Abstract
Investigation of neuromuscular deficits and diseases such as SMA, as well as for next generation prosthetics, utilizing in vitro phenotypic models would benefit from the development of a functional neuromuscular reflex arc. The neuromuscular reflex arc is the system that integrates the proprioceptive information for muscle length and activity (sensory afferent), to modify motoneuron output to achieve graded muscle contraction (actuation efferent). The sensory portion of the arc is composed of proprioceptive sensory neurons and the muscle spindle, which is embedded in the muscle tissue and composed of intrafusal fibers. The gamma motoneurons (γ-MNs) that innervate these fibers regulate the intrafusal fiber’s stretch so that they retain proper tension and sensitivity during muscle contraction or relaxation. This mechanism is in place to maintain the sensitivity of proprioception during dynamic muscle activity and to prevent muscular damage. In this study, a co-culture system was developed for innervation of intrafusal fibers by human γ-MNs and demonstrated by morphological and immunocytochemical analysis, then validated by functional electrophysiological evaluation. This human-based fusimotor model and its incorporation into the reflex arc allows for a more accurate recapitulation of neuromuscular function for applications in disease investigations, drug discovery, prosthetic design and neuropathic pain investigations.
Highlights
There has been a recent emphasis on the development of in vitro “human-on-a-chip” systems for use in drug discovery studies as well as basic cell biology investigations
We aimed to develop a de novo defined human-based functional in vitro fusimotor system in which the innervation of intrafusal fibers by γ-MNs was evaluated by both immunocytochemical and electrophysiological approaches
We have developed a human-based in vitro fusimotor system in which functional innervation of intrafusal fibers by γ-MNs was demonstrated by morphological, immunocytochemical and electrophysiological analysis
Summary
There has been a recent emphasis on the development of in vitro “human-on-a-chip” systems for use in drug discovery studies as well as basic cell biology investigations. We have demonstrated the fundamental sensory portion of the arc by animal and human sensory neuron innervation of intrafusal fibers[12,15]. Further elaboration of this system, by incorporating additional sensory components, allows for a more accurate recapitulation of in vivo functionality and serves as a better representative platform for investigating prosthetic design, neuromuscular diseases and understanding the mechanism of action for relevant drugs and their targets[16,17]. Development and incorporation of this γ-motoneuron - intrafusal fiber system into the reflex arc would provide a better platform for the study of neuromuscular development, prosthetic design, relevant diseases and the evaluation of potential drug candidates. Functional data of postnatal in vitro γ-MNs has yet to be observed and no human systems have been studied
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