Biology subjects

Vignjevic, D.

Publications and source records attributed to Vignjevic, D..

2 recordsLinked to original sources

bioRxiv2024

PIEZO-dependent mechano-sensing of the niche is essential for intestinal stem cell fate decision and maintenance

Stem cells continuously perceive and respond to various environmental signals to maintain homeostasis. In addition to biochemical factors, the stem cell niche is subjected to mechanical and physical cues. However, it remains unclear how stem cells can sense mechanical signals from their niche in vivo. Since intestinal stem cells constantly and directly face the external environment, we investigated the roles of mechano-sensing PIEZO ion channels in the gut stem cell niche. By employing mouse genetics and performing single-cell RNAseq analysis, we revealed the absolute requirement for PIEZO channels in intestinal stem cell (ISC) state dynamics and maintenance. In vivo measurement of basement membrane region stiffness demonstrated that ISCs reside in a more rigid microenvironment at the bottom of the crypt. Using 3D and 2D organoid systems combined with bioengineered substrates and a cell stretching device, we found that PIEZO channels are activated by high extracellular matrix stiffness and tissue tension to modulate ISC behavior. This study delineates the mechanistic cascade of PIEZO channel activation in ISCs from the upstream extracellular stimuli through the downstream signaling activation that coordinates stem cell fate decision and maintenance.

cell biology↗

bioRxiv2024

Friction-induced budding of a cancer cell monolayer

The environment surrounding a tumor plays a crucial role in cancer cell dissemination. Within this microenvironment, cancer-associated fibroblasts (CAFs) generate compressive forces and actively remodel tumors. Using in vitro circular clusters of cancer cell monolayers surrounded by CAFs, we generate structures that are reminiscent of multicellular buds observed in vivo for colo-rectal cancer. A supracellular contractile ring spontaneously assembles at the inner edge of the CAF monolayer and drives its closure on top of the cancer cells through a purse-string mechanism. The frictional shear stress exerted by CAFs triggers multilayering of cancer cells, followed by the emergence of a multicellular bud constricted by the CAF ring. To explain this observation, we developed a theoretical model based on continuum mechanics. This model outlines the early transformations in the shape of cancer cell monolayer and links the layering of cells to a general criterion involving height deformation. It identifies the specific physical conditions that favors budding, and reproduces the observed dependence of the budding probability and bud sizes with the diameter of the cancer cell cluster. Our findings highlight the importance of active mechanical interactions between the tumor and its micro-environment on aggressive modes of cancer invasion.

biophysics↗