Deciphering the origins of heterogeneity in biological tissues

Cell heterogeneity in biological tissues is ubiquitous and known to play an essential role in organ development and disease progression. While genotypic heterogeneity has been extensively studied, much remains unknown about the emergence of cell morphological and mechanical heterogeneity. Previous experimental and theoretical studies mainly attribute such heterogeneity to the effect of physical packing, ignoring essential biological contributions (e.g., random cell partitioning and epigenetics). To examine this paradigm, we experimentally disentangle the physical and biological contributions. To do so, we compare monolayers of randomly seeded cells to cloned cells, where both experience the same physical packing effect, but different genetic heterogeneity distributions. By analyzing the spatial correlation of morphological properties, we observe a preferential cell morphology that may be generationally inherited, suggesting that the biological contribution is significant. Using vertex-model based simulations, we further quantified the physical and biological contributions. Our results suggest that the interplay between both contributions is essential to understand collective organization and mechanics of epithelia.