Mesoscale heterogeneity is a critical determinant for spiral pattern formation in developing social amoeba.

Heterogeneity is a critical determinant for multicellular pattern formation. Although the importance of microscale and macroscale heterogeneity at the single-cell and whole-system levels, respectively, has been well accepted, the presence and functions of mesoscale heterogeneity, such as cell clusters with distinct properties, have been poorly recognized. We investigated the biological importance of mesoscale heterogeneity in signal-relaying abilities (excitability) in the self-organization of spiral waves of intercellular communications by studying the self-organized pattern formation in a population of Dictyostelium discoideum cells, a classical signal-relaying system model. By utilizing pulse-count analysis to evaluate cellular excitability, we successfully visualized the development of mesoscale heterogeneity in excitability, whose spatial scale was comparably large to that of the traveling waves of intercellular communication. Together with perturbation experiments, our detailed analysis of the structural change in mesoscale heterogeneity and associated wave dynamics demonstrated the functional importance of mesoscale heterogeneity in generating the spiral wave pattern, whose experimental observations were first realized. We propose that mesoscale heterogeneity, in addition to microscale and macroscale heterogeneities, is a critical determinant of diverse multicellular pattern formations.