Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Histological Signatures Reveal Anti-Fibrotic Factors in Mouse and Human Lungs [scRNA-seq]

ABSTRACT: Fibrosis, the replacement of healthy tissue with collagen-rich matrix, can occur following injury in almost every organ. Mouse lungs follow stereotyped sequences of fibrogenesis-to-resolution after bleomycin injury, and we reasoned that profiling post-injury histological progression could uncover pro- vs. anti-fibrotic features with functional value for human fibrosis. We mapped spatiotemporally-resolved transformations in lung extracellular matrix (ECM) architecture to spatially-resolved, multi-omic data. First, we charted stepwise trajectories of matrix aberration vs. resolution using unsupervised machine learning, denoting a reversible transition in uniform-to-disordered histological architecture. Single-cell sequencing along these trajectories identified temporally-enriched “ECM-secreting” (Csmd1+) and “pro-resolving” (Cd248+) fibroblasts, for which Visium inferred divergent histological signatures and spatial-transcriptional “neighborhoods”. Critically, pro-resolving fibroblast instillation helped ameliorate fibrosis in vivo. Further, fibroblast neighborhood-associated moieties, Serpine2 and Pi16, functionally modulated human lung fibrosis ex vivo. Spatial phenotyping of idiopathic pulmonary fibrosis further uncovered analogous fibroblast subtypes and neighborhoods in human disease. Collectively, these findings establish an atlas of pro-/anti-fibrotic factors underlying lung matrix architecture and implicate fibroblast-centered moieties in modulating fibrotic progression vs. resolution.

ORGANISM(S): Mus musculus

PROVIDER: GSE250396 | GEO | 2025/01/07

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Histological Signatures Reveal Anti-Fibrotic Factors in Mouse and Human Lungs [scATAC-Seq]

Project description:Fibrosis, the replacement of healthy tissue with collagen-rich matrix, can occur following injury in almost every organ. Mouse lungs follow stereotyped sequences of fibrogenesis-to-resolution after bleomycin injury, and we reasoned that profiling post-injury histological progression could uncover pro- vs. anti-fibrotic features with functional value for human fibrosis. We mapped spatiotemporally-resolved transformations in lung extracellular matrix (ECM) architecture to spatially-resolved, multi-omic data. First, we charted stepwise trajectories of matrix aberration vs. resolution using unsupervised machine learning, denoting a reversible transition in uniform-to-disordered histological architecture. Single-cell sequencing along these trajectories identified temporally-enriched “ECM-secreting” (Csmd1+) and “pro-resolving” (Cd248+) fibroblasts, for which Visium inferred divergent histological signatures and spatial-transcriptional “neighborhoods”. Critically, pro-resolving fibroblast instillation helped ameliorate fibrosis in vivo. Further, fibroblast neighborhood-associated moieties, Serpine2 and Pi16, functionally modulated human lung fibrosis ex vivo. Spatial phenotyping of idiopathic pulmonary fibrosis further uncovered analogous fibroblast subtypes and neighborhoods in human disease. Collectively, these findings establish an atlas of pro-/anti-fibrotic factors underlying lung matrix architecture and implicate fibroblast-centered moieties in modulating fibrotic progression vs. resolution.

2025-01-07 | GSE250397 | GEO

Histological Signatures Reveal Anti-Fibrotic Factors in Mouse and Human Lungs [Visium]

2025-01-07 | GSE250395 | GEO

ZNF416 is a pivotal transcriptional regulator of fibroblast mechano-activation [ChIP-seq]

Project description:Matrix stiffness is a central regulator of fibroblast function. However, the transcriptional mechanisms linking matrix stiffness to changes in fibroblast phenotype are incompletely understood. Here, we evaluated the effect of matrix stiffness on genome-wide chromatin accessibility in freshly-isolated lung fibroblasts using ATAC-seq. We found higher matrix stiffness profoundly increased global chromatin accessibility relative to lower matrix stiffness, and these alterations were in close genomic proximity to known pro-fibrotic gene programs. Motif analysis of these regulated genomic loci identified ZNF416 as a putative mediator of fibroblast stiffness responses. Genome occupancy analysis using ChIP-seq confirmed that ZNF416 occupies a broad range of genes implicated in fibroblast activation and tissue-fibrosis, with relatively little overlap in genomic occupancy with other mechanoresponsive and pro-fibrotic transcriptional regulators. Using loss and gain of function studies we demonstrated that ZNF416 plays a critical role in fibroblast proliferation, extracellular matrix synthesis and contractile function. Together these observations identify ZNF416 as novel mechano-activated transcriptional regulator of fibroblast biology.

2020-11-14 | GSE161446 | GEO

ZNF416 is a pivotal transcriptional regulator of fibroblast mechano-activation [ATAC-seq]

2020-11-14 | GSE161434 | GEO

Loss of Fas-signaling in pro-fibrotic fibroblasts impairs homeostatic fibrosis resolution and promotes persistent pulmonary fibrosis

Project description:Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible fibrotic disease of the distal lung alveoli that culminates in respiratory failure and reduced lifespan. Unlike normal lung repair in response to injury, IPF is associated with the accumulation and persistence of fibroblasts and myofibroblasts and continued production of collagen and other extracellular matrix (ECM) components. Prior in vitro studies have led to the hypothesis that the development of resistance to Fas-induced apoptosis by lung fibroblasts and myofibroblasts contibributes to their accumulation in the distal lung tissues of IPF patients. Here, we test this hypothesis in vivo in the resolving model of bleomycin-induced pulmonary fibrosis in mice. Using genetic loss-of-function approaches to inhibit Fas signaling in fibroblasts, novel flow cytometry strategies to quantify lung fibroblast subsets and transcriptional profiling of lung fibroblasts by bulk and single cell RNA-sequencing, we show that Fas is necessary for lung fibroblast apoptosis during homeostatic resolution of bleomycin-induced pulmonary fibrosis in vivo. Furthermore, we show that loss of Fas signaling leads to the persistence and continued pro-fibrotic functions of lung fibroblasts. Our studies provide novel insights into the mechanisms that contribute to fibroblast survival, persistence and continued ECM deposition in the context of IPF and how failure to undergo Fas-induced apoptosis prevents fibrosis resolution.

2020-11-18 | GSE161648 | GEO

1. SILAC based secretome analysis of WT and tKO cells

Project description:Integrins play a vital role in coordinating between the extracellular matrix (ECM) and the intracellular environment, thus enabling transduction of biomechanical signals to maintain tissue homeostasis. Here we investigate the significance of collagen-binding integrins in regulating fibroblast functions with relevance to fibrosis. Our data suggest that secretome from primary dermal fibroblasts isolated from mice lacking three collagen-binding integrins α1, α2 and α11 shows downregulation of several proteins essential for structure and regulation of crucial pro-fibrotic ECM components. In summary, abrogation of integrin-mediated cell-collagen association attenuates fibrosis.

2023-08-21 | PXD044683 | Pride

RNA-seq: STAT1 and STAT3 transcription factors sense and interpret changes in inflammation through engagement of specific enhancers

Project description:To investigate potential changes in the provision of competent host defence versus inflammation-induced tissue injury, we used RNA-seq to profile gene signatures in ‘resolving’ and ‘pro-fibrotic’ peritoneal lining tissues. We performed RNA-seq in peritoneal membranes from WT and IL6KO mice challenge with SES - Lyophilized cell-free supernatant prepared from Staphylococcus epidermidis ('resolving') and mice challenged with SES and CD4+ Th1 cells at the same time ('pro-fibrotic'). The peritoneal membrane was harvested at 3h and 6h after the injection.

2022-04-04 | E-MTAB-10087 | biostudies-arrayexpress

Single-cell RNA sequencing reveals cellular composition of fibrotic fascia associated with gluteal muscle contracture

Project description:Fibrosis is a common and integral pathological feature in various chronic diseases, capable of affecting any tissue or organ. Fibrosis within deep fascia is implicated in many myofascial disorders, including gluteal muscle contracture (GMC), Dupuytren’s disease, plantar fasciitis, iliotibial band syndrome, and chronic muscle pain. In this study, we performed scRNA seq analysis on fibrotic fascia associated with GMC and compared them to nonfibrotic control fascial samples. Our findings show that fibroblast and macrophage cells play a role in pathological tissue remodeling within fibrotic deep fascia. We observed an upregulation of various collagens, proteoglycans, and extracellular matrix (ECM) glycoproteins in contracture deep fascia, attributed to the widespread activation of fibroblast subclusters. Additionally, two pro fibrotic macrophage subpopulations, SPP1+ MP and ECM like MP, appear to facilitate ECM deposition in fibrotic deep fascia by either regulating fibroblast activation or directly contributing to ECM production. SPP1+ MP and ECM like MP cells, as well as the signal interaction between SPP1+ MP and fibroblast cells, present novel and potential therapeutic target for treating GMC and other related myofascial disorders.

2025-02-26 | GSE273293 | GEO

SPI1/PU.1 controls fibroblast polarization and tissue fibrosis

Project description:Fibroblasts are polymorphic cells with pleiotropic roles in organ morphogenesis, tissue homeostasis and immune responses. In fibrotic diseases, fibroblasts synthesize abundant amounts of extracellular matrix which lead to scaring and organ failure. In sharp contrast, the hallmark feature of fibroblasts in arthritis is matrix degradation by the release of metalloproteinases and degrading enzymes, and subsequent tissue destruction. The mechanisms driving these functionally opposing pro-fibrotic and pro-inflammatory phenotypes of fibroblasts are enigmatic. We have compared resting, fibrotic, and inflammatory fibroblasts; PU.1 was overexpressed in dermal fibroblasts and compared to scr-transfected controls. Fibrotic fibroblasts isolated from the skin of patients with systemic sclerosis were treated with PU.1 inhibitor and compared to untreated fibrotic fibroblasts and respective healthy controls. Through this, we identified the transcription factor PU.1 as an essential orchestrator of the pro-fibrotic gene expression program. The interplay between transcriptional and post-transcriptional mechanisms which normally control PU.1 expression is perturbed in fibrotic diseases such as pulmonary fibrosis, systemic sclerosis, liver cirrhosis, kidney fibrosis and chronic graft-versus-host disease, resulting in upregulation of PU.1, the induction of fibrosis-associated gene sets, and a phenotypic switch in matrix-producing pro-fibrotic fibroblasts. In contrast, inactivation of PU.1 disrupts the fibrotic network and enables re-programming of fibrotic fibroblasts into resting fibroblasts with regression of fibrosis in different organs. Targeting of PU.1 may thus represent a novel therapeutic approach for the treatment of a wide range of fibrotic diseases.

2018-11-09 | GSE122334 | GEO

The Forkhead Box F1 Transcription Factor Inhibits Collagen Deposition and Accumulation of Myofibroblasts During Liver Fibrosis

Project description:Hepatic fibrosis is the common end stage to a variety of chronic liver injuries and is characterized by an excessive deposition of extracellular matrix (ECM), which disrupts the liver architecture and impairs liver function. The fibrous lesions are produced by myofibroblasts, which differentiate from hepatic stellate cells (HSC). The myofibroblasts transcriptional networks remain poorly characterized. Previous studies have shown that the Forkhead box F1 (FOXF1) transcription factor is expressed in HSCs and stimulates their activation during acute liver injury; however, the role of FOXF1 in the progression of hepatic fibrosis is unknown. In the present study, we generated αSMACreER;Foxf1fl/fl mice to conditionally inactivate Foxf1 in myofibroblasts during carbon tetrachloride-mediated liver fibrosis. Foxf1 deletion increased collagen depositions and disrupted liver architecture. Timp2 expression was significantly increased in Foxf1-deficient mice while MMP9 activity was reduced. RNA sequencing of purified liver myofibroblasts demonstrated that FOXF1 inhibits expression of pro-fibrotic genes, Col1α2, Col5α2, and Mmp2 in fibrotic livers and binds to active repressors located in promotors and introns of these genes. Overexpression of FOXF1 inhibits Col1a2, Col5a2, and MMP2 in primary murine HSCs in vitro. Altogether, FOXF1 prevents aberrant ECM depositions during hepatic fibrosis by repressing pro-fibrotic gene transcription in myofibroblasts and HSCs.

2019-02-05 | GSE123726 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data