Evaluation of M2-like macrophage enrichment after diffuse traumatic brain injury through transient interleukin-4 expression from engineered mesenchymal stromal cells
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ABSTRACT:
PROVIDER: PRJNA602999 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
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| SRR10960600_1.fastq.gz | Fastqsanger.gz | |||
| SRR10960600_2.fastq.gz | Fastqsanger.gz | |||
| SRR10960601_1.fastq.gz | Fastqsanger.gz | |||
| SRR10960601_2.fastq.gz | Fastqsanger.gz | |||
| SRR10960602_1.fastq.gz | Fastqsanger.gz |
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Project description:We report the effects of acute M2-like macrophage enrichment in a mouse closed head injury model of diffuse traumatic brain injury. Enrichment is achieved by engineering mesenchymal stromal cells with synthetic interleukin-4 (IL-4) mRNA to transiently express IL-4. Through a transcriptomic analysis of treated brain tissue, we begin to understand the effects of acute IL-4 and M2-like macrophage enrichment.
2020-01-25 | GSE144193 | GEO
Project description:BackgroundAppropriately modulating inflammation after traumatic brain injury (TBI) may prevent disabilities for the millions of those inflicted annually. In TBI, cellular mediators of inflammation, including macrophages and microglia, possess a range of phenotypes relevant for an immunomodulatory therapeutic approach. It is thought that early phenotypic modulation of these cells will have a cascading healing effect. In fact, an anti-inflammatory, "M2-like" macrophage phenotype after TBI has been associated with neurogenesis, axonal regeneration, and improved white matter integrity (WMI). There already exist clinical trials seeking an M2-like bias through mesenchymal stem/stromal cells (MSCs). However, MSCs do not endogenously synthesize key signals that induce robust M2-like phenotypes such as interleukin-4 (IL-4).MethodsTo enrich M2-like macrophages in a clinically relevant manner, we augmented MSCs with synthetic IL-4 mRNA to transiently express IL-4. These IL-4 expressing MSCs (IL-4 MSCs) were characterized for expression and functionality and then delivered in a modified mouse TBI model of closed head injury. Groups were assessed for functional deficits and MR imaging. Brain tissue was analyzed through flow cytometry, multi-plex ELISA, qPCR, histology, and RNA sequencing.ResultsWe observed that IL-4 MSCs indeed induce a robust M2-like macrophage phenotype and promote anti-inflammatory gene expression after TBI. However, here we demonstrate that acute enrichment of M2-like macrophages did not translate to improved functional or histological outcomes, or improvements in WMI on MR imaging. To further understand whether dysfunctional pathways underlie the lack of therapeutic effect, we report transcriptomic analysis of injured and treated brains. Through this, we discovered that inflammation persists despite acute enrichment of M2-like macrophages in the brain.ConclusionThe results demonstrate that MSCs can be engineered to induce a stronger M2-like macrophage response in vivo. However, they also suggest that acute enrichment of only M2-like macrophages after diffuse TBI cannot orchestrate neurogenesis, axonal regeneration, or improve WMI. Here, we also discuss our modified TBI model and methods to assess severity, behavioral studies, and propose that IL-4 expressing MSCs may also have relevance in other cavitary diseases or in improving biomaterial integration into tissues.
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Project description:Cortical neuropathology RNA expression time-course after diffuse traumatic brain injury
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Project description:Diffuse large B cell lymphoma is a heterogenous malignancy that is diagnosed in over 60,000 patients each year. Interleukin-21 has been shown to induce apoptosis in certain B cells originating from mice. Diffuse large B cell lyphomas express the Interleukin-21 Receptor yet the effects of Interleukin-21 on this malignancy are uknown. Identified genes responsive to IL-21 treatment in diffuse large B cell lymphoma.
2010-01-01 | GSE18967 | GEO
Project description:Traumatic brain injury (TBI) can lead to significant neuropsychiatric problems and neurodegenerative pathologies, which develop and persist years after injury. Neuroinflammatory processes evolve over this same period. Therefore, we aimed to determine the contribution of microglia to neuropathology at acute (1-day post-injury; dpi), subacute (7 dpi), and chronic (30 dpi) time-points. Microglia were depleted with PLX5622, a CSF1R antagonist, prior to midline fluid percussion injury in male mice and cortical neuropathology/inflammation was assessed using a neuropathology mRNA panel. NanoString Neuropathology gene expression panel was used to quantify expression from RNA microdissected from the mouse cortex.
2020-11-15 | GSE160651 | GEO
Project description:Interleukin-2 (IL-2) is a pleiotropic cytokine that regulates lymphocyte function by signaling through heterodimerization of the IL-2Rβ and γc receptor subunits. Previously, we engineered an IL-2 “superkine” (H9) with enhanced affinity for IL-2Rβ. Here, we describe next-generation IL-2 variants that function as “receptor signaling clamps.” They retain high-affinity for IL-2Rβ, thereby inhibiting binding of endogenous IL-2, but their engagement of γc is weakened, thereby attenuating IL-2Rβ-γc heterodimerization. These IL-2 analogues act as partial agonists and can differentially affect lymphocytes poised at distinct activation thresholds. Moreover, one of these variants potently antagonized IL-2 and IL-15 signaling and function better than blocking antibodies against IL-2Rα or IL-2Rβ. Furthermore, this mutein prolonged survival in a model of graft versus host disease and blocked spontaneous proliferation of smoldering adult T-cell leukemia (ATL) T cells ex vivo. This receptor-clamping approach may be a general mechanism-based strategy for engineering cytokine partial agonists for therapeutic immunomodulation. Genome-wide transcription factors binding of STAT5 and mRNA-Sequencing of gene expression profiles in human pre-activated CD8+ T cells.
2015-06-16 | E-GEOD-64713 | biostudies-arrayexpress
Project description:Important differences in the biology of focal and diffuse traumatic brain injury (TBI) subtypes may result in unique pathophysiological responses to shared molecular mechanisms. Interleukin-1 (IL-1) signaling has been tested as a potential therapeutic target in preclinical models of cerebral contusion and diffuse TBI, and in a phase II clinical trial, but no published studies have examined IL-1 signaling in an impact/acceleration closed head injury (CHI) model. We hypothesized that genetic deletion of IL-1 receptor-1 (IL-1R1 KO) would be beneficial in focal (contusion) and CHI in mice. Wild type and IL-1R1 KO mice were subjected to controlled cortical impact (CCI), or to CHI. CCI produced brain leukocyte infiltration, HMGB1 translocation and release, edema, cell death, and cognitive deficits. CHI induced peak rotational acceleration of 9.7?×?105?±?8.1?×?104 rad/s2, delayed time to righting reflex, and robust Morris water maze deficits without deficits in tests of anxiety, locomotion, sensorimotor function, or depression. CHI produced no discernable acute plasmalemma damage or cell death, blood-brain barrier permeability to IgG, or brain edema and only a modest increase in brain leukocyte infiltration at 72?h. In both models, mature (17?kDa) interleukin-1 beta (IL-1?) was induced by 24?h in CD31+ endothelial cells isolated from injured brain but was not induced in CD11b+ cells in either model. High mobility group box protein-1 was released from injured brain cells in CCI but not CHI. Surprisingly, cognitive outcome in mice with global deletion of IL-1R1 was improved in CHI, but worse after CCI without affecting lesion size, edema, or infiltration of CD11b+/CD45+ leukocytes in CCI. IL-1R1 may induce unique biological responses, beneficial or detrimental to cognitive outcome, after TBI depending on the pathoanatomical subtype. Brain endothelium is a hitherto unrecognized source of mature IL-1? in both models.
| S-EPMC6338578 | biostudies-literature
Project description:Objective To identify transcript level differences between traumatic and degenerative tears of tendon tissues in shoulder joint using RNA-seq. Methods Tendon tissues were isolated from female and male patients with traumatic or degenerative tears during arthroscopic surgery (N = 31). Differentially expressed transcript were identified and biological processes enriched in traumatic and degenerative tears were probed computationally. Expression pattern of selected transcripts was validated by real-time qPCR. Results We identified 339 and 336 transcripts differentially expressed between traumatic and degenerative tears in females and males respectively at a fold-change greater than |2| and a p-value 0.05. In females, GSTM1, MT1G, S1008A, ACSM3, DSC, FAM110C and VNN2 were the most prominent transcripts elevated in traumatic tears and CHAD, CLEC3A, IBSP, TNMD, APLNR, and CPA3 were most highly repressed in traumatic tears. Transcripts elevated in traumatic tears represented catabolic processes, immune response, and metabolic processes while those repressed in traumatic tears represented tissue morphogenesis and developmental processes, angiogenesis, and extracellular matrix organization. In males, ELOA3B, CXCL8, ADM, TNS4 and SPOCK1 were the most prominent transcripts elevated in traumatic tears and MYL2, TNNC1, MB, CPA3, APLNR, and CA3 were most highly repressed in traumatic tears. Transcripts elevated in traumatic tears represented localization of endoplasmic reticulum, chromosome organization, leukocyte/neutrophil degranulation, and protein transport whereas those repressed in traumatic tears represented muscle development, blood circulation (angiogenesis), and muscle cell differentiation. Numerous novel lncRNAs were also identified to be differentially expressed between traumatic and degenerative tears in both sexes. Conclusions and Clinical Relevance This study improves our molecular understanding of tendon tissues in patients with rotator cuff tendinopathy based on underlying etiology (trauma and degeneration). It also provides new insights into sex-based transcript differences that may help drive clinical decision making in female and male patients with traumatic and degenerative shoulder injuries.
2022-03-15 | GSE180836 | GEO
Project description:Time dependent-profiles in the gene expression level following lateral moderate fluid percussion injury in the rat brain We used microarray to elucidate relationship between the alteration of gene expression levels and the progression of brain damages following traumatic brain injury. To examine the levels of gene expression in the early phase of traumatic brain injury, we analyzed the gene expression at 3, 6, 12, and 48 h after trauma using the lateral moderate fluid percussion TBI model. The ratios of the gene expression level were compared between chips corresponding to the 3, 6 and 12 h fluid percussion groups and the sham group chips. On the other hand, the rations of gene expression level after 48 h FPI were compared with 48 h sham chip, because the gene expression levels of 48 h sham chip were distinct from sham group chips (3, 6 and 12 h) in the cluster and principal components analyses.
2010-12-07 | E-GEOD-24047 | biostudies-arrayexpress
Project description:Objective: To identify transcript level differences between traumatic and degenerative tears of subacromial bursal tissues in shoulder joint using RNA-seq. Methods: Bursal tissues were collected from female and male patients with traumatic or degenerative tears during arthroscopic surgery (N=32). Differentially expressed transcript between traumatic and degenerative tears were detected by RNA-seq and biological processes were identified computationally. RNA-seq results were selectively validated by real-time qPCR. Results: We identified 334 protein-coding transcripts differentially expressed between traumatic and degenerative tears in females and 167 in males at a fold-change greater than |2| and a P < 0.05. In females, XIRP2, MYL1, MYBPC1, TNNT1, and LMOD2, were the highly expressed in traumatic tears and TPSD1, CDSN, RCVRN, LTBP4, and PTGS1 were prominently repressed in traumatic tears. Transcripts elevated in traumatic tears represented muscle cell differentiation and development, and muscle contraction whereas those elevated in degenerative tears represented cell activation, neutrophil granulation, immune response, and protein transport. In males, AZGP1, CNTFR, COL9A1, ZNF98 and EREG were highly elevated in traumatic tears whereas MYL2, HOXD11, SLC6A7, CADM1, and MMP17 were most highly repressed in traumatic tears. Transcripts elevated in traumatic tears represented metabolic processes, catabolic processes, and transmembrane protein transport while processes related to cell cycle were mainly repressed in traumatic tears. We also identified a number of novel lncRNAs differentially expressed between traumatic and degenerative tears in both females and males. Conclusions: This study increases our molecular understanding of bursal tissues in patients with rotator cuff tendinopathy based on the nature of disease that is trauma or degeneration. These finding also provide new insights into sex-based transcript differences that could inform clinical decision making in treating patients with traumatic and degenerative shoulder injuries.
2022-03-15 | GSE180857 | GEO