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HEIndividual fellowship2023–2025

ReGutBM · Regulation of epithelial-cells renewal by basement membrane protein composition and stiffness during gut homeostasis

Horizon Europe — Marie Skłodowska-Curie Actions

Duration
2023-09-01 → 2025-08-31
EU contribution
€211,755
Participants
1
Scheme
HORIZON-TMA-MSCA-PF-EF

Lines connect the coordinator with its partners.

Results in brief

Regulation of epithelial-cells renewal by basement membrane protein composition and stiffness during gut homeostasis

The intestinal epithelium is the fastest self-renewing tissue in the human body, completely regenerating every few days. Understanding how this renewal is regulated is fundamental to biology and has implications for diseases such as inflammatory bowel disease- which can result from excessive cell extrusion that is not complemented by enough cell proliferation- or for colorectal cancer, which can result from excessive proliferation of cells that is not met by sufficient cell extrusion. The ReGutBM project investigated whether the basement membrane—a thin layer of specialized proteins underlying intestinal epithelial cells—actively regulates epithelial cell behavior. While traditionally viewed as structural support, this research examined whether variations in basement membrane protein composition across the tissue provide chemical or mechanical signals that control when cells proliferate, migrate, extrude and die. The project objectives were to characterize basement membrane protein composition and mechanical properties, determine whether these properties influence cell behavior, and identify the molecular pathways through which basement membrane signals regulate tissue homeostasis. This research was interdisciplinary and combined cell biology, mechanobiology, and advanced imaging to address fundamental questions about tissue regulation.

Data: CORDIS, © European Union

Project objective

The intestinal epithelium forms a tight barrier against pathogens and toxins while simultaneously absorbing ions and nutrients. It is the fastest self-renewing tissue in the body, as over 3-5 days, a complete turnover of epithelial cells is achieved. Homeostasis is maintained by tight coordination between epithelial cell proliferation, differentiation, migration, and extrusion. Epithelial cells adhere and migrate on the basement membrane, a unique, sheet-like extracellular matrix that separates epithelial cells from the underlying mesenchyme. Composed primarily of laminins and type-IV collagen, the basement membrane provides structural support, promotes cell adhesion and polarity, and serves as a mechanical and biochemical signaling hub. Although great advances have been made in identifying morphogenetic regulators of epithelial-cell renewal, spatial regulators that limit proliferating cells to the crypt or guide cell migration towards the villus tip are still missing. Interestingly, basement membrane protein composition varies across the crypt-villus axis, which could also affect its stiffness. However, whether these variations play a role in regulating epithelial cell renewal has not been addressed. The overarching hypothesis of ReGutBM is that basement membrane protein composition and / or stiffness define specific zones that promote cell proliferation or cell death, and provide cues for directional migration of epithelial cells in gut homeostasis. Using ex-vivo tissue cultures and in-vivo mouse models, I will characterize the basement membrane protein composition and stiffness. Using 2D intestinal organoid cultures, I will decouple the regulatory impact of tissue stiffness and protein identity on epithelial cell renewal, and identify the molecular mechanism which facilitates BM-epithelia crosstalk during gut homeostasis.

Original text from CORDIS.

Participants

  • INSTITUT CURIE · ParisCoordinatorFrance

Links

Data: CORDIS, © European Union