Biology subjects

Narasimhan, B. N.

Publications and source records attributed to Narasimhan, B. N..

3 recordsLinked to original sources

bioRxiv2025

Single-cell chiral symmetry breaking under confinement

Single cells confined by the extracellular matrix can exhibit persistent rotational motion, yet the physical mechanisms underlying this chiral symmetry breaking remain unclear. Here, we address this gap with a cellular phase field model that couples cell deformation, cell polarization governed by stochastic excitable dynamics, and confinement. We identify the confinement strength as a bifurcation parameter determining three regimes: strong confinement prevents rotation through spatial constraints, intermediate confinement induces stochastic transitions between chiral and non-chiral states, and weak confinement allows persistent rotational motion. For the intermediate regime, we develop a semi-Markovian renewal process framework that characterizes the stochastic dynamics through dwell time statistics, transition probabilities and first-passage times. For the weak confinement regime, we reveal that a mechanochemical feedback enables coherent rotations despite internal noise through the reduction of local excitability mediated by mechanical contraction. We formalize this feedback analytically using Kramers escape theory. Experiments on epithelial MCF10A cells in Matrigel validate predictions for the weak confinement regime. Our results establish a theoretical approach for understanding single-cell chiral symmetry breaking under confinement, with implications for controlling single-cell dynamics by tuning extracellular matrix properties.

biophysics↗

bioRxiv2024

Modeling collagen fibril degradation as a function of matrix microarchitecture

Collagenolytic degradation is a process fundamental to tissue remodeling. The microarchitecture of collagen fibril networks changes during development, aging, and disease. Such changes to microarchitecture are often accompanied by changes in matrix degradability. In vitro, collagen matrices of the same concentration but different microarchitectures also vary in degradation rate. How do different microarchitectures affect matrix degradation? To answer this question, we developed a computational model of collagen degradation. We first developed a lattice model that describes collagen degradation at the scale of a single fibril. We then extended this model to investigate the role of microarchitecture using Brownian dynamics simulation of enzymes in a multi-fibril three dimensional matrix to predict its degradability. Our simulations predict that the distribution of enzymes around the fibrils is non-uniform and depends on the microarchitecture of the matrix. This non-uniformity in enzyme distribution can lead to different extents of degradability for matrices of different microarchitectures. Our model predictions were tested using in vitro experiments with synthesized collagen gels of different microarchitectures. Experiments showed that indeed degradation of collagen depends on the matrix architecture and fibril thickness. In summary, our study shows that the microarchitecture of the collagen matrix is an important determinant of its degradability.

biophysics↗

bioRxiv2024

Degradability tunes ECM stress relaxation and cellular mechanics

In native extracellular matrices (ECM), cells can use matrix metalloproteinases (MMPs) to degrade and remodel their surroundings. Likewise, synthetic matrices have been engineered to facilitate MMP-mediated cleavage that enables cell spreading, migration, and interactions. However, the intersection of matrix degradability and mechanical properties has not been fully considered. We hypothesized that immediate mechanical changes result from the action of MMPs on the ECM and that these changes are sensed by cells. Using atomic force microscopy (AFM) to measure cell-scale mechanical properties, we find that both fibrillar collagen and synthetic degradable matrices exhibit enhanced stress relaxation after MMP exposure. Cells respond to these relaxation differences by altering their spreading and focal adhesions. We demonstrate that stress relaxation can be tuned through the rational design of matrix degradability. These findings establish a fundamental link between matrix degradability and stress relaxation, which may impact a range of biological applications. Table of contentsThis work reveals that matrix degradability, through its effects on stress relaxation, is an important cellular mechanotransduction cue. Cell-scale mechanical characterization shows that collagen gels and degradable synthetic gels display enhanced stress relaxation post-degradation. Stress relaxation is then tuned by systematically varying degradability, resulting in the regulation of cell spreading. This identifies degradability as a key chemomechanical design feature. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=181 SRC="FIGDIR/small/605514v1_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@13a701dorg.highwire.dtl.DTLVardef@196bb05org.highwire.dtl.DTLVardef@d04613org.highwire.dtl.DTLVardef@1a8b1d1_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗