Inhibition of muscarinic receptor signaling protects human enteric inhibitory neurons against platin chemotherapy toxicity
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PROVIDER: PRJNA937738 | ENA |
REPOSITORIES: ENA
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Project description:Gastrointestinal toxicity is a common dose-limiting adverse effect of platin chemotherapy treatment. 50% of cancer survivors continue to experience symptoms of chronic constipation or diarrhea induced by their chemotherapy for many years after their treatment. This drug toxicity is largely attributed to damage to enteric neurons that innervate the gastrointestinal tract and control gastrointestinal motility. The mechanisms responsible for platin-induced enteric neurotoxicity and potential preventative strategies have remained unknown. Here, we use human pluripotent stem cell-derived enteric neurons to establish a new model system capable of uncovering the mechanism of platin-induced enteric neuropathy. Utilizing this scalable system, we performed a high throughput screen and identified drug candidates and pathways involved in the disease. Our analyses revealed that excitotoxicity through muscarinic cholinergic signaling is a key driver of platin-induced enteric neuropathy. Using single nuclei transcriptomics and functional assays, we discovered that this disease mechanism leads to increased susceptibility of specific neuronal subtypes, including inhibitory nitrergic neurons, to platins. Histological assessment of the enteric nervous system in platin-treated patients confirmed the selective loss of nitrergic neurons. Finally, we demonstrated that pharmacological and genetic inhibition of muscarinic cholinergic signaling is sufficient to rescue enteric neurons from platin excitotoxicity in vitro and can prevent platin-induced constipation and degeneration of nitrergic neurons in mice. These studies define the mechanisms of platin-induced enteric neuropathy and serve as a framework for uncovering cell type-specific manifestations of cellular stress underlying numerous intractable peripheral neuropathies.
2025-02-22 | GSE225871 | GEO
Project description:Gastrointestinal toxicity is a common dose-limiting adverse effect of platin chemotherapy treatment. 50% of cancer survivors continue to experience symptoms of chronic constipation or diarrhea induced by their chemotherapy for many years after their treatment. This drug toxicity is largely attributed to damage to enteric neurons that innervate the gastrointestinal tract and control gastrointestinal motility. The mechanisms responsible for platin-induced enteric neurotoxicity and potential preventative strategies have remained unknown. Here, we use human pluripotent stem cell-derived enteric neurons to establish a new model system capable of uncovering the mechanism of platin-induced enteric neuropathy. Utilizing this scalable system, we performed a high throughput screen and identified drug candidates and pathways involved in the disease. Our analyses revealed that excitotoxicity through muscarinic cholinergic signaling is a key driver of platin-induced enteric neuropathy. Using single nuclei transcriptomics and functional assays, we discovered that this disease mechanism leads to increased susceptibility of specific neuronal subtypes, including inhibitory nitrergic neurons, to platins. Histological assessment of the enteric nervous system in platin-treated patients confirmed the selective loss of nitrergic neurons. Finally, we demonstrated that pharmacological and genetic inhibition of muscarinic cholinergic signaling is sufficient to rescue enteric neurons from platin excitotoxicity in vitro and can prevent platin-induced constipation and degeneration of nitrergic neurons in mice. These studies define the mechanisms of platin-induced enteric neuropathy and serve as a framework for uncovering cell type-specific manifestations of cellular stress underlying numerous intractable peripheral neuropathies.
2025-02-28 | GSE226332 | GEO
Project description:Inhibition of muscarinic receptor signaling protects human enteric inhibitory neurons against platin chemotherapy toxicity [snRNA-seq]
| PRJNA939714 | ENA
Project description:We investigated whether prognostic information is reflected in the expression patterns of ovarian carcinoma samples. RNA obtained from seven FIGO stage I without recurrence, seven platin-sensitive advanced-stage (III or IV), and six platin-resistant advanced-stage ovarian tumors was hybridized on a complementary DNA microarray with 21,372 spotted clones. The results revealed that a considerable number of genes exhibit nonaccidental differential expression between the different tumor classes. Principal component analysis reflected the differences between the three tumor classes and their order of transition. Using a leave-one-out approach together with least squares support vector machines, we obtained an estimated classification test accuracy of 100% for the distinction between stage I and advanced-stage disease and 76.92% for the distinction between platin-resistant versus platin-sensitive disease in FIGO stage III/IV. These results indicate that gene expression patterns could be useful in clinical management of ovarian cancer.<br> KEYWORDS: clinical, FIGO stage, microarrays, ovarian cancer, platin resistance.
2007-02-10 | E-MEXP-979 | biostudies-arrayexpress
Project description:Chronic damage to tissues and organs is deemed irreversible. This has led to a focus on the development of regenerative therapies that replace tissues. Here, we break with this dogma by demonstrating that the chronically injured degenerating salivary gland can be functionally and structurally restored through a nerve-associated mechanism. Extensive disruption of the chronically injured secretory acinar-nerve niche can be reversed by muscarinic agonism, with the tissue maintaining a homeostatic-like state months after treatment ends. In addition, the proportion of de-differentiated acinar cell types that appear with chronic damage are greatly reduced by muscarinic stimulation, suggesting recovery of cells critical for function. This reversal is due, in part, to re-balancing a calcium-dependent metabolic pathway that enables cell replacement. Finally, we show that radiation damaged hair follicles also benefit from muscarinic stimulation through a similar mechanism. Thus, these data challenge the concept that chronic damage is irreversible and provide a new avenue for the development of restorative treatments, a paradigm shift that can be explored more broadly.
2025-01-21 | GSE272766 | GEO
Project description:BACKGROUND Enteric glia contribute to the pathophysiology of various intestinal immune-driven diseases, such as postoperative ileus (POI), a motility disorder and common complication after abdominal surgery. Enteric gliosis of the intestinal muscularis externa (ME) has been identified as part of POI development. However, the glia-restricted responses and activation mechanisms are poorly understood. The sympathetic nervous system becomes rapidly activated by abdominal surgery. It modulates intestinal immunity, innervates all intestinal layers, and directly interfaces with enteric glia. We hypothesized that sympathetic innervation controls enteric glia reactivity in response to surgical trauma. METHODS Sox10iCreERT2/Rpl22HA/+ mice were subjected to a mouse model of laparotomy or intestinal manipulation to induce POI. Histological, protein, and transcriptomic analyses were performed to analyze glia-specific responses. Interactions between the sympathetic nervous system and enteric glia were studied in mice chemically depleted of TH+ sympathetic neurons and glial-restricted Sox10iCreERT2/JellyOPfl/+/Rpl22HA/+ mice, allowing optogenetic stimulation of β-adrenergic downstream signaling and glial-specific transcriptome analyses. A laparotomy model was used to study the effect of sympathetic signaling on enteric glia in the absence of intestinal manipulation. Mechanistic studies included adrenergic receptor expression profiling in vivo and in vitro and adrenergic agonism treatments of primary enteric glial cell cultures to elucidate the role of sympathetic signaling in acute enteric gliosis and POI. RESULTS With ~4000 differentially expressed genes, the most substantial enteric glia response occurs early after intestinal manipulation. During POI, enteric glia switch into a reactive state and continuously shape their microenvironment by releasing inflammatory and migratory factors. Sympathetic denervation reduced the inflammatory response of enteric glia in the early postoperative phase. Optogenetic and pharmacological stimulation of β-adrenergic downstream signaling triggered enteric glia reactivity. Finally, distinct adrenergic agonists revealed β-1/2 adrenoceptors as the molecular targets of sympathetic–driven enteric glial reactivity. CONCLUSIONS Enteric glia act as early responders during post-traumatic intestinal injury and inflammation. Intact sympathetic innervation and active β-adrenergic receptor signaling in enteric glia is a trigger of the immediate glial postoperative inflammatory response. With immune-activating cues originating from the sympathetic nervous system as early as the initial surgical incision, adrenergic signaling in enteric glia presents a promising target for preventing POI development.
2023-11-15 | GSE198889 | GEO
Project description:This study was undertaken to define the molecular subtypes of cells within enteric neurospheres. Methods: We performed single-cell RNA sequencing on 3-dimensional neurosphere cultures derived from the small intestines of Plp1::GFP mice. These data show profiling results from the PLP1::GFP negative cell fraction ancillary to the positive fraction in series GSE184981. Results: We identify populations of enteric neurons and fibroblasts in the PLP1::GFP negative cell fraction of enteric neurospheres.
2024-07-16 | GSE264155 | GEO
Project description:Acquired or congenital disruption in enteric nervous system (ENS) development or function can lead to significant mechanical dysmotility. ENS restoration through cellular transplantation may provide a cure for enteric neuropathies. We have previously generated human pluripotent stem cell (hPSC)-derived tissue-engineered small intestine (TESI) from human intestinal organoids (HIO). However, HIO-TESI fails to develop an ENS. In a previous report of combined HIO with additional human enteric neural crest cells (ENCC), an ENS was established but lacked maturity. The purpose of our study is to establish a mature ENS derived exclusively from hPSC in HIO-TESI. hPSC-derived ENCC supplementation of HIO-TESI generates ENCC-HIO-TESI with mature submucosal and myenteric ganglia, repopulates excitatory, inhibitory, and sensory neurons, and restores the neuroepithelial circuit and neuron-dependent contractility and relaxation. Our findings validate a novel approach to restoring a functional hPSC-derived ENS in ENCC-HIO-TESI and implicate their potential for the treatment of enteric neuropathies.
2017-10-20 | GSE99317 | GEO
Project description:Enteric glia are the predominant cell type in the enteric nervous system yet their identities and roles in gastrointestinal function are not well classified. Using our optimized single nucleus RNA-sequencing method, we identified distinct molecular classes of enteric glia and defined their morphological and spatial diversity. Our findings revealed a functionally specialized biosensor subtype of enteric glia that we call “hub cells.” Deletion of the mechanosensory ion channel PIEZO2 from adult enteric glial hub cells, but not other subtypes of enteric glia, led to defects in intestinal motility and gastric emptying in mice. These results provide insight into the multifaceted functions of different enteric glial cell subtypes in gut health and emphasize that therapies targeting enteric glia could advance the treatment of gastrointestinal diseases.
2023-09-08 | GSE232703 | GEO
Project description:The M3 Muscarinic Acetylcholine Receptor Promotes Epidermal Differentiation
| PRJNA833409 | ENA