A cellular taxonomy of the adult human spinal cord

Neuron, Год журнала: 2023, Номер 111(3), С. 328 - 344.e7

Опубликована: Фев. 1, 2023

The mammalian spinal cord functions as a community of cell types for sensory processing, autonomic control, and movement. While animal models have advanced our understanding cellular diversity, characterizing human biology directly is important to uncover specialized features basic function pathology. Here, we present taxonomy the adult using single-nucleus RNA sequencing with spatial transcriptomics antibody validation. We identified 29 glial clusters 35 neuronal clusters, organized principally by anatomical location. To demonstrate relevance this resource disease, analyzed motoneurons, which degenerate in amyotrophic lateral sclerosis (ALS) other diseases. found that compared neurons, motoneurons are defined genes related size, cytoskeletal structure, ALS, suggesting molecular repertoire underlying their selective vulnerability. include web facilitate further investigations into biology.

Язык: Английский

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Age-dependent immune and lymphatic responses after spinal cord injury

Neuron, Год журнала: 2023, Номер 111(14), С. 2155 - 2169.e9

Опубликована: Май 5, 2023

Язык: Английский

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Neuronal maturation and axon regeneration: unfixing circuitry to enable repair

Nature reviews. Neuroscience, Год журнала: 2024, Номер 25(10), С. 649 - 667

Опубликована: Авг. 20, 2024

Язык: Английский

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Defining the molecular identity and morphology of glia limitans superficialis astrocytes in vertebrates

Cell Reports, Год журнала: 2025, Номер 44(3), С. 115344 - 115344

Опубликована: Фев. 20, 2025

Язык: Английский

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Single-cell analysis reveals region-heterogeneous responses in rhesus monkey spinal cord with complete injury

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Авг. 9, 2023

Spinal cord injury (SCI) leads to severe sensory and motor dysfunction below the lesion. However, cellular dynamic responses heterogeneity across different regions lesion remain be elusive. Here, we used single-cell transcriptomics investigate region-related in female rhesus monkeys with complete thoracic SCI from acute chronic phases. We found that distal lumbar tissue cells were severely impacted, leading degenerative microenvironments characterized by disease-associated microglia oligodendrocytes activation alongside increased inhibitory interneurons proportion following SCI. By implanting scaffold into sites, could improve microenvironment through glial fibroblast regulation while remodeling spared tissues via reduced neurons improved phagocytosis myelination. Our findings offer crucial pathological insights proximal after SCI, emphasizing importance of scaffold-based treatment approaches targeting heterogeneous microenvironments.

Язык: Английский

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Spatiotemporal transcriptomic map of glial cell response in a mouse model of acute brain ischemia

Proceedings of the National Academy of Sciences, Год журнала: 2024, Номер 121(46)

Опубликована: Ноя. 5, 2024

The role of nonneuronal cells in the resolution cerebral ischemia remains to be fully understood. To decode key molecular and cellular processes that occur after ischemia, we performed spatial single-cell transcriptomic profiling male mouse brain during first week injury. Cortical gene expression was severely disrupted, defined by inflammation cell death lesion core, glial scar formation orchestrated multiple types on periphery. identified as a zone with intense cell–cell communication, prominent ApoE-Trem2 signaling pathway modulating microglial activation. For each three major populations, an inflammatory-responsive state, resembling reactive states observed neurodegenerative contexts, observed. recovered spectrum ischemia-induced oligodendrocyte supports emerging hypothesis oligodendrocytes actively respond modulate neuroinflammatory stimulus. findings are further supported analysis other datasets from different models ischemic Collectively, present landmark dataset accompanied interactive visualization provides comprehensive view spatiotemporal organization postischemic brain.

Язык: Английский

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Repopulated spinal cord microglia exhibit a unique transcriptome and contribute to pain resolution

Cell Reports, Год журнала: 2024, Номер 43(2), С. 113683 - 113683

Опубликована: Янв. 22, 2024

Microglia are implicated as primarily detrimental in pain models; however, they exist across a continuum of states that contribute to homeostasis or pathology depending on timing and context. To clarify the specific contribution microglia progression, we take advantage temporally controlled transgenic approach transiently deplete microglia. Unexpectedly, observe complete resolution coinciding with microglial repopulation rather than depletion. We find repopulated mouse spinal cord morphologically distinct from control exhibit unique transcriptome. Repopulated males females express overlapping networks genes related phagocytosis response stress. intersect identified single-nuclei dataset human identify human-relevant may ultimately promote after injury. This work presents comprehensive gene discovery provides datasets for development future microglial-targeted therapeutics.

Язык: Английский

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Defining the molecular identity and morphology ofglia limitans superficialisastrocytes in mouse and human

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Апрель 6, 2023

Astrocytes are a highly abundant glial cell type that perform critical homeostatic functions in the central nervous system. Like neurons, astrocytes have many discrete heterogenous subtypes. The subtype identity and are, at least part, associated with their anatomical location can be restricted to strategically important domains. Here, we report forming glia limitans superficialis, outermost border of brain spinal cord, specialized astrocyte identified by single marker: Myocilin (Myoc). We show Myoc+ cover entire cord surface, exhibit an atypical morphology, evolutionarily conserved from rodents humans. Identification this will advance our understanding CNS homeostasis potentially targeted for therapeutic intervention combat peripheral inflammatory effects on CNS.

Язык: Английский

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Axonal growth inhibitors and their receptors in spinal cord injury: from biology to clinical translation

Neural Regeneration Research, Год журнала: 2023, Номер 18(12), С. 2573 - 2581

Опубликована: Май 12, 2023

Axonal growth inhibitors are released during traumatic injuries to the adult mammalian central nervous system, including after spinal cord injury. These molecules accumulate at injury site and form a highly inhibitory environment for axonal regeneration. Among these molecules, myelin-associated inhibitors, neurite outgrowth inhibitor A, oligodendrocyte myelin glycoprotein, chondroitin sulfate proteoglycans repulsive guidance molecule A of particular importance. Due their nature, they represent exciting molecular targets study inhibition regeneration injuries. mainly produced by neurons, oligodendrocytes, astrocytes within scar in its immediate vicinity. They exert effects binding specific receptors, localized membranes neurons. Receptors cues include Nogo receptor 1, leucine-rich repeat, Ig domain containing 1 p75 neurotrophin receptor/tumor necrosis factor superfamily member 19 (that complex that binds all inhibitors), also paired immunoglobulin-like B. Chondroitin bind 3, protein tyrosine phosphatase σ leucocyte common antigen related phosphatase, neogenin, respectively. Once activated, receptors initiate downstream signaling pathways, most amongst them being RhoA/ROCK pathway. cascades result actin depolymerization, inhibition, failure regenerate Currently, there no approved pharmacological treatments overcome other than physical rehabilitation management array symptoms brought on However, several novel therapies aiming modulate proteins and/or under investigation ongoing clinical trials. Investigation has been demonstrating combinatorial with therapies, such as factors or stem-cell produce stronger results potential application clinics opens new venues treatment.

Язык: Английский

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Injury distance limits the transcriptional response to spinal injury

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Июнь 1, 2024

Abstract The ability of neurons to sense and respond damage is fundamental homeostasis nervous system repair. For some cell types, notably dorsal root ganglia (DRG) retinal ganglion cells (RGCs), extensive profiling has revealed a large transcriptional response axon injury that determines survival regenerative outcomes. In contrast, the most supraspinal whose limited regeneration constrains recovery from spinal injury, mostly unknown. Here we employed single-nuclei sequencing in mice profile responses diverse types injury. Surprisingly, thoracic triggered only modest changes gene expression across all populations, including corticospinal tract (CST) neurons. Moreover, CST also responded minimally cervical but much more strongly intracortical axotomy, upregulation numerous apoptosis-related transcripts shared with injured DRG RGC Thus, muted neuron linked injury’s distal location, rather than intrinsic cellular characteristics. More broadly, these findings indicate central challenge for enhancing after sensing distant injuries subsequent baseline neuronal response.

Язык: Английский

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