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Differentiating visceral sensory ganglion organoids from induced pluripotent stem cells

ABSTRACT: The ability to generate visceral sensory neurons (VSN) from induced pluripotent stem (iPS) cells may help to gain insights into how the gut-nerve-brain axis is involved in neurological disorders. We established a protocol to differentiate human iPS-cell-derived visceral sensory ganglion organoids (VSGOs). VSGOs exhibit canonical VSN markers, and single-cell RNA sequencing revealed heterogenous molecular signatures and developmental trajectories of VSGOs aligned with native VSN. We integrated VSGOs with human colon organoids on a microfluidic device and applied this axis-on-a-chip model to Alzheimer's disease. Our results suggest that VSN could be a potential mediator for propagating gut-derived amyloid and tau to the brain in an APOE4- and LRP1-dependent manner. Furthermore, our approach was extended to include patient-derived iPS cells, which demonstrated a strong correlation with clinical data.

ORGANISM(S): Homo sapiens

PROVIDER: GSE264303 | GEO | 2024/07/19

REPOSITORIES: GEO

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Differentiating visceral sensory ganglion organoids from induced pluripotent stem cells[chip_scRNAseq]

Project description:The ability to generate visceral sensory neurons (VSN) from induced pluripotent stem (iPS) cells may help to gain insights into how the gut-nerve-brain axis is involved in neurological disorders. We established a protocol to differentiate human iPS-cell-derived visceral sensory ganglion organoids (VSGOs). VSGOs exhibit canonical VSN markers, and single-cell RNA sequencing revealed heterogenous molecular signatures and developmental trajectories of VSGOs aligned with native VSN. We integrated VSGOs with human colon organoids on a microfluidic device and applied this axis-on-a-chip model to Alzheimer's disease. Our results suggest that VSN could be a potential mediator for propagating gut-derived amyloid and tau to the brain in an APOE4- and LRP1-dependent manner. Furthermore, our approach was extended to include patient-derived iPS cells, which demonstrated a strong correlation with clinical data.

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A molecular architecture of the vagal interoceptive system

Project description:Interoception, the ability to timely and precisely sense changes inside the body, is critical for survival. Vagal sensory neurons (VSNs) form an important body-to-brain axis, navigating along body’s rostral-caudal axis to their target organs and dive across organ’s surface-lumen axis into appropriate tissue layers to sense stimuli with various physical properties. The brain can discriminate numerous body signals through VSNs, yet the underlying molecular coding strategy remains poorly understood. Here we show that VSNs code visceral organ, tissue layer, and stimulus modality, three key features of an interoceptive signal, in different dimensions. Large-scale single-cell profiling of VSNs from seven major organs, including the lung, heart, stomach, esophagus, duodenum, pancreas, and transverse colon, using multiplexed projection-barcodes reveals a ‘visceral organ’ dimension composed of differentially expressed gene modules coding VSN target organs along body’s rostral-caudal axis. Surprisingly, we discover another ‘tissue layer’ dimension with gene modules coding VSN ending locations along organ’s surface-lumen axis. The three independent feature-coding dimensions together specify many parallel VSN pathways in a combinatorial fashion and facilitate complex VSN projection in the brainstem. Our study thus highlights a novel multidimensional coding architecture of the mammalian vagal interoceptive system for effective signal communication.

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Single-cell RNAseq Reveals Seven Classes of Visceral Sensory Neuron

Project description:Integration of nutritional, microbial and inflammatory events along the gut-brain axis can alter bowel physiology and organism behaviour. The principal neural unit in the bowel encoding these stimuli is the visceral sensory neuron with endings at the mucosa, intramurally and along mesenteric blood vessels. Sensory neurons activate reflex pathways and give rise to conscious sensation, however, the diversity and division of function within these neurons is poorly understood. The identification of signalling pathways contributing to visceral sensation is constrained by the current paucity of molecular markers. Here we overcome these limitations by comprehensive transcriptomic profiling and unsupervised clustering of single colonic sensory neurons revealing 7 classes characterised from both lumbar splanchnic (LSN) and pelvic nerves (PN). We identify and classify neurons based on novel marker genes, confirm translation of patterning to protein expression and show subtype-selective differential agonist activation, describing sensory diversity encompassing all modalities of colonic neuronal sensitivity.

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Differentiating visceral sensory ganglion organoids from induced pluripotent stem cells

Project description:Differentiating visceral sensory ganglion organoids from induced pluripotent stem cells

| PRJNA1101932 | ENA

Microglia gravitate toward amyloid plaques surrounded by externalized phosphatidylserine via TREM2

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