Unveiling the Development Specific Regenerative Potential of Spinal Cord: Insights from Extracellular Matrix

Neonatal spinal cord tissues exhibit remarkable regenerative capabilities compared to adult tissues following injury. Although some cellular signaling pathways involved in the process have been identified, the specific role of extracellular matrix (ECM) responsible for neonatal spinal cord regeneration has remained elusive. Here we revealed that early developmental spinal cord contained a higher abundance of ECM proteins associated with neural development and axon growth but fewer inhibitory proteoglycans compared to adult spinal cord. Decellularized spinal cord ECM from neonatal (DNSCM) and adult (DASCM) rabbits preserve the major difference of native spinal cord tissues in both stages. Compared to DASCM, DNSCM promoted proliferation, migration, and neuronal differentiation of neural progenitor cells (NPCs), as well as facilitated the long-distance axonal outgrowth and axon regeneration of spinal cord organoids. Pleiotrophin (PTN) and Tenascin (TNC) in DNSCM were identified as contributors to the remarkable neural regeneration ability. Furthermore, DNSCM demonstrated superior performance when used as a delivery vehicle for NPCs and organoids in rats with spinal cord injury (SCI). It suggests that ECM cues derived from different development stage might contribute to the distinct regeneration ability of spinal cord.与成年脊髓组织相比，新生脊髓组织在损伤后展现出显著的再生能力。尽管该过程中涉及的部分细胞信号通路已被阐明，但介导新生脊髓再生的细胞外基质（extracellular matrix, ECM）的具体作用仍不明确。本研究发现，相较于成年脊髓，发育早期的脊髓中富含与神经发育及轴突生长相关的ECM蛋白，而抑制性蛋白聚糖的含量更低。来自新生兔和成年兔的脱细胞脊髓基质（分别为DNSCM和DASCM）保留了两个发育阶段原生脊髓组织的主要差异。相较于DASCM，DNSCM可促进神经祖细胞（neural progenitor cells, NPCs）的增殖、迁移及神经元分化，同时还能推动脊髓类器官的长距离轴突生长与轴突再生。本研究鉴定出DNSCM中的多效蛋白（Pleiotrophin, PTN）与腱生蛋白（Tenascin, TNC）是其具备优异神经再生能力的关键因子。此外，在脊髓损伤（spinal cord injury, SCI）模型大鼠中，DNSCM作为NPC与类器官的递送载体时展现出更优的性能。该研究结果表明，不同发育阶段来源的ECM信号或可解释脊髓再生能力的差异。