Human Tendon-on-a-Chip for modeling vascular inflammatory fibrosis II
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1032856 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26265252.fastq.gz | Fastqsanger.gz | |||
| SRR26265253.fastq.gz | Fastqsanger.gz | |||
| SRR26265254.fastq.gz | Fastqsanger.gz | |||
| SRR26265255.fastq.gz | Fastqsanger.gz | |||
| SRR26265256.fastq.gz | Fastqsanger.gz |
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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: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.
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Project description:Human Tendon-on-a-Chip for modeling vascular inflammatory fibrosis
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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.
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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
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Project description:Chronic fibrosis is a hallmark of pathologic tissue remodelling that deteriorates organ function and eventually leads to death. Although fibroblasts are typically made responsible, it was recently suggested that endothelial cells contribute to fibrosis, although the functional importance of this phenomenon remained unclear. In this study, we addressed this question by genetic manipulation of the fibrogenic HMG-box transcription factor SOX9 specifically in vascular endothelial cells. Induced transgenic overexpression of SOX9 in these cells in mice triggered extensive fibrosis, organ growth and dysfunction in the heart, lung, liver and spleen. We found an upregulation of endogenous Sox9 in endothelial cells during cardiac, lung and liver fibrosis, and endothelial specific Sox9 deletion prevented fibrosis and organ dysfunction in mouse models of systolic and diastolic heart failure, as well as in mouse bleomycin induced pulmonary and non-alcoholic steato-hepatitis (NASH) triggered liver fibrosis. Mechanistically, a combined approach of bulk and single cell RNA sequencing of endothelial cells across multiple vascular beds revealed that Sox9 promoted the expression of extracellular matrix and matrix remodelling genes, growth factors, and inflammatory mediators, which triggered the expression of extracellular matrix directly by endothelial cells, but also activated fibroblasts. As we found the upregulation of endothelial Sox9 also in failing human hearts, we propose that endothelial Sox9 could be a target for anti-fibrotic therapy.
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