Profiling sensory neuron microenvironment after peripheral and central axon injury reveals key pathways for axon regeneration

AbstractSensory neurons with cell bodies in dorsal root ganglia (DRG) represent a useful model to study axon regeneration. Whereas regeneration and functional recovery occurs after peripheral nerve injury, spinal cord injury or dorsal root injury is not followed by regenerative outcomes. This results in part from a failure of central injury to elicit a pro-regenerative response in sensory neurons. However, regeneration of sensory axons in peripheral nerves is not entirely cell autonomous. Whether the different regenerative capacities after peripheral or central injury result in part from a lack of response of macrophages, satellite glial cells (SGC) or other non-neuronal cells in the DRG microenvironment remains largely unknown. To answer this question, we performed a single cell transcriptional profiling of DRG in response to peripheral (sciatic nerve crush) and central injuries (dorsal root crush and spinal cord injury). Each cell type responded differently to peripheral and central injuries. Activation of the PPAR signaling pathway in SGC, which promotes axon regeneration after nerve injury, did not occur after central injuries. Treatment with the FDA-approved PPARα agonist fenofibrate, increased axon regeneration after dorsal root injury. This study provides a map of the distinct DRG microenvironment responses to peripheral and central injuries at the single cell level and highlights that manipulating non-neuronal cells could lead to avenues to promote functional recovery after CNS injuries.

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Profiling sensory neuron microenvironment after peripheral and central axon injury reveals key pathways for neural repair

eLife ◽

10.7554/elife.68457 ◽

2021 ◽

Vol 10 ◽

Author(s):

Oshri Avraham ◽

Rui Feng ◽

Eric Edward Ewan ◽

Justin Rustenhoven ◽

Guoyan Zhao ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Peripheral Nerve ◽

Nerve Injury ◽

Peripheral Nerve Injury ◽

Dorsal Root ◽

Axon Regeneration ◽

Cell Type ◽

Root Injury ◽

Cord Injury

Sensory neurons with cell bodies in dorsal root ganglia (DRG) represent a useful model to study axon regeneration. Whereas regeneration and functional recovery occurs after peripheral nerve injury, spinal cord injury or dorsal root injury is not followed by regenerative outcomes. Regeneration of sensory axons in peripheral nerves is not entirely cell autonomous. Whether the DRG microenvironment influences the different regenerative capacities after injury to peripheral or central axons remains largely unknown. To answer this question, we performed a single-cell transcriptional profiling of mouse DRG in response to peripheral (sciatic nerve crush) and central axon injuries (dorsal root crush and spinal cord injury). Each cell type responded differently to the three types of injuries. All injuries increased the proportion of a cell type that shares features of both immune cells and glial cells. A distinct subset of satellite glial cells (SGC) appeared specifically in response to peripheral nerve injury. Activation of the PPARα signaling pathway in SGC, which promotes axon regeneration after peripheral nerve injury, failed to occur after central axon injuries. Treatment with the FDA-approved PPARα agonist fenofibrate increased axon regeneration after dorsal root injury. This study provides a map of the distinct DRG microenvironment responses to peripheral and central injuries at the single-cell level and highlights that manipulating non-neuronal cells could lead to avenues to promote functional recovery after CNS injuries or disease.

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Exercise dependent increase in axon regeneration into peripheral nerve grafts by propriospinal but not sensory neurons after spinal cord injury is associated with modulation of regeneration-associated genes

Experimental Neurology ◽

10.1016/j.expneurol.2015.09.004 ◽

2016 ◽

Vol 276 ◽

pp. 72-82 ◽

Cited By ~ 10

Author(s):

Rahul Sachdeva ◽

Catherine C. Theisen ◽

Vinu Ninan ◽

Jeffery L. Twiss ◽

John D. Houlé

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Peripheral Nerve ◽

Sensory Neurons ◽

Axon Regeneration ◽

Nerve Grafts ◽

Cord Injury ◽

Peripheral Nerve Grafts

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Combinatory repair strategy to promote axon regeneration and functional recovery after chronic spinal cord injury

Scientific Reports ◽

10.1038/s41598-017-09432-6 ◽

2017 ◽

Vol 7 (1) ◽

Cited By ~ 18

Author(s):

Marc A. DePaul ◽

Ching-Yi Lin ◽

Jerry Silver ◽

Yu-Shang Lee

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Functional Recovery ◽

Axon Regeneration ◽

Chronic Spinal Cord Injury ◽

Repair Strategy ◽

Cord Injury

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Nitrous Oxide Impairs Axon Regeneration after Nervous System Injury in Male Rats

Anesthesiology ◽

10.1097/aln.0000000000002906 ◽

2019 ◽

Vol 131 (5) ◽

pp. 1063-1076

Author(s):

Krista J. Stewart ◽

Bermans J. Iskandar ◽

Brenton M. Meier ◽

Elias B. Rizk ◽

Nithya Hariharan ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Nervous System ◽

Nitrous Oxide ◽

Folic Acid ◽

Functional Recovery ◽

Axon Regeneration ◽

Retinal Ganglion ◽

Cord Injury

Abstract Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New Background Nitrous oxide can induce neurotoxicity. The authors hypothesized that exposure to nitrous oxide impairs axonal regeneration and functional recovery after central nervous system injury. Methods The consequences of single and serial in vivo nitrous oxide exposures on axon regeneration in four experimental male rat models of nervous system injury were measured: in vitro axon regeneration in cell culture after in vivo nitrous oxide administration, in vivo axon regeneration after sharp spinal cord injury, in vivo axon regeneration after sharp optic nerve injury, and in vivo functional recovery after blunt contusion spinal cord injury. Results In vitro axon regeneration 48 h after a single in vivo 70% N2O exposure is less than half that in the absence of nitrous oxide (mean ± SD, 478 ± 275 um; n = 48) versus 210 ± 152 um (n = 48; P < 0.0001). A single exposure to 80% N2O inhibits the beneficial effects of folic acid on in vivo axonal regeneration after sharp spinal cord injury (13.4 ± 7.1% regenerating neurons [n = 12] vs. 0.6 ± 0.7% regenerating neurons [n = 4], P = 0.004). Serial 80% N2O administration reverses the benefit of folic acid on in vivo retinal ganglion cell axon regeneration after sharp optic nerve injury (1277 ± 180 regenerating retinal ganglion cells [n = 7] vs. 895 ± 164 regenerating retinal ganglion cells [n = 7], P = 0.005). Serial 80% N2O exposures reverses the benefit of folic acid on in vivo functional recovery after blunt spinal cord contusion (estimate for fixed effects ± standard error of the estimate: folic acid 5.60 ± 0.54 [n = 9] vs. folic acid + 80% N2O 5.19 ± 0.62 [n = 7], P < 0.0001). Conclusions These data indicate that nitrous oxide can impair the ability of central nervous system neurons to regenerate axons after sharp and blunt trauma.

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Nogo-66 Receptor Prevents Raphespinal and Rubrospinal Axon Regeneration and Limits Functional Recovery from Spinal Cord Injury

Neuron ◽

10.1016/j.neuron.2004.10.015 ◽

2004 ◽

Vol 44 (3) ◽

pp. 439-451 ◽

Cited By ~ 209

Author(s):

Ji-Eun Kim ◽

Betty P. Liu ◽

James H. Park ◽

Stephen M. Strittmatter

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Functional Recovery ◽

Axon Regeneration ◽

Cord Injury

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Assessment of Nogo-66 Receptor 1 Function In Vivo After Spinal Cord Injury

Neurosurgery ◽

10.1227/neu.0000000000000337 ◽

2014 ◽

Vol 75 (1) ◽

pp. 51-60 ◽

Cited By ~ 5

Author(s):

Jing Tong ◽

Yi Ren ◽

Xiaowei Wang ◽

Vassilios G. Dimopoulos ◽

Henry N. Kesler ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Matrix Metalloproteinase ◽

Functional Recovery ◽

Axon Regeneration ◽

Matrix Metalloproteinase 9 ◽

Mutant Mice ◽

Locomotor Function ◽

Cord Injury ◽

Metalloproteinase 9

Abstract BACKGROUND: Neuronal Nogo-66 receptor 1 (NgR1) has attracted attention as a converging point for mediating the effects of myelin-associate inhibitory ligands in the central nervous system, establishing the growth-restrictive environment, and limiting axon regeneration after traumatic injury. OBJECTIVE: To investigate the factors that may be contributing to the discrepancy in the importance of NgR1, which has been undermined by several studies that have shown the lack of substantial axon regeneration after spinal cord injury (SCI) in NgR1-knockout or -knockdown animal models. METHODS: We used mice carrying either a homozygous or heterozygous null mutation in the NgR1 gene and subjected them to either a moderate or severe SCI. RESULTS: Locomotor function assessments revealed that the level of functional recovery is affected by the degree of injury suffered. NgR1 ablation enhanced local collateral sprouting in the mutant mice. Reactive astrocytes and chondroitin sulfate proteoglycans (CSPGs) are upregulated surrounding the injury site. Matrix metalloproteinase-9, which has been shown to degrade CSPGs, was significantly upregulated in the homozygous mutant mice compared with the heterozygous or wild-type mice. However, CSPG levels remained higher in the homozygous compared with the heterozygous mice, suggesting that CSPG-degrading activity of matrix metalloproteinase-9 may require the presence of NgR1. CONCLUSION: Genetic ablation of NgR1 may lead to significant recovery in locomotor function after SCI. The difference in locomotor recovery we observed between the groups that suffered various degrees of injury suggests that injury severity may be a confounding factor in functional recovery after SCI.

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