal that stimulates all these processes in vivo. The axon is able to sense force, generate force and, ultimately, transduce the force in a signal for growth. This opens up fascinating scenarios. How are forces generated and sensed in vivo? Which molecular mechanisms are responsible for this mechanotransduction signal? Can we exploit exogenously applied forces to mimic and control this process? How can these extremely low forces be generated in vivo in a non-invasive manner? Can these methodologies for force generation be used in regenerative therapies? This review addresses these questions, providing a general overview of current knowledge on the applications of exogenous forces to manipulate axonal outgrowth, with a special focus on forces whose magnitude is similar to those generated in vivo. We also review the principal methodologies for applying these forces, providing new inspiration and insights into the potential of this approach for future regenerative therapies.

Induction of Axonal Outgrowth in Mouse Hippocampal Neurons via Bacterial Magnetosomes

“…Neurons are mechanosensitive cells, and the application of extremely low force positively modulate axonal elongation, neurite branching, and neuron maturation [5,[58][59][60][61][62][63][64][65]. Many studies demonstrated that magnetic nanoparticles are an efficient tool for magnetizing axons, and the subsequent application of a magnetic field gradient can generate such extremely low forces that drive productive axonal outgrowth [5,6,56,66,67].…”

Neuromechanobiology: An Expanding Field Driven by the Force of Greater Focus

“…[78][79][80] There is a large body of literature on these topics and the interested reader is referred to several recent reviews for more details. [6,13,72,81]…”

“…[395,396] In general, force is a potent stimulus for axonal growth, with the elongation rate being directly proportional to the magnitude of tension. [6,397] From a translation perspective, one immediate application of stretch growth is ex vivo development of elongated nerve conduits that are ready to transplant for peripheral nerve repair. [398] Interestingly, in models of cyclic low magnitude strain, it was shown that glial cells exhibited signs of inflammatory reactive gliosis, and neurons became vulnerable to apoptosis.…”

“…However, there was little examination of the role of mechanical stimuli in the function of the nervous system until much later, perhaps because for a long time the brain had not intuitively been thought of as a mechanically rich environment (which it is as shown later). In 1941, Weiss hypothesized that the growth of an animal's body places axons in a condition of stretching that could be responsible for axonal growth following synaptogenesis, [5,6] yet this hypothesis was not directly tested until the 1970's when mechanical aspects of the nervous system were considered and tested (Figure 1). Central nervous system (CNS) tissue is one of the softest tissues in the body, and in the absence of the arachnoid membranes, blood vessels, and skull, would collapse under its own weight.…”

Unraveling Axon Guidance during Axotomy and Regeneration

“…In addition to adhesive molecules and chemical signals, the mechanical forces to which the growth cone is subjected determine the growth cone movements as well [ 16 , 17 ]. For example, some axons, such as the ones from Xenopus retinal ganglion cells, are guided from stiffer to softer surfaces, showing straight and fast movement in stiffer surfaces, turning when exposed to stiffness gradients, and showing slower movement accompanied by increased growth cone area in softer surfaces [ 18 ], most probably due to changes in point contacts and thus growth cone traction forces.…”