Can injured adult CNS axons regenerate by recapitulating development?

Abstract

In the adult mammalian central nervous system (CNS), neurons typically fail to regenerate their axons after injury. During development, by contrast, neurons extend axons effectively. A variety of intracellular mechanisms mediate this difference, including changes in gene expression, the ability to form a growth cone, differences in mitochondrial function/axonal transport and the efficacy of synaptic transmission. In turn, these intracellular processes are linked to extracellular differences between the developing and adult CNS. During development, the extracellular environment directs axon growth and circuit formation. In adulthood, by contrast, extracellular factors, such as myelin and the extracellular matrix, restrict axon growth. Here, we discuss whether the reactivation of developmental processes can elicit axon regeneration in the injured CNS.

Therapeutic repair for spinal cord injury: combinatory approaches to address a multifaceted problem

“…Several families of molecules present in the extracellular matrix (ECM) prevent axon growth including chondroitin sulphate proteoglycans (CSPGs), myelin-associated molecules, ephrins and semaphorins (Miranda et al, 1999;Chen et al, 2000;Willson et al, 2002;Silver & Miller, 2004;Geoffroy & Zheng, 2014;Worzfeld & Offermanns, 2014). Yet even when provided with a growth-permissive environment, central neurons regenerate feebly compared to their peripheral or immature CNS counterparts, indicating that they also have intrinsic growth limiting factors (Hilton & Bradke, 2017). On the brighter side and nearly 100 years on from Cajal's statement that "in adult centres, the nerve paths are something fixed, ended, immutable; everything may die, nothing may be regenerated" (Ramon-Cueto et al, 1998), we now know this statement to be not entirely true.…”

The nerve conditioning lesion: A strategy to enhance nerve regeneration

“…This review provides a comprehensive overview of the CL literature, directed at (1) discussing the mechanisms of and barriers to nerve regeneration influenced by the CL, (2) describing the cellular and molecular pathways implicated in the CL effect, and (3) deliberating on how these insights might be applied clinically. Past review articles have focused primarily on the implications of CLs on regeneration in the central nervous system . However, because the vast majority of nerve repair performed clinically is on peripheral nerves, regeneration in the peripheral nervous system is the primary focus of this review.…”

Regenerative Potential of Carbon Monoxide in Adult Neural Circuits of the Central Nervous System

“…Investigators have tried to discover precise mechanisms to augment the limited ability of CNS neurons to recover normal functions [5,6]. The purpose of this work was to decipher the crucial barriers to regeneration, so that they may be overcome [7]. One critical question regarding the poor regeneration of central axons is whether the low recovery reflects an inability of neurons themselves to grow or an inability of the environment to support axonal growth [5].…”

“…The ability of a CNS neuron to regenerate following injury may be dependent on both its intrinsic growth capacity and the extracellular environment enriched by the cell-cell network [5][6][7]44]. In this section, the intrinsic mechanisms of neuronal axon regeneration will be discussed.…”