Macroscopic Tissue Growth, Expansion, and Collision: Biophysical Insights Toward Tissue Sheet Engineering Strategies

Abstract

As an organism develops and maintains homeostasis, many thousands of cells must act in concert within and between tissues. How these collective cellular behaviors are coordinated has been a question of interest for over a century, with importance to developmental, regenerative, and pathological processes. In the last decade, in vitro studies of tissues have brought breakthroughs showing how forces, stresses, traveling waves, and other physical processes provide a basis for biological processes within a tissue like cell migration and proliferation. However, these studies most commonly involve much smaller length scales and shorter time scales than the physiological processes they represent. Additionally, biophysical studies of epithelial tissues rarely examine the interactions between tissues that occur when these systems come into contact. Together, we lack knowledge on how epithelial tissues coordinate biophysical processes across larger length scales, over longer timescales, and during higher-level interactions. We address this first by studying millimeter-scale tissue expansion at high resolution over several days. We find that the tissue edge starkly decouples from the tissue bulk, producing size and memory effects in patterns of cell migration and proliferation. We also find the first example of millimeter-scale coordinated vortices in unconfined cohesive tissue and explore this process with an active polar fluid model. We finally investigate how cell migration, cell density, and cell proliferation all evolve concomitantly. We then probe higher-level tissue-tissue interactions by studying the collisions between expanding tissues. We find that these tissues change shape as they collide, which we predict according to the dynamics of single tissue expansion. We then find that genetically identical tissues displace one another due to cell density gradients at their collision boundaries and use the dynamics of this process to extract mechanical properties from the colliding tissues. Finally, we harness the dynamics of tissue expansion and collision to design arrays that self-assemble into centimeter-scale tessellations. Overall, we find that macroscale epithelial tissues support large and long-lasting coordinated behaviors, which we harness to engineer tissue as a living material.