Long-Range Mechanical Force Enables Self-Assembly of Epithelial Tubules

Abstract

Spatiotemporal coordination of cell positioning and differentiation is critical in morphogenesis. Loss of coordination is often a hallmark of tissue abnormality and tumorigenesis. Recent studies indicate the importance of mechanical force in morphogenesis such as tubular pattern formation. However, how cells coordinate mechanical interactions between each other and with extracellular matrix (ECM), to initiate, regulate, or maintain long-range tubular patterns is unclear. Using a two-step process to quantitatively control cell-ECM interaction, we find that epithelial cells, in response to a fine-tuned percentage of type I collagen (COL) in ECM, develop various patterns resembling those observed in tubulo-lobular organs. In contrast with conventional thought, these patterns arise through mechanical interactions between cells, but not through gradients of diffusible biochemical factors. Remarkably, a very large spatial scale of tubular patterns is found by cell-COL self-organization in the liquid phase, leading to the formation of long-range (~1 cm) epithelial tubule. Our results suggest a potential mechanism cells can use to form and coordinate long-range tubular patterns, independent of those controlled by diffusible biochemical factors, and provide a new strategy to engineer/regenerate tubular organs.

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