Harnessing developmental dynamics of spinal cord extracellular matrix improves regenerative potential of spinal cord organoids

Neonatal spinal cord tissues exhibit remarkable regenerative capabilities as compared to adult spinal cord tissues after injury, but the role of extracellular matrix (ECM) in this process has remained elusive. Here, we found that early developmental spinal cord had higher levels of ECM proteins associated with neural development and axon growth, but fewer inhibitory proteoglycans, compared to those of adult spinal cord. Decellularized spinal cord ECM from neonatal (DNSCM) and adult (DASCM) rabbits preserved these differences. DNSCM promoted proliferation, migration, and neuronal differentiation of neural progenitor cells (NPCs) and facilitated axonal outgrowth and regeneration of spinal cord organoids more effectively than DASCM. Pleiotrophin (PTN) and Tenascin (TNC) in DNSCM were identified as contributors to these abilities. Furthermore, DNSCM demonstrated superior performance as a delivery vehicle for NPCs and organoids in spinal cord injury (SCI) models. This suggests that ECM cues from early development stages might significantly contribute to the prominent regeneration ability in spinal cord. [Display omitted] •Early developmental spinal cord contains more beneficial ECM and less inhibitory ECM•DNSCM promotes NPC proliferation, migration, and neuronal differentiation•DNSCM promotes scMN-Organs’ maturation, neurite extension, and neural projection•DNSCM and NPC/scMN-Organs synergistically enhance motor function recovery after SCI Neonatal spinal cord exhibits impressive regenerative capabilities after injury. Sun et al. demonstrate that the neonatal spinal cord extracellular matrix creates a developmental microenvironment for the proliferation, migration, neuronal differentiation, and axon extension of neural progenitor cells, which aids to reconstruct a regenerative niche after spinal cord injury.