Artificially reprogrammed stem cells deliver transcytosable nanocomplexes for improved spinal cord repair
Artificially reprogrammed stem cells deliver transcytosable nanocomplexes for improved spinal cord repair
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DOI：
10.1016/j.jconrel.2023.10.051
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发表时间：
2023-11-16
影响因子：
10.8
通讯作者：
Fan，Shunwu
中科院分区：
文献类型：
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作者：
Liu，Xin;Zheng，Yufei;Fan，Shunwu
干细胞移植在脊髓损伤(SCI)后的功能恢复方面有很大的希望，但其治疗效果在很大程度上依赖于细胞的先天能力和病变部位的微环境。在这里，一种有效的细胞治疗(NCS@SCs)是通过人工将骨髓间充质干细胞(BMSCs)与氧化响应性跨细胞基因递送纳米复合体(NCS)重新编程来设计的，NCS赋予细胞强大的抗氧化应激能力和改善细胞因子的分泌。静脉给药后，NCS@SCs可通过趋化作用在损伤脊髓中蓄积，并促进后续的跨细胞反应，将NCS传递给神经元，增加BMSCs和神经元中睫状神经营养因子(CNTF)的产生，以响应ROS水平的升高。此外，NCS@SCs可以主动感知和消除ROS，并将招募的M1样巨噬细胞重新培养到抗炎M2表型旁分泌途径中，最终重塑炎症微环境。协同作用，NCS@SCs表现出持久的存活并提供针对继发性损伤的神经保护，使SCI大鼠的运动功能显著恢复。转录组分析表明，NCS@SCs参与了ROS/MAPK信号通路的调控，参与了脊髓损伤的治疗。这项研究提出了一种纳米材料介导的细胞重编程方法来开发活细胞疗法，在治疗脊髓损伤和其他神经损伤疾病方面显示出巨大的潜力。
Stem cell transplantation holds great promise for restoring function after spinal cord injury (SCI), but its therapeutic efficacy heavily depends on the innate capabilities of the cells and the microenvironment at the lesion site. Herein, a potent cell therapeutic (NCs@SCs) is engineered by artificially reprogramming bone marrow mesenchymal stem cells (BMSCs) with oxidation-responsive transcytosable gene-delivery nanocomplexes (NCs), which endows cells with robust oxidative stress resistance and improved cytokine secretion. NCs@SCs can accumulate in the injured spinal cord after intravenous administrationviachemotaxis and boost successive transcytosis to deliver NCs to neurons, augmenting ciliary neurotrophic factor (CNTF) production in both BMSCs and neurons in response to elevated ROS levels. Furthermore, NCs@SCs can actively sense and eliminate ROS and re-educate recruited M1-like macrophages into the anti-inflammatory M2 phenotypeviaa paracrine pathway, ultimately reshaping the inflammatory microenvironment. Synergistically, NCs@SCs exhibit durable survival and provide neuroprotection against secondary damage, enabling significant locomotor function recovery in SCI rats. Transcriptome analysis reveals that regulation of the ROS/MAPK signaling pathway is involved in SCI therapy by NCs@SCs. This study presents a nanomaterial-mediated cell-reprogramming approach for developing live cell therapeutics, showing significant potential in the treatment of SCI and other neuro-injury disorders.