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Meniscus-On-a-Chip model to delineate multi-tissue crosstalk

ABSTRACT: Meniscus has been largely ignored for the emerging research interest of multi-tissue crosstalk in knee joints. This study discovers the novel roles of three-way crosstalk between meniscus, synovial membrane, and fat in regulation of meniscus injury, degeneration, and healing. A novel meniscus-on-a-chip (MoC) model is developed, equipped with bioprinted synovial membrane, engineered fat tissue, and meniscus explant healing model, treated with bioactive glue and synovial mesenchymal stem cells (syMSCs). Our MoC integrated with meniscus-specific bioreactor enables a comprehensive investigation into the combinational effects of inflammation and physiological/pathological loading on meniscus healing and degeneration. The MoC successfully not only replicates meniscus healing induced by bioactive glue but also the OA initiation and progression from meniscus injury. Comprehensive scRNA-seq with CellChat analysis discovers how communications between adipocytes, macrophages, fibrochondrocytes, and syMSCs regulate the fate of meniscus injury in response to exogenous stimulations. This study represents the first identification of essential cell-cell communication signals between meniscus, synovial membrane, fat, and syMSCs, which are responsible for regulating meniscus healing under inflammation and mechanical loading. These novel findings may have significant implications for developing next-generation therapeutics for meniscus injury and prevention of joint degeneration through regulating multi-tissue crosstalk in the joint.

ORGANISM(S): Homo sapiens

PROVIDER: GSE316376 | GEO | 2026/09/23

REPOSITORIES: GEO

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Project description:Background: Meniscus tears are the most common injury in the knee and are associated with an increased risk of osteoarthritis (OA). The molecular profile of knees with meniscus tears is not well-studied. Therefore, to advance our understanding of the early response of the knee to injury, we compared the gene expression profile of meniscus and articular cartilage within the same knees following meniscus injury. Hypothesis/Purpose: To identify differences between the molecular signatures of meniscus and articular cartilage from knees with intact articular cartilage undergoing arthroscopic partial meniscectomy. Study Design: Descriptive laboratory study Methods: Patients (n=12) with a known isolated medial meniscus tear without any knee chondrosis or radiographic OA were consented prior to surgery. During arthroscopic partial meniscectomy, a sample of their injured meniscus and a sample of their articular cartilage off the medial femoral condyle were procured. The transcriptome signatures, as measured through Affymetrix microarray, were compared between the two tissues and underlying biological processes were explored computationally. Results: 3566 gene transcripts were differentially expressed between meniscus and articular cartilage. Gene transcripts down-regulated in articular cartilage were associated with extracellular matrix organization, wound healing, cell adhesion, and chemotaxis. Gene transcripts up-regulated in articular cartilage were associated with blood vessels morphogenesis and angiogenesis. Examples of individual genes with significant differences in expression between the two tissues include IBSP (23.76 fold; P < 0.001), upregulated in meniscus, and TREM1 (3.23 fold; P = 0.006), upregulated in meniscus. Conclusion: The meniscus and articular cartilage have distinct gene expression profiles in knees with meniscus tears and intact articular cartilage. Total RNA obtained from injured meniscus and normal articular cartilage from patients undergoing partial meniscectomy.

Project description:Ectopic calcification in synovial tissues is devastating to diarthrodial joints. While some forms of synovial ectopic calcification have genetically simple basis, most cases manifest as complex traits with environmental and multigenic components. The location of causal loci or the physiological processes affected by allelic variants is poorly understood. Here, we report on genetic susceptibility to ectopic calcification in the LG/J and SM/J advanced intercross mice. Using 347 mice in 98 full-sibships, destabilization of medial meniscus was performed to induce joint injury. We performed quantitative trait locus (QTL) analysis to map calcification phenotypes to discrete genomic locations. To validate the functional significance of the selected QTL candidate genes, we compared mRNA expression between parental LG/J and SM/J inbred strains. Our findings showed that joint destabilization instigated ectopic calcifications as detected and quantified by micro-CT. Overall, we detected 20 QTLs affecting synovial and meniscus calcification phenotypes with 11 QTLs linked to synovial calcification. Functional and bioinformatic analyses of single nucleotide polymorphism identified functional classifications relevant to angiogenesis (Myo1e, Kif26b, Nprl3, Stab2, Fam105b), bone metabolism/calcification (Tle3, Tgfb2, Lipc, Nfe2l1, Ank, Fam105b), arthritis (Stab2, Tbx21, Map4k4, Hoxb9, Larp6, Col1a2, Adam10, Timp3, Nfe2l1, Trpm3), and ankylosing-spondylitis (Ank, Pon1, Il1r2, Tbkbp1) indicating that ectopic calcification involves multiple mechanisms. Furthermore, the expression of 11 candidate genes was significantly different between LG/J and SM/J. Correlation analysis showed that Aff3, Fam81a, Syn3, and Ank were correlated with synovial calcification. Our findings of multiple genetic loci affecting the phenotype suggest the involvement of multiple genes contributing to its pathogenesis. We collected tissue lysates from the formalin-fixed paraffin-embedded sections from mouse knee joints and analyzed the expression of several genes by Affymetrix QuantiGene Plex assay.

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Meniscus-On-a-Chip model to delineate multi-tissue crosstalk

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