Hyaluronan Underlies the Emergence of Form, Fate, and Function in Human Cardioids

The extracellular matrix (ECM) is crucial for organ development and disease. Yet, the interplay among cells, function, and the ECM during human cardiogenesis remains obscure. Using human cardioids, we discovered that cardiac mesoderm-synthesized hyaluronan (HA) underlies early cardiac functional development. HA drives cardioid cavity formation through hydrogel swelling and bioscaffolding, critical functions of the cardiac jelly in the early vertebrate heart. During an early developmental window, HA is essential for establishing cardiac cell identity, while at later stages, HA-generated forces promote beating function through mechanosensitive channels. Chamber-specific differences in mechanical sensitivity ensure robust contractions in multi-chambered tissues. Our findings reveal how a single endogenous ECM component orchestrates the co-emergence of form, fate, and function during human organogenesis, opening new avenues for bioengineering physiologically relevant organ models.