Human intestinal myofibroblasts deposited collagen VI enhances adhesiveness for T cells – A novel mechanism for maintenance of intestinal inflammation

Lin, Sinan; Musso, Alessandro; Wang, Jie; Mukherjee, Pranab K.; West, Gail; Mao, Ren; Lyu, Ruishen; Li, Jiannan; Zhao, Shuai; Elias, Michael; Haberman, Yael; Denson, Lee A.; Kugathasan, Subra; Chen, Minhu; Czarnecki, Doug; Dejanovic, Dina; Le, Hongnga T.; Chandra, Jyotsna; Lipman, Jeremy M.; Steele, Scott R.; Nguyen, Quan; Fiocchi, Claudio; Rieder, Florian

doi:10.1016/j.matbio.2022.09.001

Cited by 12 publications

(7 citation statements)

References 73 publications

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“…Co-treatment with ETYA and LPS resulted in differential expression of 859 genes, relative to stimulation with LPS alone (Fig.3A and Supplemental Table 3). This included suppression of genes expressed by small intestinal monocytes and myeloid cells (FDR B&H: 2.26E-45), including those encoding CD risk genes involved in host:microbe interactions (FDR B&H: 1.22E-11) and the matrisome 13 (FDR B&H: 1.65E-08, Figs. 3B & 3C and Supplemental Table 3).…”

Section: Resultsmentioning

confidence: 99%

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Eicosatetraynoic Acid Regulates Pro-Fibrotic Pathways in an Induced Pluripotent Stem Cell Derived Macrophage:Human Intestinal Organoid Model of Crohn’s Disease

Jurickova,

Dreskin,

Angerman

et al. 2024

Preprint

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Background and Aims: We previously identified small molecules predicted to reverse an ileal gene signature for future Crohns Disease (CD) strictures. Here we used a new human intestinal organoid (HIO) model system containing macrophages to test a lead candidate, eicosatetraynoic acid (ETYA). Methods: Induced pluripotent stem cell lines (iPSC) were derived from CD patients and differentiated into macrophages and HIOs. Macrophages and macrophage:HIO co-cultures were exposed to lipopolysaccharide (LPS) with and without ETYA pre-treatment. Cytospin and flow cytometry characterized macrophage morphology and activation markers, and RNA sequencing defined the global pattern of macrophage gene expression. TaqMan Low Density Array, Luminex multiplex assay, immunohistologic staining, and sirius red polarized light microscopy were performed to measure macrophage cytokine production and HIO pro-fibrotic gene expression and collagen content. Results: iPSC-derived macrophages exhibited morphology similar to primary macrophages and expressed inflammatory macrophage cell surface markers including CD64 and CD68. LPS-stimulated macrophages expressed a global pattern of gene expression enriched in CD ileal inflammatory macrophages and matrisome secreted products, and produced cytokines and chemokines including CCL2, IL1B, and OSM implicated in refractory disease. ETYA suppressed CD64 abundance and pro-fibrotic gene expression pathways in LPS stimulated macrophages. Co-culture of LPS-primed macrophages with HIO led to up-regulation of fibroblast activation genes including ACTA2 and COL1A1, and an increase in HIO collagen content. ETYA pre-treatment prevented pro-fibrotic effects of LPS-primed macrophages. Conclusions: ETYA inhibits pro-fibrotic effects of LPS-primed macrophages upon co-cultured HIO. This model may be used in future untargeted screens for small molecules to treat refractory CD.

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Section: Resultsmentioning

confidence: 99%

“…3A and Supplemental Table 3). This included suppression of genes expressed by small intestinal monocytes and myeloid cells (FDR B&H: 2.26E-45), including those encoding CD risk genes involved in host:microbe interactions (FDR B&H: 1.22E-11) and the matrisome 13 (FDR B&H:…”

Section: Patient Ipsc-derived Macrophages Exhibit Primary Macrophage ...mentioning

confidence: 99%

Eicosatetraynoic Acid Regulates Pro-Fibrotic Pathways in an Induced Pluripotent Stem Cell Derived Macrophage:Human Intestinal Organoid Model of Crohn’s Disease

Jurickova,

Dreskin,

Angerman

et al. 2024

Preprint

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“…6D ). The top 10 overlapped genes included SERPINA3 , C3 , COL6A2 , LTBP4 , MGP , APOE , MT2 , ITGA5 , THBS1 , and IGFBP4 , most of which are associated with inflammatory response and fibrosis ( Bai et al, 2022 ; Isola et al, 2023 ; Lin et al, 2022 ) ( Fig. 6E ).…”

Section: Resultsmentioning

confidence: 99%

Aging hallmarks of the primate ovary revealed by spatiotemporal transcriptomics

Lu,

Jing,

Zhang

et al. 2023

Protein &Amp; Cell

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The ovary is indispensable for female reproduction, and its age-dependent functional decline is the primary cause of infertility. However, the molecular basis of ovarian aging in higher vertebrates remains poorly understood. Herein, we apply spatiotemporal transcriptomics to benchmark architecture organization as well as cellular and molecular determinants in young primate ovaries and compare these to aged primate ovaries. From a global view, somatic cells within the non-follicle region undergo more pronounced transcriptional fluctuation relative to those in the follicle region, likely constituting a hostile microenvironment that facilitates ovarian aging. Further, we uncovered that inflammation, the senescent associated secretory phenotype (SASP), senescence and fibrosis are the likely primary contributors to ovarian aging (PCOA). Of note, we identified spatial co-localization between a PCOA-featured spot and an unappreciated MT2 (Metallothionein 2) highly expressing spot (MT2high) characterized by high levels of inflammation, potentially serving as an aging hotspot in the primate ovary. Moreover, with advanced age, a subpopulation of MT2high accumulates, likely disseminating and amplifying the senescent signal outward. Our study establishes the first primate spatiotemporal transcriptomic atlas, advancing our understanding of mechanistic determinants underpinning primate ovarian aging and unraveling potential biomarkers and therapeutic targets for aging and age-associated human ovarian disorders.

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“…CD-associated stricture was caused by the imbalance of fibrosis and repair; in other words, the imbalance of ECM production and degradation ( 39 ). Specific ECM patterns have been reported to be associated with future disease behavior progression of CD ( 40 – 42 ). From this perspective, the increasing stiffness of the intestine caused by ECM accumulation and assessed using SWE is present before the progression of symptomatic internal penetrating and/or stricturing disease, suggesting that early anatomic structure damage may occur.…”

Section: Discussionmentioning

confidence: 99%

Bowel Stiffness Assessed by Shear-Wave Ultrasound Elastography Predicts Disease Behavior Progression in Patients With Crohn's Disease

Chen,

He,

Xiong

et al. 2024

Clinical and Translational Gastroenterology

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Objectives: There is a lack of reliable predictors of disease behavior progression in patients with Crohn’s disease (CD). Real-time shear-wave elastography (SWE) is a novel method for evaluating tissue stiffness. However, its value for assessing CD has not yet been investigated. We aimed to explore the value of SWE and other ultrasound parameters at diagnosis in predicting CD behavior progression. Methods: We retrospectively collected data from CD patients with the non-stenotic non-penetrating disease (B1 phenotype based on the Montreal classification). All patients underwent intestinal ultrasound at baseline and were followed up. The endpoint was defined as disease behavior progression to stricturing (B2) or penetrating (B3) disease. Cox regression analysis was performed for the association between baseline characteristics and subsequent endpoints. Additionally, a multivariate nomogram was established to predict the risk of disease behavior progression quantitatively. Results: A total of 130 CD patients with B1 phenotype were enrolled. Twenty-seven patients (20.8%) developed B2 or B3 disease, with a median follow-up of 33 months. Multivariate analysis identified that SWE was the only independent predictor of disease behavior progression (HR 1.08, 95% CI 1.03–1.12, P=0.001). A reverse of the hazard ratio appeared at the cut-off 12.75 kPa. The nomogram incorporating SWE and other clinical characteristics showed a good prediction performance (AUC=0.792). Conclusions: Intestinal stiffness assessed using SWE is an independent predictor of disease behavior progression in patients with CD. CD patients with SWE >12.75 kPa at diagnosis are prone to progress toward stricturing or penetrating diseases.

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Human intestinal myofibroblasts deposited collagen VI enhances adhesiveness for T cells – A novel mechanism for maintenance of intestinal inflammation

Cited by 12 publications

References 73 publications

Eicosatetraynoic Acid Regulates Pro-Fibrotic Pathways in an Induced Pluripotent Stem Cell Derived Macrophage:Human Intestinal Organoid Model of Crohn’s Disease

Eicosatetraynoic Acid Regulates Pro-Fibrotic Pathways in an Induced Pluripotent Stem Cell Derived Macrophage:Human Intestinal Organoid Model of Crohn’s Disease

Aging hallmarks of the primate ovary revealed by spatiotemporal transcriptomics

Bowel Stiffness Assessed by Shear-Wave Ultrasound Elastography Predicts Disease Behavior Progression in Patients With Crohn's Disease

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