Unleashing Intrinsic Growth Pathways in Regenerating Peripheral Neurons

Abstract

Common mechanisms of peripheral axon regeneration are recruited following diverse forms of damage to peripheral nerve axons. Whether the injury is traumatic or disease related neuropathy, reconnection of axons to their targets is required to restore function. Supporting peripheral axon regrowth, while not yet available in clinics, might be accomplished from several directions focusing on one or more of the complex stages of regrowth. Direct axon support, with follow on participation of supporting Schwann cells is one approach, emphasized in this review. However alternative approaches might include direct support of Schwann cells that instruct axons to regrow, manipulation of the inflammatory milieu to prevent ongoing bystander axon damage, or use of inflammatory cytokines as growth factors. Axons may be supported by a growing list of growth factors, extending well beyond the classical neurotrophin family. The understanding of growth factor roles continues to expand but their impact experimentally and in humans has faced serious limitations. The downstream signaling pathways that impact neuron growth have been exploited less frequently in regeneration models and rarely in human work, despite their promise and potency. Here we review the major regenerative signaling cascades that are known to influence adult peripheral axon regeneration. Within these pathways there are major checkpoints or roadblocks that normally check unwanted growth, but are an impediment to robust growth after injury. Several molecular roadblocks, overlapping with tumour suppressor systems in oncology, operate at the level of the perikarya. They have impacts on overall neuron plasticity and growth. A second approach targets proteins that largely operate at growth cones. Addressing both sites might offer synergistic benefits to regrowing neurons. This review emphasizes intrinsic aspects of adult peripheral axon regeneration, emphasizing several molecular barriers to regrowth that have been studied in our laboratory.

Emerging role of extracellular vesicles and exogenous stimuli in molecular mechanisms of peripheral nerve regeneration

“…Growth cone formation and axonal elongation have been associated with the PI3K/pAkt/mTOR signaling pathway ( Agthong et al, 2006 ; Hur and Saijilafu, 2012 ; Menorca et al, 2013 ; Poitras and Zochodne, 2022 ). To initiate this pathway, neurotrophic molecules bind to Trk receptors, transducing signals through the cellular membrane.…”

“…This pathway is controlled by the mTOR effector, which facilitates PNR. Downstream activation of mTOR complex-1 (mTORC1), a mediator of growth factor signaling, occurs via Akt-mediated phosphorylation to ensure cell survival and neuronal growth, as shown in Figure 1 ( Aoki and Fujishita, 2017 ; Abe et al, 2021 ; Poitras and Zochodne, 2022 ). The PI3K/Akt/mTOR pathway must be tightly regulated, as its overactivation can lead to uncontrolled cellular proliferation and tumor formation instead of regulated regeneration ( Liu et al, 2014 ; Aoki and Fujishita, 2017 ; Poitras and Zochodne, 2022 ).…”

“…Another pathway contributing to neuronal plasticity, axonal guidance, and regeneration is the JAK/STAT, as shown in Figure 2Aii . Unlike many regulatory pathways, JAK/STAT is not activated by neurotrophic Trk receptors, but rather by a G-protein-coupled receptor that binds neurotrophic factors, such as ciliary neurotrophic factor (CNTF), NT3, and BDNF, to initiate the signaling cascade ( Sheu et al, 2000 ; Qiu et al, 2005 ; Kiryu-Seo and Kiyama, 2011 ; Poitras and Zochodne, 2022 ). These neurotrophic factors upregulate STAT3 in SCs, which subsequently enhances growth factor secretion and neurite sprouting ( Aoki and Fujishita, 2017 ; Poitras and Zochodne, 2022 ).…”

The Dynamics of Nerve Degeneration and Regeneration in a Healthy Milieu and in Diabetes

“…The efficiency of axonal regeneration depends on a variety of factors, including the intrinsic capacity of neurons to regrow their axons after nerve injury, the rate of the neuronal synthesis of proteins and cytoskeletal organization, and the conditions of the environment in the denervated distal nerve stumps in which the axons intend to grow [20,[33][34][35][36][37]. Contact attraction and contact repulsion and chemoattraction and chemorepulsion mechanisms direct the growth of the axonal growth cones in the extracellular matrix (ECM) at the site of injury and within the denervated nerve end [38].…”