Studying Axonal Degeneration and Regeneration Using In Vitro and In Vivo Models: the Translational Potential

Abstract

Since the initial studies by Cajal, multiple models of peripheral nerve degeneration and regeneration have been developed to address the ever-increasing complexity of the mechanisms involved in regeneration. In vitro models offer the principal benefit of a system that can be readily manipulated to address specific mechanistic questions in a deconstructed system. However, in vitro models can be overly simplified and intricacies of the interactions between neurons and glia can be lost. In vivo animal models seek to remedy some of these shortcomings, but most in vivo animal systems fail to precisely model human nerve regeneration. Rodent models of chronic nerve regeneration have been developed to better recapitulate human nerve regeneration, but are not widely used. An important development in the field has been the establishment of experimental nerve regeneration in humans, involving the reinnervation of the epidermis after cutaneous axotomy or topical capsaicin application. Use of such human models will likely accelerate the development and evaluation of new drugs that enhance peripheral nerve regeneration. KeywordsGiven the complexity of the human peripheral nervous system, a wide spectrum of models has been developed over the years to advance the field of axonal degeneration and regeneration. Predominantly, these systems of neuronal degenerative and regenerative processes have been established in model organisms, particularly in rodents and occasionally in subhuman primates. These animal systems have significantly advanced the understanding of the molecular mechanisms of how axons degenerate and regenerate and have provided an initial subject to test novel drug therapies and surgical techniques to improve regeneration after human nerve injuries.In vitro animal models have served to simplify the field of study, reducing the variable factors that are inherently present in whole organism systems. With a range of methods available, there is the potential to study the interactions of neuronal and glial cell populations or with the advent of microtechnologies, to more precisely examine regeneration at the level of the individual axon. Narrowing the lens through which to view degeneration and regeneration, in vitro models permit a greater degree of manipulation and control of the microenvironment and the potential for rapid-paced drug-screening investigations.While in vitro techniques offer highly controllable systems of study, in vivo animal models provide a closer resemblance to the human condition of nerve injury and repair. Investigating the recovery process following nerve injury in living organisms permits a more authentic glimpse into regeneration as whole body system interactions are maintained. Preserving the integrity of the neuronal environment, in vivo animal nerve injury and repair methods model the complexity of the nervous system recovery, but lack some of the precision associated with in vitro methods.Developed over the last few decades, human models of regeneration emerged as a promising novel system t...

Long-Term Cultures of Spinal Cord Interneurons

“…Various in vitro models have been established to explore CNS axon regeneration. These include primary cell cultures created by dissociating neural tissue from animals at various ages (Donaldson and Höke, 2014). Dorsal root ganglia (DRGs) (Cheah et al, 2016), hippocampal (Kaech and Banker, 2006;Moore et al, 2009), and cortical cultures (Koseki et al, 2017) are among the most commonly used models.…”