Biology subjects

Malmi-Kakkada, A. N.

Publications and source records attributed to Malmi-Kakkada, A. N..

6 recordsLinked to original sources

bioRxiv2026

Cell division dynamics generate heterogeneous contact-mediated signaling outputs

Contact mediated cell-cell communication where direct physical contact between adjacent ligand cells and receptor cells trigger signal output is important during growth, development and regeneration of organisms. While the molecular machinery underlying contact mediated cell signaling is well explored, how the local spatial context of cells affect cell-cell contact mediated gene expression is not clear. Here, we present a vertex-based computational model to study spatial and temporal behavior of contact mediated signal output (which we refer to as output) in growing cell collectives. We consider cell-cell contact length dependent output synthesis and output degradation in receptor cells together with cell division to understand how dynamics at the scale of single cells lead to heterogeneous signal output. By tracking single receptor cells over time in growing cell collectives in silico, we show that cell growth and division lead to continuous and dynamic rearrangement of cell-cell contact between receptor and ligand cells which in turn affect the output levels. Our model predicts that the orientation of cell division plays a key role in the heterogeneity of signal output. We elucidate the link between cell mechanical properties that control cell shape, growth, and division, with signal output in receptor cells during contact mediated signaling processes.

biophysics↗

bioRxiv2024

Proliferation-driven mechanical feedback regulates cell dynamics in growing tissues

Local stresses in a tissue, a collective property, regulate cell division and apoptosis. In turn, cell growth and division induce active stresses in the tissue. As a consequence, there is a feed-back between cell growth and local stresses. However, how the cell dynamics depend on local stress-dependent cell division and the feedback strength is not fully understood. Here, we probe the consequences of stress-mediated growth and cell division on cell dynamics using agent-based simulations of a two-dimensional growing tissue. We discover a rich dynamical behavior of individual cells, ranging from jamming (mean square displacement, {Delta}(t) [~] t with less than unity), to hyperdiffusion ( > 2) depending on cell division rate and the strength of the mechanical feedback. Strikingly, {Delta}(t) is determined by the tissue growth law, which quantifies cell proliferation (number of cells N (t) as a function of time). The growth law (N (t) [~] t{lambda} at long times) is regulated by the critical pressure that controls the strength of the mechanical feedback and the ratio between cell division-apoptosis rates. We show that{lambda} [~] , which implies that higher growth rate leads to a greater degree of cell migration. The variations in cell motility are linked to the emergence of highly persistent forces extending over several cell cycle times. Our predictions are testable using cell-tracking imaging techniques.

biophysics↗

bioRxiv2023

Emergent spatiotemporal patterning of synthetic Notch signal transduction in vivo

Cell-cell communication through direct contact, or juxtacrine signaling, is important in development, disease, and many areas of physiology. Synthetic forms of juxtacrine signaling can be precisely controlled and operate orthogonally to native processes, making them a powerful reductionist tool with which to address fundamental questions in cell-cell communication in vivo. Here we investigate how cell-cell contact length and tissue growth dynamics affect juxtacrine signal responses through implementing a custom synthetic gene circuit in Drosophila wing imaginal discs alongside mathematical modeling to determine synthetic Notch (synNotch) activation patterns. We find that the area of contact between cells largely determines the extent of syn-Notch activation, leading to the prediction that the shape of the interface between signal-sending and signal-receiving cells will impact the magnitude of the synNotch response. Notably, synNotch outputs form a graded spatial profile that extends several cell diameters from the signal source, providing evidence that the response to juxtacrine signals can persist in cells as they proliferate away from source cells, or that cells remain able to communicate directly over several cell diameters. Our model suggests the former mechanism may be sufficient, since it predicts graded outputs without diffusion or long-range cell-cell communication. Overall, we identify that cell-cell contact area together with output synthesis and decay rates likely govern the pattern of synNotch outputs in both space and time during tissue growth, insights that may have broader implications for juxtacrine signaling in general.

biophysics↗

bioRxiv2021

Microtubule deacetylation reduces cell stiffness to allow the onset of collective cell migration in vivo

Embryogenesis, tissue repair and cancer metastasis rely on collective cell migration (CCM). In vitro studies propose that migrating cells are stiffer when exposed to stiff substrates, known to allow CCM, but softer when plated in compliant non-permissive surfaces. Here, by combining in vivo atomic force microscopy (iAFM) and modelling we reveal that to collectively migrate in vivo, cells require to dynamically decrease their stiffness in response to the temporal stiffening of their native substrate. Moreover, molecular and mechanical perturbations of embryonic tissues uncover that this unexpected cell mechanical response is achieved by a new mechanosensitive pathway involving Piezo1-mediated microtubule deacetylation. Finally, lowering microtubule acetylation and consequently cell stiffness was sufficient to allow CCM in soft non-permissive substrates, suggesting that a fixed value of substrate stiffness is not as essential for CCM as it is reaching an optimal cell-to-substrate stiffness value. These in vivo insights on cell-to-substrate mechanical interplay have major implications to our re-interpretation of physiological and pathological contexts.

cell biology↗

bioRxiv2020

Cadherin clustering controls heterogeneous, asymmetric junction dynamics during vertebrate axis elongation

Morphogenesis is governed by the interplay of molecular signals and mechanical forces across multiple length scales. The last decade has seen tremendous advances in our understanding of the dynamics of protein localization and turnover at sub-cellular length scales, and at the other end of the spectrum, of mechanics at tissue-level length scales. Integrating the two remains a challenge, however, because we lack a detailed understanding of the subcellular patterns of mechanical properties of cells within tissues. Here, in the context of the elongating body axis of a vertebrate embryo, we combine tools from cell biology and physics to demonstrate that individual cell-cell junctions display finely-patterned local mechanical heterogeneity along their length. We show that such local mechanical patterning is essential for the cell movements of convergent extension and is imparted by locally patterned clustering of a classical cadherin. Finally, the patterning of cadherins and thus local mechanics along cell-cell junctions are controlled by Planar Cell Polarity signaling, a key genetic module for CE that is mutated in diverse human birth defects.

cell biology↗

bioRxiv2019

Dual Role of Cell-Cell Adhesion In Tumor Suppression and Proliferation

It is known that mechanical interactions couple a cell to its neighbors, enabling a feedback loop to regulate tissue growth. However, the interplay between cell-cell adhesion strength, local cell density and force fluctuations in regulating cell proliferation is poorly understood. Here, we show that spatial variations in the tumor growth rates, which depend on the location of cells within tissue spheroids, are strongly influenced by cell-cell adhesion. As the strength of the cell-cell adhesion increases, intercellular pressure initially decreases, enabling dormant cells to more readily enter into a proliferative state. We identify an optimal cell-cell adhesion regime where pressure on a cell is a minimum, allowing for maximum proliferation. We use a theoretical model to validate this novel collective feedback mechanism coupling adhesion strength, local stress fluctuations and proliferation. Our results predict the existence of a non-monotonic proliferation behavior as a function of adhesion strength, consistent with experimental results. Several experimental implications of the proposed role of cell-cell adhesion in proliferation are quantified, making our model predictions amenable to further experimental scrutiny. We show that the mechanism of contact inhibition of proliferation, based on a pressure-adhesion feedback loop, serves as a unifying mechanism to understand the role of cell-cell adhesion in proliferation.

cancer biology↗