Cell-supracellular structural relations solve the French Flag Problem without graded molecular control

The molecular characterization of tissue organization through spatial omics brings renewed attention to the issue, formulated in Wolpert’s French Flag, of how spatial patterns of cell state emerge. Here, we address the skeletal pattern of adjacent cartilage and soft tissue. We find that cellular and supracellular structures are co-constitutive and result in cell-ECM and cell-cell-based structures that canalize cartilage and soft tissue fate, respectively. A bistability in these fate-setting structures establishes pattern length scale and is sufficient to break symmetry in the mesenchyme. However, an adjacent epithelium, through signals like Wnt, can locally seed the bistability to ensure the epithelial-adjacency of soft tissue. Rather than acting in a graded manner to provide positional information, Wnt affects cell fate by promoting a supracellular structure. Together, these results support a solution to the French Flag problem where fate pattern originates through structural relations between cell and supracellular levels.