Dataset Information

COLLAGEN POST-TRANSLATIONAL MODIFICATIONS ARE ALTERED IN IPF INCLUDING WITHIN ECM RECEPTOR BINDING MOTIFS

ABSTRACT: Idiopathic pulmonary fibrosis (IPF) is a fatal chronic lung disease with a median survival of 3.8 years, a prevalence of 10 to 60 cases per 100,000 in the United States, and rising incidence and mortality rates. Currently approved antifibrotic agents can slow disease progression but are insufficient to significantly improve long-term outcomes. Tissue remodeling in IPF is driven by fibroblast activation and excessive deposition of fibrillar collagen and other extracellular matrix (ECM) components. An increasing body of evidence suggests that the ECM instructs resolution or progression of fibrotic disease. To date, ECM-targeting therapies including e.g. ECM crosslinking inhibitors, and drugs targeting ECM receptors like integrins have shown promise in preclinical animal models of organ fibrosis but were ineffective or associated with unfavorable safety profiles in clinical trials. Targeting collagen biosynthesis is a promising antifibrotic therapeutic avenue and imaging with collagen-binding peptides emerges as a non-invasive biomarker for diagnosis and disease progression. But collagen measurements in preclinical models and patient samples typically rely on methods that do not differentiate between collagen types or chains, as e.g. the hydroxyproline assay. Also, collagen post-translational modifications (PTMs), which have important biological functions, are not assessed in chain- and site-specific detail. A deeper understanding of fibrotic ECM is critical for advancing ECM-targeted diagnostics and therapies, but many molecular specifics of pathological collagen including PTMs remain elusive. Here, we fractionated protein from control lung and IPF tissue and quantified insoluble ECM components and soluble protein using iBAQ quantification in the MaxQuant software, as well as collagen PTMs in site-specific detail using our established bioinformatic pipeline (Merl-Pham et al 2029 Matrix Biology Plus).

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Lung

DISEASE(S): Idiopathic Pulmonary Fibrosis

SUBMITTER: Juliane Merl-Pham

LAB HEAD: Claudia A. Staab-Weijnitz

PROVIDER: PXD066357 | Pride | 2025-08-25

REPOSITORIES: Pride

ACCESS DATA

Dataset's files

Source:

			Action	DRS
	STC12953X002__ECM_IPF_1.raw	Raw
	STC12953X003__ECM_nonILD_1.raw	Raw
	STC12953X008__ECM_IPF_2.raw	Raw
	STC12953X010__ECM_nonILD_2.raw	Raw
	STC12953X012__ECM_nonILD_3.raw	Raw

Items per page:

1 - 5 of 34

Similar Datasets

Project description:Background: Fibrosis is a pathological scarring process characterized by persistent myofibroblasts activation with excessive accumulation of extracellular matrix (ECM). Fibrotic disorders represent an increasing burden of disease-associated morbidity and mortality worldwide for which there are limited therapeutic options. Reversing fibrosis requires the elimination of myofibroblasts, remodeling of the ECM, and regeneration of functional tissue. Multipotent mesenchymal stromal cells (MSC) have antifibrotic properties mediated by secreted factors present in their conditioned medium (MSC-CM). However, there are no standardized in vitro assays to predict the antifibrotic effects of human MSC, and, as a consequence, we lack evidence on the effect of cytokine priming on MSC’s antifibrotic effects. We hypothesize that the MSC-CM promotes fibrosis resolution in vitro and that this effect is enhanced following MSC cytokine priming. Methods: We tested the antifibrotic effects of resting and interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α) primed MSC-CM in three in vitro assays: prevention of fibroblast activation, myofibroblasts deactivation and ECM degradation. Furthermore, we performed transcriptomic analysis of myofibroblasts treated or not with resting- or primed-MSC-CM and proteomic characterization of resting- and primed-MSC-CM. Results: We report that MSC-CM treatment prevented TGF-β induced fibroblast activation and reduced fibrogenic myofibroblasts (i.e. transcriptomic upregulation of apoptosis, senescence, and inflammatory pathways). These effects were higher when primed rather than resting MSC-CM was used. Priming increased the ability of MSC-CM to remodel the extracellular matrix reducing its content of collagen I and fibronectin. Priming increased the following antifibrotic proteins in MSC-CM: DKK1, MMP-1, MMP-3, follistatin and cathepsin S. DKK1 inhibition reduced the anti-fibrotic effects of MSC-CM. Thus, cytokine priming increases antifibrotic factors in the MSC-CM which in turn amplify the anti-fibrotic effects of MSC-CM. Conclusions: In a pro-fibrotic in vitro environment MSC-CM promote fibrosis resolution, an effect enhanced following MSC cytokine priming. Specifically, MSC-CM reduces fibrogenic myofibroblasts through apoptosis, senescence, and inflammatory signals, as well as by enhancing ECM degradation. Future studies will establish the in vivo relevance of MSC priming to fibrosis resolution

Project description:Vocal fold (VF) fibrosis, often caused by phonosurgery, radiation, or trauma, leads to irreversible voice dysfunction due to excessive ECM deposition and increased tissue stiffness. VF fibrosis, a significant cause of chronic dysphonia, lacks FDA-approved treatments, highlighting the critical need for novel antifibrotic therapeutic. TGF-β1 is a major driver in the pathological transformation of fibroblasts into contractile myofibroblasts in VF fibrosis via SMAD3, YAP1, and integrin signaling pathways. These pathways lead to increased ACTA2 expression, excessive collagen production, and progressive tissue stiffening. Leveraging the principle that local cells respond to tissue-specific signals, our ECM hydrogel derived from decellularized vocal fold lamina propria (VFLP-ECM) reduced ACTA2 expression in TGF-β1 stimulated vocal fold fibroblasts, showcasing antifibrotic potential. In this study, we evaluated the therapeutic potential of VFLP-ECM hydrogel in a rabbit VF injury model—treatment involved VFLP-ECM or bovine type I collagen injections into VFs 7 days after injury, with evaluations at 28 days post-injury. We compared two VFLP-ECM formulations: a manual process (VFLP (man)) and an accelerated automated method (VFLP (au)). VFLP (man) showed more modulated fibrosis-associated gene expressions when compared to VFLP (au) and collagen. Proteomic analysis revealed that VFLP (man) preserves a broader array of bioactive proteins, such as vitronectin, crucial in TGF-β1 signaling and ECM remodeling. The transcriptomic analysis uncovered a downregulation of key fibrotic markers and potential inhibition of regulators such as SMAD3, YAP1, and MRTFA, alongside the upregulation of SMAD7, an inhibitor of TGF-β signaling. Notably, treatment with VFLP (man) resulted in vocal folds with similar stiffness as uninjured controls, whereas tissues treated with collagen or VFLP (au) remained stiffer, indicating incomplete mechanical recovery. These data provide the first in vivo evidence that VFLP-ECM hydrogel—mainly when produced via manual decellularization—attenuates fibrosis by disrupting biochemical and biomechanical drivers of myofibroblast activation.

Dataset Information

COLLAGEN POST-TRANSLATIONAL MODIFICATIONS ARE ALTERED IN IPF INCLUDING WITHIN ECM RECEPTOR BINDING MOTIFS

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets