Biology subjects

Vignjevic, D. M.

Publications and source records attributed to Vignjevic, D. M..

4 recordsLinked to original sources

bioRxiv2026

Mechanochemical synchronization of force oscillations in connective tissue models

Cells in a tissue coordinate their behavior collectively by mechanical and chemical feedback with their surroundings. To study how such feedback mechanisms interact, we embed multicellular spheroids from mouse and primary human fibroblasts of different origin in 3D collagen matrices. Immediately after embedding, spheroids apply steadily increasing, radially symmetric, inward-directed forces to the surrounding matrix. Typically, within a few hours, collective force oscillations emerge with an average time interval of {approx}30 min. Similar force oscillations also arise in engineered, parallel-aligned microtissues attached to flexible pillars. Force oscillations propagate between neighboring cells as a mechanical wave, accompanied by calcium waves that travel at comparable speeds of several hundred m/min. Blocking gap junctions or mechanosensitive Piezo1 channels impairs these oscillations, indicating that calcium signaling contributes to their propagation. Their amplitude and frequency are regulated by integrin-mediated feedback in actin-rich protrusions and by ERK signaling, which also controls collective invasion into the surrounding matrix. Neighboring spheroids mechanically synchronize their force oscillations in phase and frequency over distances of up to {approx}2 mm without direct contact. Together, our results show that oscillatory mechanochemical feedback enables multicellular systems to coordinate force generation and invasive migration across cellular and millimeter length scales in 3D matrices.

biophysics↗

bioRxiv2025

Self-organization of tumor heterogeneity and plasticity

Phenotypic heterogeneity and plasticity drive tumor growth, metastasis, therapy resistance, and relapse. This heterogeneity is mainly interpreted as a response to external signals from the microenvironment. However, here we show that cancer cells also follow intrinsic self-organized programs that are sufficient to coordinate the spatiotemporal patterning of tumor cell states. By combining quantitative measurements in tumors and organoids with theoretical modeling, we reveal emergent mechanical gradients that orchestrate cell state transitions during colorectal tumor growth. Compression at the tumor center induces a transition from a fetal-like state into a cancer stem cell (CSC) state. The CSC compartment exhibits a characteristic size determined by tumor rheological properties. Once this size is surpassed, a translationally arrested apoptotic core emerges, triggering a shift from homogeneous proliferation to a hierarchical cell turnover. These findings uncover stereotyped programs of self-organization that likely cooperate with the microenvironment to shape tumor heterogeneity and plasticity.

cancer biology↗

bioRxiv2024

Intestinal fibroblast heterogeneity: unifying RNA-seq studies and introducing consensus-driven nomenclature

O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=114 SRC="FIGDIR/small/627573v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@1ca5bfborg.highwire.dtl.DTLVardef@5cf61aorg.highwire.dtl.DTLVardef@1213382org.highwire.dtl.DTLVardef@bca9b8_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical abstractC_FLOATNO C_FIG In the colon, single-layered epithelium lines the crypts, which descend into the underlying mucosa. Colonic crypts are surrounded by a network of fibroblasts essential for various functions, including the production and remodeling of the extracellular matrix (ECM), supporting the epithelial stem cell niche, and promoting the differentiation of epithelial cells. Recent studies indicate that fibroblasts are not a homogeneous cell population. However, differences in nomenclature and a lack of exact markers hindered their classification and functional understanding. Here, we used single-cell RNA-sequencing (scRNA-seq) to identify six distinct fibroblast subpopulations in mouse colonic mucosa, each with unique molecular signatures and functional specialization. Our analysis reveals that some fibroblasts are primarily involved in ECM production and remodeling, while others exhibit high contractility. Additionally, a subset of fibroblasts produces cytokines that promote epithelial cell differentiation, whereas another group secrete cytokines essential for maintaining the epithelial stem cell niche. We also map the spatial distribution of these fibroblast subpopulations within the colonic mucosa. Differentiation trajectory analysis suggests distinct pathways for fibroblast differentiation, while cell cycle scoring reveals that fibroblasts do not proliferate under homeostatic conditions. Furthermore, we integrated our scRNA-seq data with previously published datasets to identify common fibroblast populations and propose a standardized nomenclature for intestinal fibroblasts. This unified framework aims to improve communication within the research community and enhance understanding of fibroblast roles in gut homeostasis and gastrointestinal diseases.

cell biology↗

bioRxiv2020

Mechanical compartmentalization of the intestinal organoid enables crypt folding and collective cell migration

Intestinal organoids capture essential features of the intestinal epithelium such as folding of the crypt, spatial compartmentalization of different cell types, and cellular movements from crypt to villus-like domains. Each of these processes and their coordination in time and space requires patterned physical forces that are currently unknown. Here we map the three-dimensional cell-ECM and cell-cell forces in mouse intestinal organoids grown on soft hydrogels. We show that these organoids exhibit a non-monotonic stress distribution that defines mechanical and functional compartments. The stem cell compartment pushes the ECM and folds through apical constriction, whereas the transit amplifying zone pulls the ECM and elongates through basal constriction. Tension measurements establish that the transit amplifying zone isolates mechanically the stem cell compartment and the villus-like domain. A 3D vertex model shows that the shape and force distribution of the crypt can be largely explained by cell surface tensions following the measured apical and basal actomyosin density. Finally, we show that cells are pulled out of the crypt along a gradient of increasing tension, rather than pushed by a compressive stress downstream of mitotic pressure as previously assumed. Our study unveils how patterned forces enable folding and collective migration in the intestinal crypt.

cell biology↗