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Shaping intestine epithelium using viscoelastically dynamic matrices

Project description

A closer look at intestinal tissue development

The development of the intestine’s epithelial tissue is a marvel of biological engineering, guided by complex interactions between biochemical signals and the extracellular matrix’s (ECM) mechanical properties, particularly its viscoelasticity. Recent studies underscore the role of these mechanical cues in shaping the fate of intestinal stem cells (ISCs), the polarity of epithelial cells, and the overall morphogenesis of the intestine. However, research methods often overlook the dynamic nature of the ECM in vivo. Supported by the Marie Skłodowska-Curie Actions programme, the EPIMECH project will use light-triggerable hydrogel-based matrices to simulate dynamic changes in substrate viscoelasticity. It will shed light on how mechanical stimuli influence the complex patterning of intestinal epithelium during development.

Objective

Intestine epithelium (IE) compartmentalization and morphogenesis are profoundly influenced by intrinsic biochemical signals and microenvironmental cues in the extracellular matrix (ECM), especially viscoelasticity. Recent studies have revealed substrate mechanical properties have clear influences on intestine stem cell (ISC) fate, IE polarity, self-organization and morphogenesis. However, most of these investigations were performed in constant and static conditions, neglecting the active and dynamic nature of in vivo ECM. Furthermore, whether and how dynamic matrix viscoelasticity contributes to the emergence of symmetry breaking and tissue regionalization in early intestinal morphogenesis remains elusive so far. In this project, we propose to use dynamic hydrogel-based matrices with light-triggerable changes in viscoelasticity to study the transduction of molecular mechanosensing into collective cell dynamics during symmetry breaking and tissue patterning in IE development. We hypothesize that anisotropic substrate viscoelasticity could heterogeneously activate mechanosensing pathways in ISCs and affect ISC proliferation and differentiation, leading to changes in cell activities, sorting and tissue segregation. In brief, with dynamic substrates, we will create viscoelastic patterns/gradients by in situ light patterning and elucidate IE dynamics related to the emergence of cell shape, migration, ISC fate and tissue compartmentalization as functions of the mechanical stimuli. We also aim to identify the molecular principles of IE mechanotransduction, which will improve our understanding of IE development, morphogenesis and homeostasis. The know-how from this project will also enable the fabrication of artificial intestine-on-a-chip devices for further developmental studies. Relying on the multidiscipline approaches, this action will greatly enhance the competence of the researcher as well as bring added value in scientific and societal aspects for the EU.

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Topic(s)

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Funding Scheme

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HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European Fellowships

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Call for proposal

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(opens in new window) HORIZON-MSCA-2023-PF-01

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Coordinator

CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Net EU contribution

Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.

€ 211 754,88
Total cost

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No data

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