Team
Team manager: Krndija Denis
Presentation
How physical forces, both external and internal, affect biological systems remains poorly understood in tissue and organ physiology. Epithelial tissues play an important physiological role as specialised tissue barriers that protect the internal environment of the organism from external factors. Unlike most tissues in adult organisms, epithelia undergo lifelong, continuous renewal while maintaining their barrier function. The gut epithelium, with the fastest renewal rate in the body, is uniquely able to withstand continuous mechanical insults while maintaining its integrity throughout adult life.
Our research group aims to unravel the biophysical principles governing epithelial tissue renewal and integrity in the mammalian gut, integrating cell and tissue level mechanics within this physiological context. To achieve this, we use a range of experimental models, including transgenic mice, tissue explants, organoids, and microphysiological systems. Our interdisciplinary approaches encompass live tissue imaging, genetic and pharmacological interventions, force manipulations, and theoretical modelling.
Project 1
Steady-state epithelial tissue renewal in the adult gut ensures constant supply of metabolically fit cells while preserving constant tissue size and integrity of the intestinal epithelial barrier. The gut epithelial turnover relies on the mutually coordinated processes of cell proliferation, differentiation, migration and loss. The mechanistic underpinnings of these processes remain mostly unclear, especially how these processes are coordinated to preserve constant tissue size, as well as how tissue integrity is maintained amid numerous mechanical challenges the gut epithelium is subjected to.
Our goal is to understand how epithelial renewal and tissue integrity are maintained in the adult gut homeostasis in the context of the intrinsic and extrinsic mechanical forces to which this tissue is subjected.
Project 2
The small intestinal epithelium comprises at least six different cell types where enterocytes, the absorptive cells, represent the most predominant cell type. We found that enterocytes exhibit dynamic, actin-rich, and front-back polarised basal protrusions during migration along the intestinal villi (Krndija et al, 2019). In contrast to enterocytes, the migratory behaviour dynamics of much less abundant intestinal cell types, such as goblet and tuft cells, is poorly understood.
Our goal is to understand how these rare and dispersed cells with distinct morphologies and force signatures are mechanically integrated into the tissue, and how their turnover is regulated and coordinated.
Project 3
The intestinal epithelium constantly faces mechanical stress, with forces transmitted from cell junctions and the cytoskeleton to the nucleus, which houses the cell’s genetic material. However, the mechanisms by which the nucleus dissipates mechanical stress and whether or how chromatin is protected in this process remain poorly understood.
Our goal is to characterize the nuclear response to mechanical forces in the colonic epithelium and decipher the mechanisms of nuclear mechanotransduction and mechanoadaptation.
– Pérez-González C, Ceada G, Greco F, Matejčić M, Gómez-González M, Castro M, Menendez A, Kale S, Krndija D, Clark AG, Gannavarapu RV, Alvarez-Varela A, Roca-Cusachs P, Batlle E, Matic Vignjevic D, Arroyo M, Trepat X. Mechanical compartmentalization of the intestinal organoid enables crypt folding and collective cell migration Nature Cell Biology 2021 Jul
– Verhulsel M, Simon A, Bernheim-Dennery M, Gannavarapu VR, Geremie L, Ferraro D, Krndija D, Talini L, Viovy JL, Vignjevic DM. Developing an advanced gut on chip model enabling the study of epithelial cells/fibroblasts interactions Lab on a Chip 2021 Jan
– El Marjou F, Jouhanneau C, Krndija D. Targeted Transgenic Mice Using CRISPR/Cas9 Technology Methods Mol Biol 2021 Jan
– Krndija D*, Fairhead M. IGF1R undergoes active and directed centripetal transport on filopodia upon receptor activation. Biochem J 2019 Dec *corresponding author
– Krndija D*, El Marjou F, Guirao B, Richon S, Leroy O, Bellaiche Y, Hannezo E, Matic Vignjevic D. Active cell migration is critical for steady-state epithelial turnover in the gut Science 2019 Aug *corresponding author;
– Staneva R, Barbazan J, Simon A, Vignjevic DM, Krndija D. Cell Migration in Tissues: Explant Culture and Live Imaging Methods Mol Biol 2018 Mar
Funding
Affiliation
