Yao Xuanbao, Zhang Kehua, Na Tao, Wang Yuchun, Guo Yuhan, Xi Jiajie, Li Xiang, Meng Shufang, Xu Miao
Graduate School of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, 511436, Guangdong, China.
Guangzhou National Laboratory, Guangzhou, 510005, Guangdong, China.
Cell Death Dis. 2025 Aug 22;16(1):637. doi: 10.1038/s41419-025-07961-x.
Spinal cord injury (SCI) remains a significant clinical challenge and poses a dramatic threat to the life quality of patients due to limited neural regeneration and detrimental post-injury alternations in tissue microenvironment. We developed a therapeutic approach by transplanting spinal neural progenitor cells (spNPGs), derived from human induced pluripotent stem cell (iPSC)-generated neuromesodermal progenitors, into a contusive SCI model in NOD-SCID mice. Single-cell RNA sequencing mapped the in vitro differentiation of iPSC-spNPGs, confirming their specification into spinal neuronal lineages. Single-nucleus transcriptomics at 1 week post-transplantation showed that the grafted cells differentiated in vivo into motor neurons and two interneuron subtypes (V2 and dI4). Additionally, spNPGs integrated into host neural circuits, enhancing synaptic connectivity, while simultaneously modulating the injury microenvironment by shifting microglia and astrocyte polarization toward anti-inflammatory and neuroprotective phenotypes. This dual mechanism promoted axonal regrowth, remyelination, and significant sensorimotor recovery, as evidenced by improved locomotor scores. Our findings highlight the therapeutic potential of human iPSC-spNPGs in reconstructing neural networks and mitigating secondary damage, providing compelling preclinical evidence for advancing stem cell-based SCI therapies.
脊髓损伤（SCI）仍然是一项重大的临床挑战，由于神经再生有限以及损伤后组织微环境的有害变化，对患者的生活质量构成了巨大威胁。我们开发了一种治疗方法，将源自人诱导多能干细胞（iPSC）产生的神经中胚层祖细胞的脊髓神经祖细胞（spNPGs）移植到NOD-SCID小鼠的挫伤性SCI模型中。单细胞RNA测序绘制了iPSC-spNPGs的体外分化图谱，证实了它们向脊髓神经元谱系的分化。移植后1周的单核转录组学显示，移植的细胞在体内分化为运动神经元和两种中间神经元亚型（V2和dI4）。此外，spNPGs整合到宿主神经回路中，增强了突触连接，同时通过将小胶质细胞和星形胶质细胞的极化转向抗炎和神经保护表型来调节损伤微环境。这种双重机制促进了轴突再生、髓鞘再生和显著的感觉运动恢复，运动评分的改善证明了这一点。我们的研究结果突出了人iPSC-spNPGs在重建神经网络和减轻继发性损伤方面的治疗潜力，为推进基于干细胞的SCI治疗提供了令人信服的临床前证据。
