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ScRNAseq analysis of mouse L4 whole dorsal root ganglions with and without sciatic nerve crush injury

ABSTRACT: Peripheral sensory neurons with cell body in dorsal root ganglia (DRG) switch to a regenerative state after nerve injury to enable axon regeneration and functional recovery. Studies of nerve injury responses in sensory neurons have revealed signaling and transcriptional mechanisms that increase their intrinsic regenerative capacity. However, the extent to which satellite glial cells (SGC), which completely surround the neuronal soma contribute to these responses remains unexplored. Using single cell RNA-seq, we defined the transcriptional profile of SGC in naïve and injured conditions and identified Fabp7, also known as BLBP, as a novel marker of SGC. We report that nerve injury elicits gene expression changes in SGC, which are mostly related to lipid metabolism, specifically fatty acid synthesis and the peroxisome proliferator-activated receptor (PPAR) signaling. Conditional deletion of Fatty acid synthase (Fasn), the key enzyme in de novo fatty acid synthesis, specifically in SGC, impairs axon regeneration. Treatment with fenofibrate, a PPARa agonist, rescues the impaired regeneration, suggesting that PPRAa, which belongs to a family of lipid regulated transcription factors, functions downstream of fatty acid synthesis in SGC to promote axon regeneration. These results unravel fatty acid synthesis in SGC as a fundamental novel mechanism mediating axon regeneration in mature peripheral nerves.

ORGANISM(S): Mus musculus

PROVIDER: GSE139103 | GEO | 2020/08/23

REPOSITORIES: GEO

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scRNAseq analysis of mouse L4 whole dorsal root ganglions following sciatic nerve cush, dorsal root crush and spinal cord injury

Project description:After an injury in the adult mammalian central nervous system, lesioned axons fail to regenerate. This failure to regenerate contrasts with the remarkable potential of axons to grow following an injury in the peripheral nervous system. Peripheral sensory neurons with cell soma in dorsal root ganglia (DRG) switch to a regenerative state after nerve injury to enable axon regeneration and functional recovery. Decades of research have focused on the signaling pathways elicited by injury in sensory neurons and in Schwann cells that insulate axons as central mechanisms regulating nerve repair. However, neuronal microenvironment is far more complex and is composed of multiple cell types including endothelial, immune and glial cells. Whether the microenvironment surrounding neuronal soma contribute to the poor regenerative outcomes following central injuries remains largely unexplored. To answer this question, we performed a single cell transcriptional profiling of the DRG neuronal microenvironment response to peripheral and central injuries. In dissecting the roles of the microenvironment contribution, we have focused on a poorly studied glia population of Satellite Glial Cells (SGC) surrounding the neuronal cell soma. Upon a peripheral injury, SGC contribute to axon regeneration via Fatty acid synthase (Fasn)-PPARα signaling pathway. Our analysis reveals that in response to central injuries, SGC do not activate the PPAR signaling pathway. However, induction of this pathway with fenofibrate, an FDA- approved PPARα agonist used for dyslipidemia treatment, rescued axon regeneration following an injury to the central nerves. Collectively, our results uncovered a previously unappreciated role of the neuronal microenvironment differential response in central and peripheral injuries.

2021-09-12 | GSE158892 | GEO

scRNAseq analysis of rat and human dorsal root ganglions

Project description:Peripheral sensory neurons located in dorsal root ganglia relay sensory information from the peripheral tissue to the brain. Satellite glial cells (SGC) are unique glial cells that form an envelope completely surrounding each sensory neuron soma. This organization allows for close bi-directional communication between the neuron and it surrounding glial coat. Morphological and molecular changes in SGC have been observed in pathological conditions such as inflammation, chemotherapy-induced neuropathy, viral infection and nerve injuries. SGC play critical roles in neuronal excitability and nociception, as well as contribute to promote axon regeneration. Whether findings made in rodent model systems are relevant to human physiology has not been investigated. Here we present a detailed characterization of SGC across species. We characterized the transcriptional profile of SGC in mouse, rat and human at the single cell level. Our findings suggest that key features of SGC in rodent models are conserved in human. These results support the notion that SGC in the sensory system are largely conserved between species. Our study provides the potential to leverage on rodent and human SGC properties and unravel novel mechanisms and potential targets for treating nerve injuries.

2022-04-14 | GSE169301 | GEO

Self-renewing macrophages in dorsal root ganglia contribute to promote nerve regeneration

Project description:Primary sensory neurons with cell soma in dorsal root ganglia (DRG) project axons in both the peripheral nervous system and the spinal cord. Whereas the peripheral axon can regenerate after injury, the central axon cannot, providing an opportunity to identify the mechanisms that promote axon regeneration. Using this system, multiple intrinsic mechanisms operating in sensory neurons have been shown to promote axon regeneration. Peripheral sensory neurons also benefit from a supportive environment. In particular, macrophages play important roles in nerve regeneration by clearing debris and regulating Schwann cell function at the site of injury in the nerve. Nerve macrophages have been characterized at the molecular level and derive for the most part from infiltrating monocytes. However, the role and origin of macrophages in the DRG remains poorly understood. Following a 14-days treatment with a CSF1R inhibitor, less than 10% of macrophages remained in the DRG. Recovery from this treatment resulted in a dramatic macrophage repopulation, with the number of DRG macrophages reaching level similar to untreated mice three days post injury. These repopulated DRG macrophages contribute to promote axon regeneration. Our scRNA-seq analysis allow in-depth characterization of the repopulated DRG macrophages in response to nerve injury. These data will provide a better understanding of DRG macrophages and the molecular mechanisms by which they contribute to peripheral nerve repair. These studies may lead to new potential targets to promote axon regeneration.

2023-02-07 | GSE190283 | GEO

Rat motor and sensory nerve LC-MSMS

Project description:Peripheral nerve repair and functional recovery depend on the rate of nerve regeneration and the quality of target reinnervation. It is important to fully understand the cellular and molecular basis underlying the specificity of peripheral nerve regeneration, which means the achieving of respective correct pathfinding and accurate target reinnervation for regrowing motor and sensory axons. In this study, a quantitative proteomic technique, based on isobaric tags for relative and absolute quantitation (iTRAQ) was used to profile the protein expression pattern between single motor and sensory nerves at 14 days after peripheral nerve transection. Among a total of 1259 proteins identified, 176 proteins showed the differential expressions between injured motor and sensory nerves. Quantitative real-time RT-PCR and Western blot analysis were applied to validate the proteomic data on representative differentially expressed proteins. Functional categorization indicated that differentially expressed proteins were linked to a diverse array of molecular functions, including axonogenesis, response to axon injury, tissue remodeling, axon ensheathment, cell proliferation and adhesion, vesicle-mediated transport, response to oxidative stress, internal signal cascade, and macromolecular complex assembly, which might play an essential role in peripheral motor and sensory nerve regeneration. Overall, we hope that the proteomic database obtained in this study could serve as a solid foundation for the comprehensive investigation of differentially expressed proteins between injured motor and sensory nerves and for the mechanism elucidation of the specificity of peripheral nerve regeneration.

2020-12-10 | PXD022097 | Pride

Promoting axon regeneration by enhancing the non-coding function of the injury-responsive coding gene Gpr151

Project description:Gene expression profiling in response to nerve injury has been mainly focused on protein functions of coding genes to understand mechanisms of axon regeneration and to identify targets of potential therapeutics for nerve repair. However, the protein functions of several highly injury-induced genes including Gpr151 for regulating the regenerative ability remain unclear. Here we present an alternative approach focused on non-coding functions of the coding genes, which led to the identification of the non-coding function of Gpr151 RNA interacting with RNA-binding proteins such as CSDE1. Gpr151 promotes axon regeneration by the function of its 5’- untranslated region (5’UTR) and expression of an engineered form of the 5’UTR improves regenerative capacity in vitro and in vivo in both sciatic nerve and optic nerve injury models. Our data suggest that searching injury-induced coding genes potentially functioning by their non-coding regions is required for the RNA-based gene therapy for improving axon regeneration.

2021-07-01 | GSE179145 | GEO

MicroRNA-19a-PTEN axis is involved in the developmental decline of axon regenerative capacity in retinal ganglion cells

Project description:Irreversible blindness from glaucoma and optic neuropathies is attributed to retinal ganglion cells (RGCs) losing the ability to regenerate axons. While several transcription factors and proteins have demonstrated enhancement of axon regeneration after optic nerve injury, mechanisms contributing to the age-related decline in axon regenerative capacity remains elusive. Here, we show that microRNAs are differentially expressed during RGC development, and identify microRNA-19a (miR-19a) as a heterochronic marker; developmental decline of miR-19a relieves suppression of PTEN, a key regulator of axon regeneration, and serves as a temporal indicator of decreasing axon regenerative capacity. Intravitreal injection of miR-19a promotes axon regeneration after optic nerve crush in adult mice, and increases axon extension in RGCs isolated from aged human donors. This uncovers a previously unrecognized involvement of the miR-19a-PTEN axis in RGC axon regeneration, and demonstrates therapeutic potential of microRNA-mediated restoration of axon regenerative capacity via intravitreal injection in patients with optic neuropathies.

2020-07-04 | GSE102458 | GEO

Comparative proteomics analysis of growth-primed adult dorsal root ganglia reveals key molecular mediators for peripheral nerve regeneration

Project description:Peripheral nerve injuries due to physical insults or chronic diseases are quite common, yet no pharmacological therapies are available for the effective repair of injured nerves. The slow growth rate of adult nerves and insufficient access to growth factors pose major hurdles in timely reinnervating target tissues and restoring functions after nerve injuries. A better understanding of the molecular changes that occur during the immediate regenerative reprogramming of neurons, stated here as in vivo priming, following nerve injury may reveal ideal candidates for future therapies. Hence, molecular profiling of neuronal soma within the first week of nerve injury has been the gold standard for revealing molecular candidates critical for nerve regeneration. A complementary in vitro regenerative priming approach was recently shown to induce enhanced outgrowth in adult sensory neurons. In this work, we exploited the in vitro priming model to reveal novel candidates for adult nerve regeneration. We performed the whole tissue proteomics analysis of in vitro primed DRGs and compared their molecular profile with that of the in vivo primed, and control DRGs. Through this approach, we identified several commonly and uniquely altered molecules in the in vitro and in vivo primed DRGs that have the potential to modulate adult nerve regrowth. We further validated the growth inducing potential of mesencephalic astrocyte-derived neurotrophic factor (MANF), one of the hits identified in our proteomics analysis, in primary adult sensory neurons. Overall, this study showed that in vitro priming partially reproduces the molecular features in in vivo primed adult sensory neurons. The shortlisted candidates presented here from the two priming approaches may serve as potential therapeutic targets for adult nerve regeneration.

2023-01-06 | PXD031927 | Pride

Activating injury-responsive genes with hypoxia enhances axon regeneration through neuronal HIF-1α

Project description:Injured peripheral neurons successfully activate a pro-regenerative transcriptional program to enable axon regeneration and functional recovery. How transcriptional regulators coordinate the expression of such programs remains unclear. Here we show that hypoxia-inducible factor 1α (HIF-1α) controls multiple injury-induced genes in sensory neurons and contribute to the pre-conditioning lesion effect. Knockdown of HIF-1α in vitro or conditional knockout in vivo impairs sensory axon regeneration. The HIF-1α target gene Vascular Endothelial Growth Factor A (VEGFA) is expressed in injured neurons and contributes to stimulate axon regeneration. Induction of HIF-1α using hypoxia enhances axon regeneration in vitro and in vivo in sensory neurons. Hypoxia also stimulates motor neuron regeneration and accelerates neuromuscular junction reinnervation. This study demonstrates that HIF-1α represents a critical transcriptional regulator in regenerating neurons and suggests hypoxia as a tool to stimulate axon regeneration.

2016-01-21 | GSE73415 | GEO

Transcriptional profiling of adult retinal ganglion cells during optic nerve regeneration

Project description:Objective: To identify genes that are differentially expressed in retinal ganglion cells undergoing axon regeneration after optic nerve injury. Adult mice that express cyan-fluorescent protein (CFP) in RGCs were treated with pro-regenerative treatment after optic nerve injury. The treated RGCs were selected by FACS (CFP+mcherry) and their RNA profiles were analyzed.

2020-12-29 | GSE142881 | GEO

Signaling to Transcription Networks in the Neuronal Retrograde Injury Response

Project description:Retrograde signaling from axon to soma activates intrinsic regeneration mechanisms in lesioned peripheral sensory neurons; however, the links between axonal injury signaling and the cell body response are not well understood. Here, we used phosphoproteomics and microarrays to implicate ~900 phosphoproteins in retrograde injury signaling in rat sciatic nerve axons in vivo and ~4500 transcripts in the in vivo response to injury in the dorsal root ganglia. Computational analyses of these data sets identified ~400 redundant axonal signaling networks connected to 39 transcription factors implicated in the sensory neuron response to axonal injury. Experimental perturbation of individual overrepresented signaling hub proteins, including Abl, AKT, p38, and protein kinase C, affected neurite outgrowth in sensory neurons. Paradoxically, however, combined perturbation of Abl together with other hub proteins had a reduced effect relative to perturbation of individual proteins. Our data indicate that nerve injury responses are controlled by multiple regulatory components, and suggest that network redundancies provide robustness to the injury response Microarrays were run on mRNA extracted from adult rat L4 and L5 DRGs cells after 1,3,8,12,16,18,24, and 28 hours after a sciatic nerve (proximal and distal) lesion.

2010-12-29 | E-GEOD-26350 | biostudies-arrayexpress

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