Human assembloid model of the ascending neural sensory pathway

Nature, Год журнала: 2025, Номер unknown

Опубликована: Апрель 9, 2025

Somatosensory pathways convey crucial information about pain, touch, itch and body part movement from peripheral organs to the central nervous system1,2. Despite substantial needs understand how these assemble develop pain therapeutics, clinical translation remains challenging. This is probably related species-specific features lack of in vitro models polysynaptic pathway. Here we established a human ascending somatosensory assembloid (hASA), four-part generated pluripotent stem cells that integrates somatosensory, spinal, thalamic cortical organoids model spinothalamic Transcriptomic profiling confirmed presence key cell types this circuit. Rabies tracing calcium imaging showed sensory neurons connect dorsal spinal cord neurons, which further neurons. Following noxious chemical stimulation, hASA demonstrated coordinated response. In addition, extracellular recordings revealed synchronized activity across assembloid. Notably, loss sodium channel NaV1.7, causes insensitivity, disrupted synchrony hASA. By contrast, gain-of-function SCN9A variant associated with extreme disorder induced hypersynchrony. These experiments ability functionally essential components pathway, could accelerate our understanding circuits facilitate therapeutic development.

Язык: Английский

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A functional subdivision within the somatosensory system and its implications for pain research

Neuron, Год журнала: 2022, Номер 110(5), С. 749 - 769

Опубликована: Янв. 10, 2022

Язык: Английский

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Generation and characterization of hair-bearing skin organoids from human pluripotent stem cells

Nature Protocols, Год журнала: 2022, Номер 17(5), С. 1266 - 1305

Опубликована: Март 23, 2022

Язык: Английский

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Cardiovascular Brain Circuits

Circulation Research, Год журнала: 2023, Номер 132(11), С. 1546 - 1565

Опубликована: Май 25, 2023

The cardiovascular system is hardwired to the brain via multilayered afferent and efferent polysynaptic axonal connections. Two major anatomically functionally distinct though closely interacting subcircuits within have recently been defined: artery-brain circuit heart-brain circuit. However, how nervous impacts disease progression remains poorly understood. Here, we review recent findings on anatomy, structures, inner workings of lesser-known better-established We explore evidence that signals from arteries or heart form a systemic finely tuned circuit: inputs originating in arterial tree are conveyed sensory neurons brain. There, primary integration centers act as hubs receive integrate circuit–derived process them together with connections humoral cues distant regions. To conclude circuit, transmit constantly modified which transfer back system. Importantly, wired information secondary control wide variety traits encoded engrams including immune memory, stress-regulating hormone release, pain, reward, emotions, even motivated types behavior. Finally, important possibility effector network connect other peripheral organs system, gut, liver, adipose tissue. enormous progress vis-à-vis allows us propose novel neurobiology-centered hypothesis term neuroimmune hypothesis.

Язык: Английский

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γ-Protocadherins control synapse formation and peripheral branching of touch sensory neurons

Neuron, Год журнала: 2023, Номер 111(11), С. 1776 - 1794.e10

Опубликована: Апрель 6, 2023

Light touch sensation begins with activation of low-threshold mechanoreceptor (LTMR) endings in the skin and propagation their signals to spinal cord brainstem. We found that clustered protocadherin gamma (Pcdhg) gene locus, which encodes 22 cell-surface homophilic binding proteins, is required somatosensory neurons for normal behavioral reactivity a range tactile stimuli. Developmentally, distinct Pcdhg isoforms mediate LTMR synapse formation through neuron-neuron interactions peripheral axonal branching neuron-glia interactions. The Pcdhgc3 isoform mediates between sensory axons promote vivo sufficient induce postsynaptic specializations vitro. Moreover, loss Pcdhgs synaptic inputs dorsal horn leads fewer corticospinal synapses on neurons. These findings reveal essential roles diversity neuron formation, branching, stepwise assembly central mechanosensory circuitry.

Язык: Английский

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Representation and control of pain and itch by distinct prefrontal neural ensembles

Neuron, Год журнала: 2023, Номер 111(15), С. 2414 - 2431.e7

Опубликована: Май 23, 2023

Язык: Английский

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Human assembloid model of the ascending neural sensory pathway

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

Опубликована: Март 12, 2024

Abstract The ascending somatosensory pathways convey crucial information about pain, touch, itch, and body part movement from peripheral organs to the central nervous system. Despite a significant need for effective therapeutics modulating pain other modalities, clinical translation remains challenging, which is likely related species-specific features lack of in vitro models directly probe manipulate this polysynaptic pathway. Here, we established human assembloids (hASA)– four-part assembloid completely generated pluripotent stem cells that integrates somatosensory, spinal, diencephalic, cortical organoids model spinothalamic Transcriptomic profiling confirmed presence key cell types circuit. Rabies tracing calcium imaging showed sensory neurons connected with dorsal spinal cord projection neurons, axons further thalamic neurons. Following noxious chemical stimulation, single neuron intact hASA demonstrated coordinated response, while concomitant extracellular recordings revealed synchronized activity across assembloid. Loss sodium channel SCN9A, causes insensitivity humans, disrupted synchrony hASA. Taken together, these experiments demonstrate ability functionally assemble essential components These findings could both accelerate our understanding circuits facilitate therapeutic development.

Язык: Английский

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Global change and premature hatching of aquatic embryos

Global Change Biology, Год журнала: 2024, Номер 30(9)

Опубликована: Сен. 1, 2024

Abstract Anthropogenically induced changes to the natural world are increasingly exposing organisms stimuli and stress beyond that which they adapted. In aquatic systems, it is thought certain life stages more vulnerable than others, with embryos being flagged as highly susceptible environmental stressors. Interestingly, evidence from across a wide range of taxa suggests can hatch prematurely, potentially an adaptive response external stressors, despite potential for individual costs linked underdeveloped behavioural and/or physiological functions. However, surprisingly little research has investigated prevalence, causes consequences premature hatching, no compilation literature exists. Here, we review what known about hatching in discuss how this phenomenon likely become exacerbated anthropogenically global change. Specifically, (1) mechanisms including triggers experimental systems; (2) implications at different levels biological organisation individuals ecosystems; (3) outline knowledge gaps future directions understanding drivers hatching. We found prematurely broad abiotic (i.e. temperature, oxygen, toxicants, light, pH, salinity) biotic predators, pathogens) also provide empirical appears be common rapid thermal ramping fish species. argue represents fascinating yet untapped area study, may some additional resilience communities face ongoing

Язык: Английский

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Dendrite morphogenesis in Caenorhabditis elegans

Genetics, Год журнала: 2024, Номер 227(2)

Опубликована: Май 24, 2024

Abstract Since the days of Ramón y Cajal, vast diversity neuronal and particularly dendrite morphology has been used to catalog neurons into different classes. Dendrite varies greatly reflects functions performed by types neurons. Significant progress made in our understanding how dendrites form molecular factors forces that shape these often elaborately sculpted structures. Here, we review work nematode Caenorhabditis elegans shed light on developmental mechanisms mediate morphogenesis with a focus studies investigating ciliated sensory highly elaborated dendritic trees somatosensory These studies, which combine time-lapse imaging, genetics, biochemistry, reveal an intricate network function both intrinsically extrinsically from surrounding tissues. Therefore, is result multiple tissue interactions, ultimately determine arbors.

Язык: Английский

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E26 transformation-specific transcription variant 5 in development and cancer: modification, regulation and function

Journal of Biomedical Science, Год журнала: 2023, Номер 30(1)

Опубликована: Март 6, 2023

Abstract E26 transformation-specific (ETS) transcription variant 5 (ETV5), also known as ETS-related molecule (ERM), exerts versatile functions in normal physiological processes, including branching morphogenesis, neural system development, fertility, embryonic immune regulation, and cell metabolism. In addition, ETV5 is repeatedly found to be overexpressed multiple malignant tumors, where it involved cancer progression an oncogenic factor. Its roles metastasis, proliferation, oxidative stress response drug resistance indicate that a potential prognostic biomarker, well therapeutic target for treatment. Post-translational modifications, gene fusion events, sophisticated cellular signaling crosstalk non-coding RNAs contribute the dysregulation abnormal activities of ETV5. However, few studies date systematically summarized role molecular mechanisms benign diseases progression. this review, we specify structure post-translational modifications its critical are draw panorama specialists clinicians. The updated biology tumor delineated. Finally, prospect further direction research oncology translational applications clinic.

Язык: Английский

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