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

Abstract

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. 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.

IL-33 signaling in sensory neurons promotes dry skin itch

“…To address this, we analyzed a single-cell RNA-Seq data set of naive mouse DRG (Fig 1 , I). 7 We found that Il1rl1 was indeed expressed by another cell type: DRG macrophages (Fig 1 , J). Similarly, analysis of other neuronally expressed itch-associated cytokine receptors, such as Il4ra, 8 revealed expression across numerous cell types ( Fig 1,K).…”

Diversity of satellite glia in sympathetic and sensory ganglia

“…To date, limited studies suggest that satellite glia modulate ionic and neurotransmitter concentrations, promote neuronal morphogenesis, regulate synaptic transmission, and engulf dying neurons (Avraham et al, 2020;Enes et al, 2020;Hanani and Spray, 2020;Wu et al, 2009). Recent studies in sensory ganglia indicate that satellite glia regulate chronic pain through modulating neuronal excitability and promote axon regeneration after nerve injury (Avraham et al, 2020(Avraham et al, , 2021Jager et al, 2020;Kim et al, 2016).…”

Profiling the molecular signature of Satellite Glial Cells at the single cell level reveals high similarities between rodent and human

“…Our previous study demonstrated that SGC contribute to the nerve repair process in mice (Avraham, Deng, et al, 2020) and that the FDA approved PPARα agonist fenofibrate, which is used in dyslipidemia treatment, can increase axon regeneration after the dorsal root injury, a model of poor sensory axon growth (Avraham, Feng, et al, 2020). Fenofibrate was surprisingly shown in clinical trials to have neuroprotective effects in diabetic retinopathy (Bogdanov, Hernandez, Corraliza, Carvalho, & Simo, 2015;Moreno & Ceru, 2015) and traumatic brain injury (Chen et al, 2007).…”

“…1a). We chose to perform scRNAseq in rodents because we previously showed that this method efficiently captures SGC (Avraham, Deng, et al, 2020;Avraham, Feng, Ewan, Zhao, & Cavalli, 2020). We opted for snRNAseq in human DRG because the tissue was frozen and the large size of cells in human may limit their capture rate in the 10x platform.…”