A cellular taxonomy of the adult human spinal cord

Yadav, Archana; Matson, Kaya J.E.; Li, Li; Hua, Isabelle; Petrescu, Joana; Kang, Kristy; Alkaslasi, Mor R.; Lee, Dylan I.; Hasan, Saadia; Galuta, Ahmad; Dedek, Annemarie; Ameri, Sara; Parnell, Jessica; Alshardan, Mohammad; Qumqumji, Feras Abbas; Alhamad, Saud M.; Wang, Alick Pingbei; Poulen, Gaëtan; Lonjon, Nicolas; Vachiéry-Lahaye, Florence; Gaur, Pallavi; Nalls, Mike A.; Qi, Yue; Maric, Dragan; Ward, Michael E.; Hildebrand, Michael E.; Méry, Pierre‐François; Bourinet, Emmanuel; Bauchet, Luc; Tsai, Eve C.; Phatnani, Hemali; Pichon, Claire E. Le; Menon, Vilas; Levine, Ariel J.

doi:10.1016/j.neuron.2023.01.007

Cited by 93 publications

(111 citation statements)

References 94 publications

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“…SCN9A+ and TACR1+ co-expressing neurons were more densely populated in laminae 1-2 (FIG1I). This distribution closely resembles recently published human spinal cord spatial transcriptomic data(Yadav et al, 2023) in which both SCN9A and TACR1 mRNAs were found throughout the dorsal and ventral horns (FIG2A). SCN9A was detected in a broad population of excitatory and inhibitory dorsal horn neurons using single-nucleus RNA sequencing of human spinal cord(Yadav et al, 2023), many of which co-expressed TACR1 (FIG2B).…”

supporting

confidence: 89%

“…It is important to note that not all rodent projection neurons are Tacr1 + (Nk1r+), and interneurons as well as motor neurons express this gene (Russ et al, 2021). Single-nucleus RNA sequencing recapitulates this expression pattern as SCN9A and TACR1 mRNAs were co-expressed in a wide range of human spinal neuronal populations, including motor neurons (Yadav et al, 2023). The high density of the signal in known projection-neuron enriched lamina, as well as the large size profile of the neurons supports that a subset of these SCN9A / TACR1 co-expressing neurons are likely projection neurons.…”

Section: Discussionmentioning

confidence: 87%

“…Gain-of-function mutations in SCN9A could lead to increased excitability of projection neurons, which would be further amplified by increased nociceptive input from hyperexcitable nociceptors in the periphery. However, this mechanistic hypothesis may not be as straightforward as this because SCN9A mRNA was found in many neurons in the dorsal horn, including inhibitory interneurons by single-nuclear sequencing (Yadav et al, 2023). Nevertheless, dysregulated circuit dynamics in the dorsal horn caused by gain-of-function mutations in Nav1.7 potentially explain the difference in pain phenotype between humans and rodents.…”

Section: Discussionmentioning

confidence: 99%

“…We assessed the distribution of SCN9A (Na V 1.7) and TACR1 (Nk1r) mRNA in the human spinal dorsal horn using RNAscope. We found that SCN9A and TACR1 mRNAs were detected in cells throughout all laminae in the human spinal dorsal horn (FIG 1A-E A) Normalized spatial transcriptomic gene expression for SCN9A and TACR1 per barcoded spot on aggregated human lumbar spinal cord sections (Yadav et al, 2023). Solid lines mark grey matter boundaries.…”

Section: Scn9a Mrna Is Expressed In Tacr1+ Putative Projection Neuron...mentioning

confidence: 95%

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Na_V1.7 mRNA and protein expression in putative projection neurons of the human spinal dorsal horn

Shiers

Funk²,

Cervantes³

et al. 2023

Preprint

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NaV1.7, a membrane-bound voltage-gated sodium channel, is preferentially expressed along primary sensory neurons, including their peripheral & central nerve endings, axons, and soma within the dorsal root ganglia and plays an integral role in amplifying membrane depolarization and pain neurotransmission. Loss- and gain-of-function mutations in the gene encoding NaV1.7, SCN9A, are associated with a complete loss of pain sensation or exacerbated pain in humans, respectively. As an enticing pain target supported by human genetic validation, many compounds have been developed to inhibit NaV1.7 but have disappointed in clinical trials. The underlying reasons are still unclear, but recent reports suggest that inhibiting NaV1.7 in central terminals of nociceptor afferents is critical for achieving pain relief by pharmacological inhibition of NaV1.7. We report for the first time that NaV1.7 mRNA is expressed in putative projection neurons (NK1R+) in the human spinal dorsal horn, predominantly in lamina 1 and 2, as well as in deep dorsal horn neurons and motor neurons in the ventral horn. NaV1.7 protein was found in the central axons of sensory neurons terminating in lamina 1-2, but also was detected in the axon initial segment of resident spinal dorsal horn neurons and in axons entering the anterior commissure. Given that projection neurons are critical for conveying nociceptive information from the dorsal horn to the brain, these data support that dorsal horn NaV1.7 expression may play an unappreciated role in pain phenotypes observed in humans with genetic SCN9A mutations, and in achieving analgesic efficacy in clinical trials.

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supporting

confidence: 89%

Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Section: Scn9a Mrna Is Expressed In Tacr1+ Putative Projection Neuron...mentioning

confidence: 95%

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Na_V1.7 mRNA and protein expression in putative projection neurons of the human spinal dorsal horn

Shiers

Funk²,

Cervantes³

et al. 2023

Preprint

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“…However, our findings apparently provide the first evidence that activating dorsal horn inhibitory interneurons can suppress heat hypersensitivity, in addition to cold and mechanical allodynia, in persistent pain states. A population of NPY-expressing inhibitory interneurons with a similar laminar location has recently been identified in human spinal cord 62 . These cells therefore provide an attractive target for the treatment of neuropathic pain, particularly for the significant cohort of patients who experience thermal hyperalgesia 63 .…”

Section: Discussionmentioning

confidence: 83%

Neuropeptide Y-expressing dorsal horn inhibitory interneurons gate spinal pain and itch signalling

Boyle

Polgár

Gutièrrez‐Mecinas

et al. 2023

Preprint

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Somatosensory information is processed by a complex network of interneurons in the spinal dorsal horn. It has been reported that inhibitory interneurons that express neuropeptide Y (NPY), either permanently or during development, suppress mechanical itch, with no effect on pain. Here we investigate the role of interneurons that continue to express NPY (NPY-INs) in adulthood. We find that chemogenetic activation of NPY-INs reduces behaviours associated with acute pain and pruritogen evoked itch, whereas silencing them causes exaggerated itch responses that depend on cells expressing the gastrin-releasing peptide receptor. As predicted by our previous studies, silencing of another population of inhibitory interneurons (those expressing dynorphin) also increases itch, but to a lesser extent. Importantly, NPY IN activation also reduces behavioural signs of inflammatory and neuropathic pain. These results demonstrate that NPY-INs gate pain and itch transmission at the spinal level, and therefore represent a potential treatment target for pathological pain and itch.

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Symmetry Breaking of Human Pluripotent Stem Cells (hPSCs) in Micropattern Generates a Polarized Spinal Cord‐Like Organoid (pSCO) with Dorsoventral Organization

et al. 2023

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Axis formation and related spatial patterning are initiated by symmetry breaking during development. A geometrically confined culture of human pluripotent stem cells (hPSCs) mimics symmetry breaking and cell patterning. Using this, polarized spinal cord organoids (pSCOs) with a self-organized dorsoventral (DV) organization are generated. The application of caudalization signals promoted regionalized cell differentiation along the radial axis and protrusion morphogenesis in confined hPSC colonies. These detached colonies grew into extended spinal cord-like organoids, which established self-ordered DV patterning along the long axis through the spontaneous expression of polarized DV patterning morphogens. The proportions of dorsal/ventral domains in the pSCOs can be controlled by the changes in the initial size of micropatterns, which altered the ratio of center-edge cells in 2D. In mature pSCOs, highly synchronized neural activity is separately detected in the dorsal and ventral side, indicating functional as well as structural patterning established in the organoids. This study provides a simple and precisely controllable method to generate spatially ordered organoids for the understanding of the biological principles of cell patterning and axis formation during neural development.

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A cellular taxonomy of the adult human spinal cord

Cited by 93 publications

References 94 publications

Na_V1.7 mRNA and protein expression in putative projection neurons of the human spinal dorsal horn

Na_V1.7 mRNA and protein expression in putative projection neurons of the human spinal dorsal horn

Neuropeptide Y-expressing dorsal horn inhibitory interneurons gate spinal pain and itch signalling

Symmetry Breaking of Human Pluripotent Stem Cells (hPSCs) in Micropattern Generates a Polarized Spinal Cord‐Like Organoid (pSCO) with Dorsoventral Organization

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A cellular taxonomy of the adult human spinal cord

Cited by 93 publications

References 94 publications

NaV1.7 mRNA and protein expression in putative projection neurons of the human spinal dorsal horn

NaV1.7 mRNA and protein expression in putative projection neurons of the human spinal dorsal horn

Neuropeptide Y-expressing dorsal horn inhibitory interneurons gate spinal pain and itch signalling

Symmetry Breaking of Human Pluripotent Stem Cells (hPSCs) in Micropattern Generates a Polarized Spinal Cord‐Like Organoid (pSCO) with Dorsoventral Organization

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Product

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Na_V1.7 mRNA and protein expression in putative projection neurons of the human spinal dorsal horn

Na_V1.7 mRNA and protein expression in putative projection neurons of the human spinal dorsal horn