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

Abstract

How patterns of cell state emerge across a tissue field is a fundamental question brought into renewed focus by spatial omics tools that map molecular states onto tissue organization. Here, we investigate how a field of limb progenitor mesenchyme transforms into distinct, adjacent cartilage and soft tissue compartments. We find that mesenchymal tissue fields self-organize their own differentiation through co-constitutive relationships between cell and supracellular structures, which produce cell-ECM or cell-cell-based supracellular cues that canalize cartilage or soft tissue cell fate change, respectively. At the tissue level, bifurcation in intrinsically generated supracellular structures guides the specification of tissue compartment size. We find that Wnt secreted from neighboring epithelial tissue influences mesenchymal cell fate and patterning by functioning as a modulator of cell-supracellular structural relations. Taken together, our results provide insight into how mesenchymal self-organization interfaces with epithelial signaling to enable a tissue compartmentalization process that initiates the skeleton.