Establishment of a Cochlear Organoid Platform for Remodeling the Extracellular Matrix

Irreparable injury and depletion of inner ear hair cells lead to permanent hearing impairment. Cochlear organoids serve as a robust in vitro platform for investigating the pathogenesis of deafness and exploring therapeutic approaches. However, the widely used commercial Matrigel in cochlear organoid culture suffers from issues related to consistency and structural stability. Here, we developed a cochlear organoid culture system using synthetic GelMA hydrogel, which promoted the spontaneous clustering and organization of cochlear stem cells, thereby accelerating organoid formation and facilitating the functional maturation of cochlear hair cells. Moreover, we observed that the extracellular matrix (ECM) underwent rapid and extensive remodeling during the early phase of organoid self-organization. During cochlear organoid development, matrix metalloproteinases (Mmps) were markedly upregulated, with Mmp9 displaying relatively higher expression. Notably, inhibition of Mmps significantly interfered with the organoid formation process, suggesting their important role in cochlear organoid morphogenesis. Collectively, this work provides an alternative approach for cochlear organoid generation and underscores the contribution of Mmp-mediated ECM remodeling during organoid formation.