Satellite glial contact enhances differentiation and maturation of human induced sensory neurons
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ABSTRACT:
PROVIDER: PRJNA1139153 | ENA |
REPOSITORIES: ENA
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Project description:Induced sensory neurons (iSNs) generated from pluripotent stem cells are used to model human peripheral neuropathies, however current differentiation protocols produce sensory neurons with an embryonic phenotype. Peripheral glial cells contact sensory neurons early in development and contribute to formation of the canonical pseudounipolar morphology, but these signals are not encompassed in current iSN differentiation protocols. Here, we show that terminal differentiation of iSNs in co-culture with rodent Dorsal Root Ganglion satellite glia (rSG) advances their differentiation and maturation. Co-cultured iSNs develop pseudounipolar morphology through contact with rSGs. This transition depends on semaphorin-plexin guidance cues and on glial gap junction signaling. In addition to morphological changes, iSNs terminally differentiated in co-culture exhibit enhanced spontaneous action potential firing, more mature gene expression, and increased susceptibility to paclitaxel induced axonal degeneration. Thus, iSNs differentiated in coculture with rSGs provide a better model for understanding human peripheral neuropathies.
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Project description:Diversity of satellite glia in sympathetic and sensory ganglia
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Project description:Although satellite glial cells (SGCs) are among the most abundant non-neuronal cells in dorsal root ganglia (DRG), little is known about their heterogenity and functions. We used single cell RNA sequencing (scRNA-seq) to analyze the heterogenity and unique functions of SGCs.
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Project description:Dorsal root ganglia (DRG) play a crucial role in processing sensory information, making it essential to understand their development. Here, we construct a single-cell spatiotemporal transcriptomic atlas of human embryonic DRG. This atlas reveals the diversity of cell types and highlights the extrinsic signaling cascades and intrinsic regulatory hierarchies that guide cell fate decisions, including neuronal/glial lineage restriction, sensory neuron differentiation and specification, and the formation of neuron-satellite glial cell (SGC) unit. Additionally, we identify a human-enriched NTRK3+/DCC+ nociceptor subtype, which is involved in multimodal nociceptive processing. Mimicking the programmed activation of signaling pathways in vivo, we successfully establish functional human DRG organoids and underscore the critical roles of transcriptional regulators in the fate commitment of unspecialized sensory neurons (uSNs). Overall, our research elucidates the multilevel signaling pathways and transcription factor (TF) regulatory hierarchies that underpin the diversity of somatosensory neurons, emphasizing the phenotypic distinctions in human nociceptor subtypes.
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Project description:The recent advance in single cell RNAseq technologies has enabled a new approach to investigate satellite glial cells (SGCs). Here we publish a dataset from mice subjected to sciatic nerve injury as well as a dataset from dorsal root ganglia cells after 3 days in culture. We use a meta-analysis approach to compare the injury response with that in other published datasets and conclude that SGCs share a common signature following sciatic nerve crush and sciatic ligation, involving transcriptional regulation of cholesterol biosynthesis. We also observed a considerable transcriptional change when culturing SGCs, suggesting that some differentiate into a specialised in vitro state, while others start resembling Schwann cell-like precursors.
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Project description:PNS injuries initiate transcriptional changes in glial cells and sensory neurons that promote axonal regeneration. While the factors that initiate the transcriptional changes in glial cells are well characterized, the full range of stimuli that initiate the response of sensory neurons remain elusive. Here, using a genetic model of glial cell ablation, we find that glial cell loss results in transient PNS demyelination without overt axonal loss. By profiling sensory ganglia at single-cell resolution we show that glial cell loss induces a transcriptional injury response preferentially in proprioceptive and Aβ RA-LTMR neurons. The transcriptional response of sensory neurons to mechanical injury has been assumed to be a cell autonomous response. By identifying a similar response in non-injured, demyelinated neurons, our study suggests that this represents a non-cell autonomous transcriptional response of sensory neurons to the loss of axon-glial cell interactions.
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Project description:Peripheral sensory neurons regenerate their axon after nerve injury to enable functional recovery. Intrinsic mechanisms operating in sensory neurons are known to regulate nerve repair, but whether satellite glial cells (SGC), which completely envelop the neuronal soma, contribute to nerve regeneration remains unexplored. Using a single cell RNAseq approach, we reveal that SGC are distinct from Schwann cells and share similarities with astrocytes. Nerve injury elicits changes in the expression of genes related to fatty acid synthesis and peroxisome proliferator-activated receptor (PPARα) signaling. Conditional deletion of fatty acid synthase (Fasn) in SGC impairs axon regeneration. The PPARα agonist fenofibrate rescues the impaired axon regeneration in mice lacking Fasn in SGC. These results indicate that PPARα activity downstream of FASN in SGC contributes to promote axon regeneration in adult peripheral nerves and highlight that the sensory neuron and its surrounding glial coat form a functional unit that orchestrates nerve repair.
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Project description:G protein-coupled receptor 37-like 1 (GPR37L1) is an orphan GPCR, and its function remains largely unknown. Here we report that Gpr37l1 and GPR37L1 are among the most highly expressed GPCR transcripts in mouse and human dorsal root ganglia (DRGs) and are selectively expressed in satellite glial cells (SGCs). Peripheral neuropathy following PTX-induced pain resulted in a downregulation of GPR37L1 plasma membrane expression in DRGs. Transgenic mice with Gpr37l1 deficiency exhibited impaired resolution of neuropathic pain symptoms following PTX-induced pain, whereas overexpression of Gpr37l1 in mouse DRGs reversed pain. GPR37L1 regulates the surface expression and function of these potassium channels. Thus, GPR37L1 in SGCs offers a new target for neuropathy protection and pain control.
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