Strain-Mediated Feedback Governs Muscle Alignment in Developing Heart Organoids

The human heart develops through the self-organization of thousands of cells into a mechanically and biochemically synchronized tissue. Using 3D human cardiac organoids, we track the collective alignment of muscle fibers, synchronization of calcium pulses, and strength of mechanical contractions to understand how such spatial and temporal order emerges from local interactions between cells. Our experiments show that muscle fibers gradually align as an organoid matures and that pharmacologically inhibiting contractility or calcium signaling disrupts this emergent order. To explain these findings, we model the tissue as a contractile active nematic solid, where contractile stresses generate strains that, in turn, promote fiber alignment. Our model demonstrates how this feedback loop can spontaneously create nematic order, even from an initially isotropic state. Simulations and theory not only reproduce the experimental observations but also reveal the underlying mechanism: a slow, gradual increase in contractility enhances global alignment, whereas excessive contractility, counterintuitively, reduces global alignment by quenching the nematic field too rapidly. Going forward, our integrated experimental and theoretical framework provides an opportunity to investigate the interplay of mechanical feedback with calcium dynamics and address the important question of how calcium pulses first become synchronized during early heart development.