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A strategy for tissue self-organization that is robust to cellular heterogeneity and plasticity


Classic models of cell sorting invoke differences in cell-cell cohesion to explain how multiple cell types can self-organize into spatially resolved tissues. However, tissues contain motile populations of cells that are heterogeneous in time and space and that change their cohesion in response to cell-intrinsic and extrinsic cues. The human mammary gland is a prototypical heterogeneous and dynamic tissue. Its ducts and acini comprise two concentrically arranged cell types that retain their relative spatial positions despite enormous plasticity and motility associated with development, estrous cycles, pregnancy, and the onset of malignant disease. To investigate the consequences of cellular heterogeneity and plasticity on cell positioning in this adult human tissue, we reconstituted its self-organization from aggregates of primary cells in vitro. We find that self-organization is dominated by a self-generated adhesive interaction between a single cell type (i.e. the basal lineage) and the tissue boundary (i.e. the Extracellular Matrix - ECM), rather than through a hierarchy of homo and heterotypic cell-cell interactions. Surprisingly, cell-ECM adhesion is binary, in that the other cell type (i.e. the luminal lineage) lacks the entire cell-ECM adhesion machinery required to adhere to the tissue-boundary. Using mathematical modeling and cell-type specific knock-down of key adhesion molecules, we show that this strategy of self-organization is robust to severe perturbations that affect cell-cell cohesion. We also find that this mechanism of self-organization is conserved in related tissues such as the human prostate. Therefore, our model supports the notion that a binary regulation of cell adhesion to the tissue boundary provides a flexible and generalizable strategy for forming and maintaining the structure of human bilayered and secretory epithelia. The model allows us to also make specific predictions about how this strategy might breakdown in the context of injury or malignant disease. In particular, our results suggest that while decreases in cell-cell cohesion can challenge the architectural maintenance of the human mammy gland, an increase in adhesion between the luminal cell-type and the tissue-ECM boundary is the aberration that will trigger catastrophic tissue breakdown.

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