Mechanical Unloading of Engineered Human Meniscus Models Under Simulated Microgravity
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PROVIDER: PRJNA794056 | ENA |
REPOSITORIES: ENA
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Project description:The aim of this study is to demonstrate that mechanical unloading via SMG will induce a higher osteoarthritic-like gene profile in bioengineered meniscal cartilage from healthy female MFC versus healthy male MFC. This would serve as the molecular basis for early onset of knee osteoarthritis in females
2022-05-20 | GSE192983 | GEO
Project description:This study aimed to evaluate the effects of mechanical loading and unloading via CHP and SMG, respectively, on the OA-related profile changes of engineered meniscus tissues and explore biological sex-related differences
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Project description:Meniscus fibrochondrocytes (MFCs) experience simultaneous hypoxia and mechanical loading in the knee, conditions that have promising applications in human meniscus tissue engineering. We hypothesized that “mechano-hypoxia conditioning,” using mechanical loading such as dynamic compression (DC) and cyclic hydrostatic pressure (CHP), would enhance development of human meniscus fibrocartilage extracellular matrix in vitro. MFCs from inner human meniscus surgical discards were pre-cultured on porous type I collagen scaffolds with TGF-β3 supplementation to form baseline tissues with newly-formed matrix. They were then treated with DC or CHP under hypoxia (HYP, 3% O2) for 5 days. DC was the more effective load regime, and combined HYP/DC enhanced gene expression of fibrocartilage precursors. The individual treatments of DC and HYP regulated thousands of genes and combined in an overwhelmingly additive rather than synergistic manner. Baseline tissues were then treated with a short course of DC (5 vs 60 minutes, 10-20% vs 30-40% strain) with different pre-culture durations (3 vs 6 weeks). Longer courses of loading had diminishing returns in terms of gene regulation. There was a dose-effect for higher DC strains, whereas outcomes were mixed for different MFC donors in pre-culture durations. Finally, baseline tissues were conditioned for 3 weeks with mechano-hypoxia conditioning to assess mechanical and protein-level outcomes. There were 1.8 to 5.1-fold gains in the dynamic modulus relative to baseline in HYP/DC, but matrix outcomes were equal or inferior to static controls. Long-term mechano-hypoxia conditioning was effective in suppressing hypertrophic markers (e.g., COL10A1 10-fold suppression vs static/normoxia). Applied appropriately, mechano-hypoxia conditioning can support meniscus fibrocartilage development in vitro and may be useful as a strategy for developing non-hypertrophic articular cartilage using mesenchymal stem cells.
2021-08-23 | GSE180467 | GEO
Project description:This study investigates the transcriptome response of meniscus fibrochondrocytes (MFCs) to the low oxygen and mechanical loading signals experienced in the knee joint using a model system. We hypothesized that short term exposure to the combined treatment would promote a matrix-forming phenotype supportive of inner meniscus tissue formation. Human MFCs on a collagen scaffold were stimulated to form fibrocartilage over 6weeks under normoxic (NRX, 20% O2) conditions with supplemented TGF -β3. Tissues experienced a delayed 24h hypoxia treatment (HYP, 3% O2) and then 5min of dynamic compression (DC) between 30 and 40% strain. Delayed HYP induced an anabolic and anti-catabolic expression profile for hyaline cartilage matrix markers, while DC induced an inflammatory matrix remodeling response along with upregulation of both SOX9 and COL1A1. There were 41 genes regulated by both HYP and DC. Overall, the combined treatment supported a unique gene expression profile favouring the hyaline cartilage aspect of inner meniscus matrix and matrix remodeling.
2021-02-17 | GSE166908 | GEO
Project description:Microgravity is known to affect the organization of the cytoskeleton, cell and nuclear morphology and to elicit differential expression of genes associated with the cytoskeleton, focal adhesions and the extracellular matrix. Although the nucleus is mechanically connected to the cytoskeleton through the LInker of Nucleoskeleton and Cytoskeleton (LINC) complex, the role of this group of proteins in these responses to microgravity has yet to be defined. Therefore, we used simulated microgravity achieved by growing cells on a 3d clinostat to investigate whether the LINC complex acts to mediate responses to the microgravity environment. We show that nuclear shape and differential gene expression are both responsive to simulated microgravity in a LINC-dependent manner and that this response changes with the duration of exposure to simulated microgravity. These LINC-dependent genes likely represent elements normally regulated by the mechanical forces imposed by gravity on Earth.
2021-01-31 | GSE153893 | GEO
Project description:The below table includes a smaller list of data that was analyzed by dChip and filtered by pvalue such that a file with about 4600 genes was obtained, which allowed for ease of use from 40,000 genes. Keywords: static vs simulated microgravity
2006-12-31 | GSE4658 | GEO
Project description:Cardiogenic shock (CS) alters whole body metabolism and circulating biomarkers serve as prognostic markers in CS patients. Percutaneous ventricular assist devices (pVADs) unload the left ventricle by actively ejecting blood into the aorta. The goal of the present study was to identify alterations in circulating metabolites and transcripts in a large animal model that might serve as potential prognostic biomarkers in acute CS and additional left ventricular unloading by Impella® pVAD support. Methods: CS was induced in a preclinical large animal model by injecting microspheres into the left coronary artery system in six pigs. After the induction of CS, mechanical pVAD support was implemented for 30 minutes total. Serum samples were collected under basal conditions, after the onset of CS, and following additional pVAD unloading. Circulating metabolites were determined by metabolomic analysis, circulating RNA entities by RNA sequencing. Results: CS and additional pVAD support alter the abundance of circulating metabolites involved in Aminoacyl-tRNA biosynthesis and amino acid metabolism. RNA sequencing revealed decreased abundance of the hypoxia sensitive miRNA-200b following the induction of CS, which was reversed following pVAD support. Conclusions: The hypoxamir miRNA-200b is a potential circulating marker that is repressed in CS and is restored following pVAD support. The early transcriptional response with increased miRNA-200b expression following only 30 minutes of pVAD support suggests that mechanical unloading alters whole body metabolism. Future studies are required to delineate the impact of serum miRNA-200b levels as a prognostic marker in patients with acute CS and pVAD unloading.
2022-06-15 | GSE199090 | GEO
Project description:Meniscus injuries are highly prevalent and are linked to the development of post-traumatic osteoarthritis (PTOA). The inflammatory cytokine IL-1 is elevated in synovial fluid following knee injuries, causes degradation of meniscus tissue, and inhibits meniscus repair. Dynamic mechanical compression of meniscus tissue has been shown to improve integrative repair in the presence of IL-1; however, there remains a dearth of knowledge on global effects of loading on meniscus cell phenotype and transcriptomic profiles. In this study, we performed mRNA-Seq on meniscus tissue explants from inner and outer zone regions of porcine menisci subjected to dynamic compression in the presence and absence of IL-1 to identify cellular responses to mechanical load, identify differences in response to load based on zonal characteristics, and identify IL-1 induced inflammatory responses modulated by load.
2021-12-24 | GSE191175 | GEO
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Project description:Microgravity impacts various aspects of human health. Yet the mechanisms of spaceflight-induced health problems are not elucidated. Here we mapped the fusion systemic analysis of the serum metabolome and the circulating microRNAome in a hindlimb unloading rat model to simulate microgravity. The response of serum metabolites and microRNAs to simulated microgravity (SMG) was striking. Integrated pathway analysis of altered serum metabolites and target genes of the significantly altered circulating miRNAs with Integrated Molecular Pathway-Level Analysis (IMPaLA) software was mainly suggestive of modulation of neurofunctional signaling pathways. Particularly, we revealed significantly increased miR-383-5p and decreased aquaporin 4 (AQP4) - in the hippocampus. Utilizing Rrabies Virus Glycoprotein (RVG)-modified exosomes, delivery of miR-383-5p inhibited the expression of AQP4 not only in rat C6 glioma cells in vitro but also in the hippocampus in vivo. Using bioinformatics to map the crosstalk between the circulating metabolome and miRNAome could offer opportunities to understand complex biological systems under microgravity. Our present results suggested that the change of miR-383-5p level and its regulation of target gene AQP4 was one of the potential molecular mechanisms of microgravity induced cognitive impairment in the hippocampus. MiRNA plays an important role during the adaptation to microgavity. In this study, effects of simulated microgravity on circulating microRNA profiles were performed to sreen different expression miRNA and gravity-sensitive miRNAs.
2020-07-08 | GSE153681 | GEO