HUC-MSC-mediated recovery of subacute spinal cord injury through enhancing the pivotal subunits β3 and γ2 of the GABAA receptor
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA739663 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14870869_1.fastq.gz | Fastqsanger.gz | |||
| SRR14870869_2.fastq.gz | Fastqsanger.gz | |||
| SRR14870870_1.fastq.gz | Fastqsanger.gz | |||
| SRR14870870_2.fastq.gz | Fastqsanger.gz | |||
| SRR14870872_1.fastq.gz | Fastqsanger.gz |
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Project description:We conducted a time-course RNA-seq of spinal cord segments at the lesion site without or with hUC-MSC treatment at subacute phase of SCI to identify genes involved in hUC-MSC-mediated recovery
2022-04-07 | GSE178564 | GEO
Project description:Rationale: Spinal cord injury (SCI) remains an incurable neurological disorder leading to permanent and profound neurologic deficits and disabilities. Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) are particularly appealing in SCI treatment to curtail damage, restore homeostasis and possible neural relay. However, the detailed mechanisms underlying hUC-MSC-mediated functional recovery of SCI have not been fully elucidated. The purpose of our current study is to identify novel therapeutic targets and depict the molecular mechanisms underlying the hUC-MSC-mediated recovery of subacute SCI. Methods: Adult female rats suffering from subacute incomplete thoracic SCI were treated with intrathecal transplantation of hUC-MSCs. The beneficial effects of hUC-MSCs on SCI repair were evaluated by a series of behavioral analyses, motor evoked potentials (MEPs) recording of hindlimb and immunohistochemistry. We carried out extensive transcriptome comparative analyses of spinal cord tissues at the lesion site from the subacute phase of SCI (sub-SCI) either treated without (+PBS) or with hUC-MSCs (+MSC) at 0 (sub-SCI), 1, 2, and 4 weeks post-transplantation (wpt), as well as normal spinal cord segments of intact/sham rats (Intact). Adeno-associated virus (AAV)-mediated neuron-specific expression system was employed to functionally screen specific γ-aminobutyric acid type A receptor (GABAAR) subunits promoting the functional recovery of SCI in vivo. The mature cortical axon scrape assay and transplantation of genetically modified MSCs with either overexpression or knockdown of brain-derived neurotrophic factor (BDNF) were employed to demonstrate that hUC-MSCs ameliorated the reduction of GABAAR subunits in the injured spinal cord via BDNF secretion in vitro and in vivo, respectively. Results: Comparative transcriptome analysis revealed the GABAergic synapse pathway is significantly enriched as a main target of hUC-MSC-activated genes in the injured spinal cord. Functional screening of the primary GABAAR subunits uncovered that Gabrb3 and Garbg2 harbored the motor and electrophysiological recovery-promoting competence. Moreover, targeting either of the two pivotal subunits β3 or γ2 in combination with/without the K+/Cl- cotransporter 2 (KCC2) reinforced the therapeutic effects. Mechanistically, BDNF secreted by hUC-MSCs contributed to the upregulation of GABAAR subunits (β3 & γ2) and KCC2 in the injured neurons. Conclusions: Our study identifies a novel mode for hUC-MSC-mediated locomotor recovery of SCI through synergistic upregulation of GABAAR β3 and γ2 along with KCC2 by BDNF secretion, indicating the significance of restoring the excitation/inhibition balance in the injured neurons for the reestablishment of neuronal circuits. This study also provides a potential combinatorial approach by targeting the pivotal subunit β3 or γ2 and KCC2, opening up possibilities for efficacious drug design.
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Project description:HUC model includes three cell lines: HUC-BC, HUC-PC, and MCT11. They were all originally derived from human uroepithelium. However, three cell lines have different malignant potential. We here performed micro array to examine the differences in gene expression among three cell lines.
2020-10-20 | E-MTAB-9699 | biostudies-arrayexpress
Project description:HUC model includes three cell lines: HUC-BC, HUC-PC, and MCT11. They were all originally derived from human uroepithelium. However, three cell lines have different malignant potential. We here performed micro array to examine the differences in gene expression among three cell lines.
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Project description:Crohn’s disease is a chronic, debilitating inflammatory bowel disease. Here we report a critical role for phospholipase C-β3 (PLC-β3) in intestinal homeostasis. In PLC-β3- deficient mice, exposure to oral dextran sodium sulfate induced lethality and severe inflammation in the small intestine. The lethality was due to PLC-β3 deficiency in multiple non-hematopoietic cell types. PLC-β3 deficiency resulted in reduced Wnt/β-catenin signaling, which is essential for homeostasis and regeneration of the intestinal epithelium. PLC-β3 regulated the Wnt/β-catenin pathway in small intestinal epithelial cells (IECs) at transcriptional, epigenetic, and potentially protein-protein interaction levels. PLC-β3- deficient IECs were unable to respond to stimulation by R-spondin 1, an enhancer of Wnt/β-catenin signaling. Reduced expression of PLC-β3 and its signature genes was found in biopsies of ileal Crohn’s disease patients. PLC-β regulation of Wnt signaling was evolutionally conserved in Drosophila. Our data indicate that reduction of PLC-β3- mediated Wnt/β-catenin signaling contributes to the pathogenesis of ileal Crohn’s disease.
2024-10-06 | GSE244937 | GEO
Project description:Crohn’s disease is a chronic, debilitating inflammatory bowel disease. Here we report a critical role for phospholipase C-β3 (PLC-β3) in intestinal homeostasis. In PLC-β3- deficient mice, exposure to oral dextran sodium sulfate induced lethality and severe inflammation in the small intestine. The lethality was due to PLC-3 deficiency in multiple non-hematopoietic cell types. PLC-β3 deficiency resulted in reduced Wnt/-catenin signaling, which is essential for homeostasis and regeneration of the intestinal epithelium. PLC-β3 regulated the Wnt/β-catenin pathway in small intestinal epithelial cells (IECs) at transcriptional, epigenetic, and potentially protein-protein interaction levels. PLC-β3- deficient IECs were unable to respond to stimulation by R-spondin 1, an enhancer of Wnt/β-catenin signaling. Reduced expression of PLC-β3 and its signature genes was found in biopsies of ileal Crohn’s disease patients. PLC-β regulation of Wnt signaling was evolutionally conserved in Drosophila. Our data indicate that reduction of PLC-β3- mediated Wnt/β-catenin signaling contributes to the pathogenesis of ileal Crohn’s disease.
2024-10-06 | GSE244936 | GEO
Project description:Crohn’s disease is a chronic, debilitating inflammatory bowel disease. Here we report a critical role for phospholipase C-β3 (PLC-β3) in intestinal homeostasis. In PLC-β3- deficient mice, exposure to oral dextran sodium sulfate induced lethality and severe inflammation in the small intestine. The lethality was due to PLC-3 deficiency in multiple non-hematopoietic cell types. PLC-β3 deficiency resulted in reduced Wnt/-catenin signaling, which is essential for homeostasis and regeneration of the intestinal epithelium. PLC-β3 regulated the Wnt/β-catenin pathway in small intestinal epithelial cells (IECs) at transcriptional, epigenetic, and potentially protein-protein interaction levels. PLC-β3- deficient IECs were unable to respond to stimulation by R-spondin 1, an enhancer of Wnt/β-catenin signaling. Reduced expression of PLC-β3 and its signature genes was found in biopsies of ileal Crohn’s disease patients. PLC-β regulation of Wnt signaling was evolutionally conserved in Drosophila. Our data indicate that reduction of PLC-β3- mediated Wnt/β-catenin signaling contributes to the pathogenesis of ileal Crohn’s disease.
2024-10-06 | GSE244935 | GEO
Project description:AMP-activated protein 1 kinase (AMPK), a phylogenetically conserved serine/threonine kinase regarded as a key cellular energy sensor, exists in eukaryotes as a heterotrimer comprising a catalytic α and regulatory β and γ subunits. In humans, activating mutations in the gene encoding the γ2 subunit of AMPK (PRKAG2) display a cardiac phenotype of left ventricular hypertrophy (LVH), conduction system disease, ventricular pre-excitation and increased cardiomyocyte glycogen accumulation. While existing transgenic models have elucidated the pathogenesis of several aspects of the disease5-7, the slow heart rate (sinus bradycardia) – a prominent feature of the disease – remains poorly understood. Here, using gene-targeting to generate mice which recapitulate this bradycardia, we demonstrate that γ2 AMPK activation perturbs fundamental mechanisms that determine sinoatrial pacemaker cell function. Reduction in the sarcolemmal hyperpolarization activated (“funny”) current (If) and damping of ryanodine receptor-derived diastolic local subsarcolemmal Ca2+ releases (LCRs)12,13 contribute to reduced sinoatrial cell spontaneous activity and, ultimately, to a lower heart rate. Pharmacological activation of AMPK reversibly reduces the beating rate of murine pluripotent stem cell-derived induced sinoatrial bodies. In contrast, using a mouse knock-out of γ2 AMPK, which exhibits an increased heart rate, we demonstrate a role for γ2 AMPK in physiological heart rate regulation, including an indispensable role in the bradycardic adaptation to endurance exercise. Through regulating the cardiac pacemaker and thereby heart rate, γ2 AMPK by virtue of its energy-sensing role, is a key physiological determinant of overall cardiac energy homeostasis.
2017-09-30 | GSE73047 | GEO
Project description:Peripheral infusion of human umbilical cord mesenchymal stem cells (hUC-MSCs) can profoundly suppress the activation of c-Mos and remarkably improve hepatic histology, suppress the systemic inflammatory reaction, and promote animal survival in a large non-human primate model of acute liver failure (ALF). The mechanism through which hUC-MSCs inhibits c-Mos activation in vivo remains unclear. We hypothesized that hUC-MSCs can adaptively produce certain inhibitory cytokines in response to the pro-inflammatory microenvironment. To confirm this, we stimulated cultured hUC-MSCs with inflammatory monkey serum (serum isolated at day 1 following toxin challenge). After a 30-min stimulation, the cells were collected for microarray gene expression analysis. A whole human genome oligo microarray analysis was performed to reveal the altered gene expression profiles of the hUC-MSCs
2016-05-12 | E-MTAB-4750 | biostudies-arrayexpress
Project description:Homo sapiens isolate:hUC Raw sequence reads
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