Biology subjects

Breinyn, I. B.

Publications and source records attributed to Breinyn, I. B..

5 recordsLinked to original sources

bioRxiv2024

Cellular cruise control: energy expenditure as a regulator of collective migration in epithelia

Epithelial migration is implicit in processes ranging from gastrula development to the healing of skin, and involves the coordinated motion, force production, and resulting energy expenditure of thousands of constitutive cells. However, the spatiotemporal patterning and regulation of energy expenditure during epithelial migration remains poorly understood. Here, we propose a continuum mechan-ics framework and use it to explore how energy expenditure regulates epithelial migration. We use canonical mechanical metrics such as force, work and power to define what it means for a tissue to migrate efficiently and show that freely expanding epithelia actively regulate themselves to operate within a maximally efficient regime. We then leverage electrotaxis (directed motion in response to an externally applied electric field) as a tool to study non-homeostatic migra-tion using this new framework. We show that regulation of migration is robust to external cues and acts to to attenuate a tissues response to stimuli.

biophysics↗

bioRxiv2024

Spatial heterogeneity in collective electrotaxis: continuum modelling and applications to optimal control

Collective electrotaxis is a phenomenon that occurs when a cellular collective, for example an epithelial monolayer, is subjected to an electric field. Biologically, it is well known that the velocity of migration during the collective electrotaxis of large epithelia exhibits significant spatial heterogeneity. In this work, we demonstrate that the heterogeneity of velocities in the electrotaxing epithelium can be accounted for by a continuum model of cue competition in different tissue regions. Having established a working model of competing migratory cues in the migrating epithelium, we develop and validate a reaction-convection-diffusion model that describes the movement of an epithelial monolayer as it undergoes electrotaxis. We use the model to predict how tissue size and geometry affect the collective migration of MDCK monolayers, and to propose several ways in which electric fields can be designed such that they give rise to a desired spatial pattern of collective migration. We conclude with two examples that demonstrate practical applications of the method in designing bespoke stimulation protocols.

biophysics↗

bioRxiv2023

E-cadherin biointerfaces reprogram collective cell migration and cell cycling by forcing homeostatic conditions

Cells attach to the world around them in two ways--cell:extracellular-matrix adhesion and cell:cell adhesion--and conventional biomaterials are made to resemble the matrix to encourage integrin-based cell adhesion. However, interest is growing for cell-mimetic interfaces that mimic cell-cell interactions using cadherin proteins, as this offers a new way to program cell behavior and design synthetic implants and objects that can integrate directly into living tissues. Here, we explore how these cadherin-based materials affect collective cell behaviors, focusing specifically on collective migration and cell cycle regulation in cm-scale epithelia. We built culture substrates where half of the culture area was functionalized with matrix proteins and the contiguous half was functionalized with E-cadherin proteins, and we grew large epithelia across this Janus interface. Parts of the tissues in contact with the matrix side of the Janus interface exhibited normal collective dynamics, but an abrupt shift in behaviors happened immediately across the Janus boundary onto the E-cadherin side, where cells formed hybrid E-cadherin junctions with the substrate, migration effectively froze in place, and cell-cycling significantly decreased. E-cadherin materials suppressed long-range mechanical correlations in the tissue and mechanical information reflected off the substrate interface. These effects could not be explained by conventional density, shape index, or contact inhibition explanations. E-cadherin surfaces nearly doubled the length of the G0/G1 phase of the cell cycle, which we ultimately connected to the exclusion of matrix focal adhesions induced by the E-cadherin culture surface.

bioengineering↗

bioRxiv2022

Pump it up: bioelectric stimulation controls tissue hydrostatic pressure and water transport via electro-inflation

Epithelial tissues sheath many organs, separating outside from inside and exquisitely regulating ion and water transport electromechanically to maintain homeostatic balance and tissue hydrostatic pressure. While it is increasingly clear that the ionic microenvironment and external electric stimuli can affect epithelial function and behavior, the coupling between electrical perturbation and tissue form remain unclear. We investigated this by combining electrical stimulation with three-dimensional epithelial tissues with hollow lumens--both kidney cysts and complex intestinal stem cell organoids. Our core finding is that physiological strength electrical stimulation of order 1-3 V/cm (with both direct and alternating currents) can drive powerful and rapid inflation of hollow tissues through a process we call electro-inflation, inducing up to a threefold increase in tissue volume and striking asymmetries in tissue form. Electro-inflation is primarily driven by field-induced ion crowding on the outer surface of the hollow tissue that creates an ion gradient across the epithelial shell, which drives increased ionic flux mediated by ion channels/transporters and subsequent osmotic water flow into the lumen. This influx generates hydrostatic pressure, and inflation results from a competition between this pressure and cell cytoskeletal tension. We validated these interpretations with computational models connecting ion crowding around tissues to tissue mechanics. Electrically stimulated cysts and organoids also exhibited pronounced asymmetry, where the epithelial shell thickened on the cathode-facing side and thinned on the anode-facing side of the tissue. We discovered that this process is the result of 3D electrotaxis-directed migration of cells in an electric field-causing a redistribution of cells around the shell. The ability of electrical cues to dramatically regulate tissue size and shape highlight the key role of the electrical micro-environment and the potential offered by manipulating these signals.

bioengineering↗

bioRxiv2021

Short-term stimulation of collective cell migration in tissues reprograms long-term supracellular dynamics

The ability to program collective cell migration can allow us to control critical multicellular processes in development, regenerative medicine, and invasive disease. However, while various technologies exist to make individual cells migrate, translating these tools to control myriad, collectively interacting cells within a single tissue poses many challenges. For instance, do cells within the same tissue interpret a global migration command differently based on where they are in the tissue? Similarly, since no stimulus is permanent, what are the long-term effects of transient commands on collective cell dynamics? We investigate these questions by bioelectrically programming large epithelial tissues to globally migrate rightward via electrotaxis. Tissues clearly developed distinct rear, middle, side, and front responses to a single global migration stimulus. Furthermore, at no point post-stimulation did tissues return to their pre-stimulation behavior, instead equilibrating to a third, new migratory state. These unique dynamics suggested that programmed migration resets tissue mechanical state, which was confirmed by transient chemical disruption of cell-cell junctions, analysis of strain wave propagation patterns, and quantification of cellular crowd dynamics. Overall, this work demonstrates how externally driving the collective migration of a tissue can reprogram baseline cell-cell interactions and collective dynamics, even well beyond the end of the global migratory cue, and emphasizes the importance of considering the supracellular context of tissues and other collectives when attempting to program crowd behaviors.

biophysics↗