Human Tendon-on-a-Chip for modeling vascular inflammatory fibrosis
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ABSTRACT:
PROVIDER: PRJNA1023523 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
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| SRR26265246.fastq.gz | Fastqsanger.gz | |||
| SRR26265247.fastq.gz | Fastqsanger.gz | |||
| SRR26265248.fastq.gz | Fastqsanger.gz | |||
| SRR26265249.fastq.gz | Fastqsanger.gz | |||
| SRR26265250.fastq.gz | Fastqsanger.gz |
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Project description:Vascular inflammation and activation of myofibroblasts play crucial roles in the progression of fibrosis. Transforming growth factor beta 1 (TGF-β1) has been identified as a driver of adhesion formation in various tissues, including tendons. However, the mechanisms underlying fibrotic peritendinous adhesions remain poorly understood resulting in a lack of effective therapies. To address this, we developed a novel human Tendon-on-a-Chip (hToC) model, which combines a vascular compartment, with endothelial cells and monocytes, with a tissue compartment containing fibroblasts and tissue-resident macrophages, all in serum-free conditions. Our hToC successfully replicates inflammatory and fibrotic phenotypes observed in mouse models and clinical human samples including myofibroblast differentiation and senescence, tissue contraction, excessive extracellular matrix deposition, and secretion of inflammatory cytokines. We show that fibrosis-on-a-chip is driven by the interaction between the vascular and tissue compartments, including the infiltration of monocytes. Transcriptomics validate the hToC as disease model of diseased human tendon and shows the upregulation of the PI3K/AKT/mTOR pathway—a regulatory nexus of fibrosis in tendon injury. Consistent with this finding, treatment with the mTOR inhibitor Rapamycin suppresses the fibrotic phenotype. Our findings validate the hToC as a tool for investigating human fibrosis and illuminate the underappreciated vascular contribution to tendon pathophysiology.
2024-01-10 | GSE244543 | GEO
Project description:Vascular inflammation and myofibroblast activation by TGF-β1 are key, yet-to-be-fully-understood pathological processes in fibrosis. Here we report the development of a novel human Tendon-on-a-Chip (hToC) to elucidate the role of TGF-β1 in peritendinous adhesions, a debilitating fibrosis condition affecting flexor tendon, which currently lacks biological therapies. The hToC allows the crosstalk between a vascular compartment harboring endothelial cells and monocytes with a tissue hydrogel compartment containing tendon fibroblasts and macrophages. We find that the hToC replicates in vivo inflammatory and fibrotic phenotypes in preclinical and clinical samples, including myofibroblast differentiation and tissue contraction, excessive ECM deposition, and inflammatory cytokines secretion. We further show the fibrotic phenotypes are driven by the interactions between the vascular and tissue compartments, mediating the transmigration of monocytes. We demonstrate significant overlap in fibrotic transcriptional signatures in the hToC with human tenolysis samples, including the mTOR pathway, a regulatory nexus of fibrosis across various organs. Treatment with Rapamycin suppressed the fibrotic phenotype on the hToC, which validates the hToC as a preclinical alternative for investigating fibrosis and testing therapeutics.
2024-01-10 | GSE246391 | GEO
Project description:Human Tendon-on-a-Chip for modeling vascular inflammatory fibrosis II
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Project description:Purpose: The goal of this study is to compare transcriptional profiles of flexor tendon healing in wild-type (WT, C57Bl/6J) to superhealer (MRL/MpJ) miceto gain insights in the biological drivers of the tendon injury response between the C57 and MRL mice. Methods: RNA was isolated from patially lacerated or uninjured flexor tendon 7 days post-injury. Results: Transcriptional analysis of biological drivers showed positive enrichment of TGFB1 in both C57 and MRL healing tendons. only MRL tendons exhibited downstream transcriptional effects of cell cycle regulatory genes, with negative enrichment of the cell senescence-related regulators, compared to the positively-enriched inflammatory and ECM organization pathways in the C57 tendons. Conclusions: There is altered TGFB1 regulated inflammatory, fibrosis, and cell cycle pathways in flexor tendon repair.
2022-01-04 | GSE175912 | GEO
Project description:Atherosclerosis is a persistent inflammatory state accompanied by lipid overload. Vascular fibrosis is one of the primary causes of atherosclerosis development. Although ligustilide (Lig) was shown to exert obvious antiatherogenic effects in previous studies, its precise mechanism has not been comprehensively discussed. In this paper, pharmacologic studies were performed to explore the pharmacodynamic effects of Lig on protecting aorta vascular wall structures and modulating serum inflammatory factors in ApoE-/- mice. Chemical proteomics based on a Lig-derived photoaffinity labelling (Lig-PAL) probe were applied to identify potential therapeutic targets. Mothers against decapentaplegic homologue 3 (SMAD3), which is closely related to the development of vascular fibrosis and atherosclerosis, was identified as a potential target of Lig. Lig suppressed the phosphorylation and nuclear translocation of SMAD3 by blocking the interaction between SMAD3 and transforming growth factor-β (TGF-β) receptor 1, thereby inhibiting the collagen synthesis process, preventing vascular fibrosis and improving atherosclerosis. The quantitative proteomics results from Lig-treated atherosclerotic ApoE-/- mice also indicated that Lig inhibits the expression of collagens I and III, interferes with collagen fibril organization processes and protects the aorta from vascular fibrosis. Hence, developing a novel SMAD3 inhibitor may present another therapeutic option for preventing atherosclerosis.
2020-01-21 | PXD017125 | Pride
Project description:Systems modeling of developmental vascular toxicity
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Project description:Background and aims: There are considerable evidences demonstrating that angiogenesis and chronic inflammation are mutually dependent. However, although cirrhosis progression is characterized with a chronic hepatic inflammatory process, this connection is not sufficiently explored as a therapeutic strategy. Therefore, this study was aimed to assess the potential benefits of targeting angiogenesis in cirrhotic livers to modulate inflammation and fibrosis. For this purpose, we evaluate the therapeutic utility of angiogenesis inhibitors. Methods: The in vivo effects of angiogenesis inhibitors were monitored in liver of cirrhotic rats by measuring angiogenesis, inflammatory infiltrate, fibrosis, a-smooth muscle actin (a-SMA) accumulation, differential gene expression (by microarrays), and portal pressure. Results: Cirrhosis progression was associated with a significant enhancement of vascular density and expression of vascular endothelial growth factor-A (VEGF-A), angiopoietin-1, angiopoietin-2 and placental growth factor (PlGF) in cirrhotic livers. The newly formed hepatic vasculature expressed vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1). Interestingly, the expression of these adhesion molecules correlated well with local inflammatory infiltrate. Livers of cirrhotic rats treated with angiogenesis inhibitors presented a significant decrease in hepatic vascular density, inflammatory infiltrate, a-SMA abundance, collagen expression and portal pressure. Conclusion: Angiogenesis inhibitors may offer a potential novel therapy for cirrhosis due to its multiple mechanisms of action against angiogenesis, inflammation and fibrosis in cirrhotic livers. Keywords: angiogenesis, cirrhosis, liver, Affymetrix, fibrosis
2007-10-18 | GSE6929 | GEO
Project description:Adhesion formation after flexor tendon repair remains a clinical problem. Early postoperative motion after tendon repair has been demonstrated to reduce adhesion formation while increasing tendon strength. It is hypothesized that during mobilization, tendon cells experience mechanical shear forces that alter their biology in a fashion that reduces scar formation but also activates key genes involved in tendon healing. To test this hypothesis, primary intrinsic tenocyte cultures were established from flexor tendons of 20 Sprague-Dawley rats and sheared at 50 rpm (0.41 Pa) using a cone viscometer for 6 and 12 hours. Total RNA was harvested and compared with time-matched unsheared controls using cDNA microarrays and Northern blot analysis. Microarray analysis demonstrated that mechanical shear stress induced an overall "antifibrotic" expression pattern with decreased transcription of collagen type I and collagen type III. Shear stress down-regulated profibrotic molecules in the platelet-derived growth factor, insulin-like growth factor, and fibroblast growth factor signaling pathways. In addition, shear stress induced an overall decrease in transforming growth factor (TGF)-beta signaling pathway molecules with down-regulation of TGF-beta2, TGF-beta3, TGF-RI, and TGF-RII expression. Moreover, sheared tendon cells increased expression of matrix metalloproteinases and decreased expression of tissue inhibitors of metalloproteinase, an expression pattern consistent with an antifibrotic increase in extracellular matrix degradation. However, up-regulation of genes implicated in tendon healing, specifically, vascular endothelial growth factor-A and several bone morphogenetic proteins. Interestingly, the known mechanoresponsive gene, TGF-beta1, also implicated in tendon healing, was differentially up-regulated by shear stress. Northern blot validation of our results for TGF-beta1, TGF-beta2, TGF-beta3, and collagen type I demonstrated direct correlation with microarray data. Groups of assays that are related as part of a time series. Computed
2006-01-27 | E-GEOD-4096 | biostudies-arrayexpress
Project description:Rotator cuff injuries result in over 500,000 surgeries performed annually, an alarmingly high number of which fail. These procedures typically involve repair of the injured tendon and removal of the subacromial bursa. However, recent identification of a resident population of mesenchymal stem cells and inflammatory responsiveness of the bursa to tendinopathy indicate an unexplored biological role of the bursa in the context of rotator cuff disease. Therefore, we aimed to understand the clinical relevance of bursa-tendon crosstalk, characterize the biologic role of the bursa within the shoulder, and test the therapeutic potential for targeting the bursa. Proteomic profiling of patient bursa and tendon samples demonstrated that the bursa is activated by tendon injury. Using a rat to model rotator cuff injury and repair, tenotomy-activated bursa protected the intact tendon adjacent to the injured tendon and maintained the morphology of the underlying bone. The bursa also promoted an early inflammatory response in the injured tendon, initiating key players in wound healing. In vivo results were supported by targeted organ culture studies of the bursa. To examine the potential to therapeutically target the bursa, dexamethasone was delivered to the bursa, prompting a shift in cellular signaling towards modulating inflammation in the healing tendon. In conclusion, contrary to current clinical practice, the bursa should be retained to the greatest extent possible and provides a new therapeutically target for improving tendon healing outcomes.
2023-07-07 | GSE235861 | GEO
Project description:Kidney fibrosis, characterized by excessive extracellular matrix (ECM) deposition, is a progressive disease that, despite affecting 10% of the population, lacks specific treatments and suitable biomarkers. Aimed at unraveling disease mechanisms and identifying potential therapeutic targets, this study presents a comprehensive, time-resolved multi-omics analysis of kidney fibrosis using an in vitro model system based on human kidney PDGFRβ+ mesenchymal cells. Using computational network modeling we integrated transcriptomics, proteomics, phosphoproteomics, and secretomics with imaging of the extracellular matrix (ECM). We quantified over 14,000 biomolecules across seven time points following TGF-β stimulation, revealing distinct temporal patterns in the expression and activity of known and potential novel renal fibrosis markers and modulators. The resulting time-resolved multi-omic network models allowed us to propose mechanisms related to fibrosis progression through early transcriptional reprogramming. Using siRNA knockdowns and phenotypic assays, we validated predictions and elucidated regulatory mechanisms underlying kidney fibrosis. Notably, we demonstrate that several early-activated transcription factors, including FLI1 and E2F1, act as negative regulators of collagen deposition and propose underlying molecular mechanisms. This work advances our understanding of the pathogenesis of kidney fibrosis and provides a valuable resource for the organ fibrosis research community.
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