Neuromorphic Electro-Stimulation Based on Atomically Thin Semiconductor for Damage-Free Inflammation Inhibition
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE253300 | GEO | 2024/01/20
REPOSITORIES: GEO
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Project description:Neuromorphic Electro-Stimulation Based on Atomically Thin Semiconductor for Damage-Free Inflammation Inhibition
| PRJNA1064997 | ENA
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:Abstract Background: Gene transfer by electroporation (electro gene transfer) to muscle results in high level long term transgenic expression, showing great promise for treatment of e.g. protein deficiency syndromes. However little is known about the effects of electro gene transfer on muscle fibres. We have therefore investigated transcriptional changes through gene expression profile analyses, as well as morphological changes evaluated by histological analysis. Electro gene transfer was obtained using a combination of a short high voltage pulse (HV, 1000 V/cm, 100 @s) followed by a long low voltage pulse (LV, 100 V/cm, 400 ms); a pulse combination optimised for efficient and safe gene transfer. Muscles were transfected with green fluorescent protein (GFP) and excised at 4 hours, 48 hours or 3 weeks after treatment. Results: Differentially expressed genes were investigated by microarray analysis, and descriptive statistics were performed to evaluate the effects of 1) electroporation, 2) DNA injection, and 3) time after treatment. The biological significance of the results was assessed by gene annotation and supervised cluster analysis. Generally, electroporation caused down-regulation of structural proteins e.g. sarcospan and catalytic en-zymes such as phosphoenolpuryvate carboxykinase. Injection of DNA induced down-regulation of intracellular transport proteins e.g. sentrin. The effects on muscle fibres were transient as the expression profiles 3 weeks after treatment were closely related with the control muscles. Most interestingly, no changes in the expression of proteins involved in inflammatory responses or muscle regeneration was detected, indicating limited muscle damage and regeneration. Histological analysis revealed structural changes with loss of cell integrity and striation pattern in some fibres after DNA+HV+LV treatment, while electroporation alone caused minor loss of striation pattern but preservation of cell integrity. Conclusion: The small and transient changes found in the gene expression profiles are of great importance, as this demonstrates that electro gene transfer is safe with minor effects on the muscle host cells. These findings are essential for introducing the electro gene transfer to muscle for clinical use. Indeed the HV+LV pulse combination used have been optimised to ensure highly efficient and safe electro gene transfer. Keywords: Electro gene transfer, microarray, affymetrix, gene therapy, skeletal muscle, mouse, time course
2007-07-05 | GSE6686 | GEO
Project description:Abstract; Background: Gene transfer by electroporation (electro gene transfer) to muscle results in high level long term transgenic expression, showing great promise for treatment of e.g. protein deficiency syndromes. However little is known about the effects of electro gene transfer on muscle fibres. We have therefore investigated transcriptional changes through gene expression profile analyses, as well as morphological changes evaluated by histological analysis. Electro gene transfer was obtained using a combination of a short high voltage pulse (HV, 1000 V/cm, 100 @s) followed by a long low voltage pulse (LV, 100 V/cm, 400 ms); a pulse combination optimised for efficient and safe gene transfer. Muscles were transfected with green fluorescent protein (GFP) and excised at 4 hours, 48 hours or 3 weeks after treatment. Results: Differentially expressed genes were investigated by microarray analysis, and descriptive statistics were performed to evaluate the effects of 1) electroporation, 2) DNA injection, and 3) time after treatment. The biological significance of the results was assessed by gene annotation and supervised cluster analysis. Generally, electroporation caused down-regulation of structural proteins e.g. sarcospan and catalytic en-zymes such as phosphoenolpuryvate carboxykinase. Injection of DNA induced down-regulation of intracellular transport proteins e.g. sentrin. The effects on muscle fibres were transient as the expression profiles 3 weeks after treatment were closely related with the control muscles. Most interestingly, no changes in the expression of proteins involved in inflammatory responses or muscle regeneration was detected, indicating limited muscle damage and regeneration. Histological analysis revealed structural changes with loss of cell integrity and striation pattern in some fibres after DNA+HV+LV treatment, while electroporation alone caused minor loss of striation pattern but preservation of cell integrity. Conclusion: The small and transient changes found in the gene expression profiles are of great importance, as this demonstrates that electro gene transfer is safe with minor effects on the muscle host cells. These findings are essential for introducing the electro gene transfer to muscle for clinical use. Indeed the HV+LV pulse combination used have been optimised to ensure highly efficient and safe electro gene transfer. Experiment Overall Design: The mice did recieve to their tibialis cranialis muscle either No tretment/control (CTRL), Electroporation only (EP), Plasmid injection only (DNA) or Plasmid DNA and in vivo Electro gene transfer (EP+DNA). Experiment Overall Design: Four hrs, 48 hrs and 3 weeks after treatment the mice were euthanized and the expression profile of the treated muscles were analysed. Experiment Overall Design: The following number of mice were included: Experiment Overall Design: CTRL, 3 mice, Experiment Overall Design: EP at 4 hrs, 1 mouse, Experiment Overall Design: EP at 48 hrs, 1 mouse, Experiment Overall Design: EP at 3 weeks, 1 mouse, Experiment Overall Design: DNA at 4 hrs, 1 mouse, Experiment Overall Design: DNA at 48 hrs, 1 mouse, Experiment Overall Design: DNA at 3 weeks, 1 mouse, Experiment Overall Design: EP+DNA at 4 hrs, 2 mice, Experiment Overall Design: EP+DNA at 48 hrs, 1 mouse, Experiment Overall Design: EP+DNA at 3 weeks, 1 mouse. Experiment Overall Design: A total number of mice 13.
2009-04-23 | E-GEOD-6686 | biostudies-arrayexpress
Project description:Interventions: Electro-acupuncture group:Electro-acupuncture;Sham electro-acupuncture group:Sham electro-acupuncture;Routine group:Routine therapy
Primary outcome(s): The time of first postoperative anal exhaust
Study Design: Parallel
| 41280 | ecrin-mdr-crc
Project description:Alterations in autonomic function are known to occur in cardiac conditions including sudden cardiac death. Cardiac stimulation via sympathetic neurons can potentially trigger arrhythmias. Dissecting direct neural-cardiac interactions at the cellular level is technically challenging and understudied due to the lack of experimental model systems and methodologies. Here we demonstrate the utility of optical interrogation of sympathetic neurons and their effects on macroscopic cardiomyocyte network dynamics to address research targets such as the effects of adrenergic stimulation via the release of neurotransmitters, the effect of neuronal numbers on cardiac wave behaviour and the applicability of optogenetics in mechanistic in vitro studies. We present novel methodologies to study neuron-cardiomyocyte interactions involving optogenetic selective probing and all-optical electrophysiology to measure electrical activity in an automated fashion, illustrating the power and high-throughput capability of such interrogations. We present new findings on how neurons impact cardiac macroscopic wave properties, the links between neuron density and cardiac firing rates as well as the challenges and benefits of macroscopic co-cultures as experimental model systems.
2020-07-21 | PXD019908 | Pride
Project description:lncRNA-ZFAS1, an emerging gate-keeper in DNA damage-dependent transcriptional regulation
| PRJNA1000428 | ENA
Project description:Myeloproliferative neoplasms (MPNs) are diseases caused by mutations in the haematopoietic stem cell (HSC) compartment. Most MPN patients have a common acquired mutation of Janus kinase 2 (JAK2) gene in HSCs that renders this kinase constitutively active, leading to uncontrolled cell expansion. The bone marrow (BM) microenvironment might contribute to the clinical outcomes of this common event. We previously showed that BM nestin+ mesenchymal stem cells (MSCs) innervated by sympathetic nerve fibres regulate normal HSCs. Here we demonstrate that abrogation of this regulatory circuit is essential for MPN pathogenesis. Sympathetic nerve fibres, supporting Schwann cells and nestin+ MSCs are consistently reduced in the BM of MPN patients and mice expressing the human JAK2V617F mutation in HSCs. Unexpectedly, MSC reduction is not due to differentiation but is caused by BM neural damage and Schwann cell death triggered by interleukin-1b produced by mutant HSCs. In turn, in vivo depletion of nestin+ cells or their production of CXCL12 expanded mutant HSCs and accelerated MPN progression. In contrast, administration of neuroprotective or sympathomimetic drugs prevented mutant HSC expansion. Treatment with b3-adrenergic agonists that restored the sympathetic regulation of nestin+ MSCs prevented the loss of these cells and blocked MPN progression by indirectly reducing leukaemic stem cells. Our results demonstrate that mutant HSC-driven niche damage critically contributes to disease manifestation in MPN and identify niche-forming MSCs and their neural regulation as promising therapeutic targets. CD45- CD31- Ter119- GFP+ cells were sorted from the BM of Nes-gfp;Mx1-cre;JAK2-V617F mice and control littermates 6 weeks after pIpC treatment and were subjected to RNA sequencing. Each sample was pooled from 3 animals of the same genotype.
2014-03-12 | E-GEOD-55798 | biostudies-arrayexpress
Project description:Myeloproliferative neoplasms (MPNs) are diseases caused by mutations in the haematopoietic stem cell (HSC) compartment. Most MPN patients have a common acquired mutation of Janus kinase 2 (JAK2) gene in HSCs that renders this kinase constitutively active, leading to uncontrolled cell expansion. The bone marrow (BM) microenvironment might contribute to the clinical outcomes of this common event. We previously showed that BM nestin+ mesenchymal stem cells (MSCs) innervated by sympathetic nerve fibres regulate normal HSCs. Here we demonstrate that abrogation of this regulatory circuit is essential for MPN pathogenesis. Sympathetic nerve fibres, supporting Schwann cells and nestin+ MSCs are consistently reduced in the BM of MPN patients and mice expressing the human JAK2V617F mutation in HSCs. Unexpectedly, MSC reduction is not due to differentiation but is caused by BM neural damage and Schwann cell death triggered by interleukin-1b produced by mutant HSCs. In turn, in vivo depletion of nestin+ cells or their production of CXCL12 expanded mutant HSCs and accelerated MPN progression. In contrast, administration of neuroprotective or sympathomimetic drugs prevented mutant HSC expansion. Treatment with b3-adrenergic agonists that restored the sympathetic regulation of nestin+ MSCs prevented the loss of these cells and blocked MPN progression by indirectly reducing leukaemic stem cells. Our results demonstrate that mutant HSC-driven niche damage critically contributes to disease manifestation in MPN and identify niche-forming MSCs and their neural regulation as promising therapeutic targets. Total RNA was isolated from BM CD45- CD31- Ter119- Nes-GFP+ cells obtained from Nes-gfp mice 10 weeks after transplantation with Mx1-cre;JAK2-V617F (n=3) or control cells (n=1). RNA was amplified using the NuGen Ovation system and hybridized to the Affymetrix MoGene 1.0 ST array.
2014-03-12 | E-GEOD-55801 | biostudies-arrayexpress