人皮质脊髓类器官-切片连接体模型为损伤后轴突再生增强子策略提供指导
A human corticospinal organoid-slice connectoid model informs enhancer strategies for post-injury axon regrowth.
摘要(中文译文)
哺乳动物中枢神经系统（CNS）中的轴突延伸在发育过程中逐渐减弱，从而限制了出生后的再生能力。这一过程的内在调控因子是有前景的修复靶点，因为未成熟轴突能够在原本不利于再生的组织中重新生长。然而，人类中枢神经系统中轴突生长停止的确切时间及机制仍未阐明。在此，我们开发了一种三维人类皮质脊髓运动类器官-切片连接体平台，模拟发育性轴突延伸程序及其随成熟而出现的后续限制。皮质与脊髓切片在保持空间分离的同时建立功能性连接，从而能够对皮质细胞类型进行特异性观察，而不受脊髓细胞的直接混杂影响。利用单细胞转录组学、计算分析、轴突再生长实验和活细胞成像，我们识别出导致成熟中的人类皮质投射神经元轴突生长减弱的转录改变。我们进一步证明，通过靶向成熟相关转录转变的化合物和可再利用药物，这种减弱可以被逆转，从而促进损伤后的轴突修复。
Abstract
Axon elongation in the mammalian central nervous system (CNS) declines during development, limiting regenerative capacity after birth. Intrinsic regulators of this process are promising repair targets, as immature axons can regrow in tissues otherwise not conducive to regeneration. Yet the precise timing and mechanisms underlying the cessation of axon growth in the human CNS remain unresolved. Here, we developed a three-dimensional human corticospinal motor organoid-slice connectoid platform mimicking the developmental axon elongation program and its subsequent restriction through maturation. Cortical and spinal slices establish functional connections while remaining spatially segregated, enabling cortical cell-type-specific observations without direct confounding effects by spinal cells. Using single-cell transcriptomics, computational analyses, axon regrowth assays, and live imaging, we identified transcriptional alterations contributing to decreased axon growth in maturing human cortical projection neurons. We further demonstrate that this decline can be reversed using compounds and repurposable drugs targeting a maturation-associated transcriptional shift, promoting post-injury axon repair.
如何引用
AMA
George M Gibbons, Tanja Fuchsberger, Mai Abdelgawad, Stefano L Giandomenico, Kornélia Szebényi, Veselina Petrova, et al. A human corticospinal organoid-slice connectoid model informs enhancer strategies for post-injury axon regrowth.. Cell reports. 2026; doi:10.1016/j.celrep.2026.117399.
APA
George M Gibbons, Tanja Fuchsberger, Mai Abdelgawad, Stefano L Giandomenico, Kornélia Szebényi, Veselina Petrova, et al (2026). A human corticospinal organoid-slice connectoid model informs enhancer strategies for post-injury axon regrowth.. Cell reports. https://doi.org/10.1016/j.celrep.2026.117399
GB/T 7714
George M Gibbons, Tanja Fuchsberger, Mai Abdelgawad, Stefano L Giandomenico, Kornélia Szebényi, Veselina Petrova, et al. A human corticospinal organoid-slice connectoid model informs enhancer strategies for post-injury axon regrowth.[J]. Cell reports, 2026 doi:10.1016/j.celrep.2026.117399.
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