Immune-stromal crosstalk in inflammation and fibrosis: Exploiting the spatiotemporal dynamics of the OSM-OSMR axis in inflammatory bowel disease to develop novel antifibrotic therapies

Informazioni relative al progetto

iMOTIONS

ID dell’accordo di sovvenzione: 101078069

DOI

10.3030/101078069

Data della firma CE 1 Febbraio 2023

Data di avvio 1 Settembre 2023

Data di completamento 31 Agosto 2028

Finanziato da

• European Research Council (ERC)

Costo totale

€ 1 499 816,00

Contributo UE

€ 1 499 816,00

Coordinato da

CHARITE - UNIVERSITAETSMEDIZIN BERLIN
Germany

Periodic Reporting for period 1 - iMOTIONS (Immune-stromal crosstalk in inflammation and fibrosis: Exploiting the spatiotemporal dynamics of the OSM-OSMR axis in inflammatory bowel disease to develop novel antifibrotic therapies)

Periodo di rendicontazione: 2023-09-01 al 2026-02-28

Sintesi del contesto e degli obiettivi generali del progetto

Chronic inflammatory diseases such as inflammatory bowel disease (IBD) are major global health challenges, affecting millions and leading to substantial morbidity, socioeconomic burden, and reduced quality of life. While advances in biologic therapies have improved inflammation control, they have not prevented the progressive and often irreversible tissue remodeling and fibrosis that ultimately lead to organ dysfunction and surgical intervention. In IBD, this fibrostenotic transformation remains the most frequent complication, yet there are no effective antifibrotic therapies or predictive biomarkers to identify patients at risk. The persistence of this clinical gap underscores a fundamental lack of understanding of how immune and stromal cells interact to shape tissue repair, remodeling, and fibrosis in the chronically inflamed gut.
Mounting evidence, including our own discoveries, has identified immune–stromal interactions as central to how inflammation is sustained and transformed into fibrosis. In particular, the Oncostatin M (OSM)–OSM receptor (OSMR) pathway has emerged as a key molecular circuit connecting immune activation to epithelial and stromal cell remodeling. OSM is highly expressed in inflamed mucosa of IBD patients, and elevated OSM–OSMR signaling correlates with therapy resistance and fibrotic complications. Yet, the cellular mechanisms, spatial organization, and signaling dynamics that govern this axis remain poorly defined.
The iMOTIONS project seeks to decipher and therapeutically exploit the OSM–OSMR pathway as a model for understanding immune–stromal communication in chronic intestinal inflammation and fibrosis.

Lavoro eseguito dall’inizio del progetto fino alla fine del periodo coperto dalla relazione e principali risultati finora ottenuti

During the reporting period, the project established an integrated experimental and translational platform to dissect immune–stromal crosstalk in intestinal inflammation and fibrosis, focusing on the Oncostatin M (OSM)–OSM receptor (OSMR) axis as a key regulator of mucosal remodeling. We successfully generated and validated several novel genetic mouse tools (Osmrfl/fl, Osmfl/fl, Osmr-iScarlet) enabling spatiotemporal tracing and functional perturbation of the OSM pathway in specific stromal, epithelial, endothelial, and immune cell populations. Using chronic colitis and fibrosis models (cDSS, Helicobacter hepaticus + anti–IL-10R), we mapped the temporal dynamics of OSM and OSMR expression and demonstrated that OSM signaling critically shapes epithelial and fibroblast activation, and promotes inflammation. Parallel work in human cohorts leveraged the IBDome biobank (>370 sequenced mucosal samples) to define OSM-driven transcriptional modules associated with extracellular matrix remodeling, mesenchymal activation, and therapy resistance to anti-TNF and anti-integrin (Vedolizumab) treatments.
The project is generating new mechanistic insight into how immune–stromal communication drives fibrogenic transformation in IBD. Emerging results include: Characterization of novel reporter and conditional mouse models for fibrosis research; A developing molecular atlas of OSM–OSMR–regulated pathways in mouse and human intestine; Identification of transcriptional signatures predictive of fibrostenotic disease and therapy resistance; Foundational preclinical evidence supporting targeted modulation of the OSM–OSMR axis as a potential antifibrotic strategy.

Progressi oltre lo stato dell’arte e potenziale impatto previsto (incluso l’impatto socioeconomico e le implicazioni sociali più ampie del progetto fino ad ora)

The project is generating significant progress toward elucidating the mechanisms linking chronic intestinal inflammation to fibrosis. Preliminary results demonstrate that the Oncostatin M (OSM)–OSM receptor (OSMR) pathway represents a central hub integrating immune and stromal signaling in inflammatory bowel disease (IBD). Using newly developed reporter and conditional mouse models, combined with single-cell and spatial transcriptomics from patient samples, we are uncovering how OSM–OSMR signaling drives fibroblast activation, matrix remodeling, and therapy resistance. These findings establish a mechanistic framework for understanding tissue remodeling and identify OSM–OSMR as a potential therapeutic target and biomarker pathway for patient stratification. The expected impacts of this work are threefold:
Scientific impact: The project is defining a new paradigm for immune–stromal communication in chronic inflammation and fibrosis, providing foundational datasets and genetic tools for the wider research community.
Clinical and translational impact: By identifying OSM-driven transcriptional signatures predictive of fibrostenotic progression and biologic non-response, the project supports the development of precision medicine approaches for IBD management and informs future antifibrotic therapy trials.
Societal and health impact: Understanding and preventing intestinal fibrosis could significantly reduce surgical intervention rates, healthcare costs, and disease burden for patients with chronic inflammatory disorders.