PDF(Pubmed)
Abstract：
Nerve regeneration and circuit reconstruction remain a challenge following spinal cord injury (SCI). Corticospinal pyramidal neurons possess strong axon projection ability. In this study, human induced pluripotent stem cells (iPSCs) were differentiated into pyramidal neuronal precursors (PNPs) by addition of small molecule dorsomorphin into the culture. iPSC-derived PNPs were transplanted acutely into a rat contusion SCI model on the same day of injury. Following engraftment, the SCI rats showed significantly improved motor functions compared with vehicle control group as revealed by behavioral tests. Eight weeks following engraftment, the PNPs matured into corticospinal pyramidal neurons and extended axons into distant host spinal cord tissues, mostly in a caudal direction. Host neurons rostral to the lesion site also grew axons into the graft. Possible synaptic connections as a bridging relay may have been formed between host and graft-derived neurons, as indicated by pre- and post-synaptic marker staining and the regulation of chemogenetic regulatory systems. PNP graft showed an anti-inflammatory effect at the injury site and could bias microglia/macrophages towards a M2 phenotype. In addition, PNP graft was safe and no tumor formation was detected after transplantation into immunodeficient mice and SCI rats. The potential to reconstruct a neuronal relay circuitry across the lesion site and to modulate the microenvironment in SCI makes PNPs a promising cellular candidate for treatment of SCI.
摘要：
脊髓损伤（SCI）后，神经再生和回路重建仍然是一个挑战。皮质脊髓锥体神经元具有很强的轴突投射能力。在这项研究中,通过向培养物中添加小分子dorsomorphin，将人诱导多能干细胞（iPSCs）分化为锥体神经元前体（PNP）。在损伤的同一天，将iPSC衍生的PNP急性移植到大鼠挫伤SCI模型中。雕刻后，行为测试显示，与载体对照组相比，SCI大鼠的运动功能显着改善。植入八周后，PNP成熟为皮质脊髓锥体神经元，并延伸轴突进入远处宿主脊髓组织，主要是在尾部方向。病变部位的宿主神经元也将轴突生长到移植物中。作为桥接中继的可能的突触连接可能已经在宿主和移植物衍生的神经元之间形成，如突触前和突触后标记染色和化学遗传调节系统的调节所示。PNP移植物在损伤部位显示出抗炎作用，并且可能使小胶质细胞/巨噬细胞偏向M2表型。此外,PNP移植物是安全的，移植到免疫缺陷小鼠和SCI大鼠中后未检测到肿瘤形成。重建整个病变部位的神经元中继电路并调节SCI微环境的潜力使PNP成为治疗SCI的有希望的细胞候选者。
