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Project description:Fibroblasts hold pivotal roles in tissue homeostasis and disease progression. However, a systematic study addressing the functional heterogeneity of fibroblasts, their dynamic shifts along disease progression, as well as their impact to tumor immune microenvironment is currently lacking. Here, we performed integrated analyses on fibroblasts spanning multiple tissues and disease conditions, especially cancer. Our study provides novel insights into fibroblast cell heterogeneity and highlights the potential clinical utilities of fibroblast cell subsets as therapeutic targets.
2024-09-19 | GSE246216 | GEO
Project description:Fibroblasts hold pivotal roles in tissue homeostasis and disease progression. However, a systematic study addressing the functional heterogeneity of fibroblasts, their dynamic shifts along disease progression, as well as their impact to tumor immune microenvironment is currently lacking. Here, we performed integrated analyses on fibroblasts spanning multiple tissues and disease conditions, especially cancer. Our study provides novel insights into fibroblast cell heterogeneity and highlights the potential clinical utilities of fibroblast cell subsets as therapeutic targets.
2024-09-19 | GSE246215 | GEO
Project description:Cross-tissue human fibroblast atlas reveals myofibroblast subtypes with distinct roles in immune modulation
| PRJNA1032053 | ENA
Project description:Cross-tissue human fibroblast atlas reveals myofibroblast subtypes with distinct roles in immune modulation [RNA-seq]
| PRJNA1032063 | ENA
Project description:Cross-tissue human fibroblast atlas reveals myofibroblast subtypes with distinct roles in immune modulation [scRNA-seq]
| PRJNA1032060 | ENA
Project description:The limited molecular classifications and disease signatures of osteoarthritis (OA) impede the development of prediagnosis and targeted therapeutics for OA patients. To classify and understand the subtypes of OA, we collected three types of tissue including cartilage, subchondral bone, and synovium from multiple clinical centers and constructed an extensive transcriptome atlas of OA patients. By applying unsupervised clustering analysis to the cartilage transcriptome, OA patients were classified into four subtypes with distinct molecular signatures: a glycosaminoglycan metabolic disorder subtype (C1), a collagen metabolic disorder subtype (C2), an activated sensory neuron subtype (C3), and an inflammation subtype (C4). Through ligand-receptor crosstalk analysis of the three knee tissue types, we linked molecular functions with the clinical symptoms of different OA subtypes. For example, the Gene Ontology functional term of vasculature development was enriched in the subchondral bone-cartilage crosstalk of C2 and the cartilage-subchondral bone crosstalk of C4, which might lead to severe osteophytes in C2 patients and apparent joint space narrowing in C4 patients. Based on the marker genes of the four OA subtypes identified in this study, we modeled OA subtypes with two independent published RNA-seq datasets through random forest classification. The findings of this work contradicted traditional OA diagnosis by medical imaging and revealed distinct molecular subtypes in knee OA patients, which may allow for precise diagnosis and treatment of OA.
| S-EPMC7658991 | biostudies-literature
Project description:BackgroundMyofibroblasts are the critical effector cells in the pathogenesis of pulmonary fibrosis which carries a high degree of morbidity and mortality. We have previously identified Type II TGF? receptor interacting protein 1 (TRIP-1), through proteomic analysis, as a key regulator of collagen contraction in primary human lung fibroblasts--a functional characteristic of myofibroblasts, and the last, but critical step in the process of fibrosis. However, whether or not TRIP-1 modulates fibroblast trans-differentiation to myofibroblasts is not known.MethodsTRIP-1 expression was altered in primary human lung fibroblasts by siRNA and plasmid transfection. Transfected fibroblasts were then analyzed for myofibroblast features and function such as ?-SMA expression, collagen contraction ability, and resistance to apoptosis.ResultsThe down-regulation of TRIP-1 expression in primary human lung fibroblasts induces ?-SMA expression and enhances resistance to apoptosis and collagen contraction ability. In contrast, TRIP-1 over-expression inhibits ?-SMA expression. Remarkably, the effects of the loss of TRIP-1 are not abrogated by blockage of TGF? ligand activation of the Smad3 pathway or by Smad3 knockdown. Rather, a TRIP-1 mediated enhancement of AKT phosphorylation is the implicated pathway. In TRIP-1 knockdown fibroblasts, AKT inhibition prevents ?-SMA induction, and transfection with a constitutively active AKT construct drives collagen contraction and decreases apoptosis.ConclusionsTRIP-1 regulates fibroblast acquisition of phenotype and function associated with myofibroblasts. The importance of this finding is it suggests TRIP-1 expression could be a potential target in therapeutic strategy aimed against pathological fibrosis.
| S-EPMC3946032 | biostudies-literature
Project description:BackgroundPro-inflammatory fibroblasts are critical for pathogenesis in rheumatoid arthritis, inflammatory bowel disease, interstitial lung disease, and Sjögren's syndrome and represent a novel therapeutic target for chronic inflammatory disease. However, the heterogeneity of fibroblast phenotypes, exacerbated by the lack of a common cross-tissue taxonomy, has limited our understanding of which pathways are shared by multiple diseases.MethodsWe profiled fibroblasts derived from inflamed and non-inflamed synovium, intestine, lungs, and salivary glands from affected individuals with single-cell RNA sequencing. We integrated all fibroblasts into a multi-tissue atlas to characterize shared and tissue-specific phenotypes.FindingsTwo shared clusters, CXCL10+CCL19+ immune-interacting and SPARC+COL3A1+ vascular-interacting fibroblasts, were expanded in all inflamed tissues and mapped to dermal analogs in a public atopic dermatitis atlas. We confirmed these human pro-inflammatory fibroblasts in animal models of lung, joint, and intestinal inflammation.ConclusionsThis work represents a thorough investigation into fibroblasts across organ systems, individual donors, and disease states that reveals shared pathogenic activation states across four chronic inflammatory diseases.FundingGrant from F. Hoffmann-La Roche (Roche) AG.
| S-EPMC9271637 | biostudies-literature
Project description:Signal transducer and activator of transcription 1 (Stat1) is a ubiquitously expressed latent transcription factor that is activated by many cytokines and growth factors. Global Stat1 knockout mice are prone to chemical-induced lung and liver fibrosis, suggesting roles for Stat1 in tissue repair. However, the importance of Stat1 in fibroblast-mediated and vascular smooth muscle cell (VSMC)-mediated injury response has not been directly evaluated in vivo. Here, we focused on two models of tissue repair in conditional Stat1 knockout mice: excisional skin wounding in mice with Stat1 deletion in dermal fibroblasts, and carotid artery ligation in mice with global Stat1 deletion or deletion specific to VSMCs. In the skin model, dermal wounds closed at a similar rate in mice with fibroblast Stat1 deletion and controls, but collagen and α-smooth muscle actin (αSMA) expression were increased in the mutant granulation tissue. Cultured Stat1 -/- and Stat1 +/- dermal fibroblasts exhibited similar αSMA+ stress fiber assembly, collagen gel contraction, proliferation, migration, and growth factor-induced gene expression. In the artery ligation model, there was a significant increase in fibroblast-driven perivascular fibrosis when Stat1 was deleted globally. However, VSMC-driven remodeling and neointima formation were unchanged when Stat1 was deleted specifically in VSMCs. These results suggest an in vivo role for Stat1 as a suppressor of fibroblast mediated, but not VSMC mediated, injury responses, and a suppressor of the myofibroblast phenotype.
| S-EPMC7321860 | biostudies-literature
Project description:Trauma and transfusion can both alter immunity, and while transfusions are common among traumatically injured patients, few studies have examined their combined effects on immunity.We tracked the plasma levels of 41 immunomodulatory proteins in 56 trauma patients from time of injury up to 1 year later. In addition, a murine model was developed to distinguish between the effects of transfusion and underlying injury and blood loss.Thirty-one of the proteins had a significant change over time after traumatic injury, with a mixed early response that was predominantly anti-inflammatory followed by a later increase in proteins involved in wound healing and homeostasis. Results from the murine model revealed similar cytokine responses to humans. In mice, trauma and hemorrhage caused early perturbations in a number of the pro- and anti-inflammatory mediators measured, and transfusion blunted early elevations in interleukin (IL)-6, IL-10, matrix metalloproteinase-9, and interferon-?. Transfusion caused or exacerbated changes in monocyte chemotactic protein-1, IL-1?, IL-5, IL-15, and soluble E-selectin. Finally, trauma and hemorrhage alone increased CXCL1 and IL-13.This work provides a detailed characterization of the major shift in the immunologic environment in response to trauma and transfusion and clarifies which immune mediators are affected by trauma and hemorrhage and which by transfusion.
| S-EPMC3392528 | biostudies-other