Bioorthogonal microglia-inspired mesenchymal stem cell bioengineering system creates livable niches for enhancing ischemic stroke recovery via the hormesis
Bioorthogonal microglia-inspired mesenchymal stem cell bioengineering system creates livable niches for enhancing ischemic stroke recovery via the hormesis
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DOI：
10.1016/j.apsb.2023.11.009
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发表时间：
2024-03-06
影响因子：
14.5
通讯作者：
Chen，Jun
中科院分区：
文献类型：
--
作者：
Xu，Jianpei;Sun，Yinzhe;Chen，Jun
间充质干细胞（MSC）在中风梗塞区域中经历实质性存活问题，限制了其治疗功效和临床转化。梗死环境中高水平的致命活性氧自由基（ROS）和促炎细胞因子（PC）杀死移植的MSC，而低水平的有益ROS和PC刺激和改善移植的MSC的活力。基于细胞生物学中的内在兴奋效应，我们建立了一个小胶质细胞启发的MSC生物工程系统，将有害的高水平ROS和PC转化为活力增强剂，用于加强MSC治疗。该系统通过用小胶质细胞膜包被的纳米颗粒和抗氧化细胞外保护层生物正交武装代谢糖工程化MSC来实现。在该系统中，细胞外ROS清除层和PC吸收层有效地缓冲了有害作用，并在单个MSC水平上建立了用于移植的微宜居生态位。同时，梗死的无生命环境在组织水平上转化为新的生命生态位，以促进愈合。移植后7天，工程化MSC的活力比天然MSC高出5倍，并在长达28天的中风恢复中表现出上级治疗效果。这种增强活力的系统证明了加速MSC治疗的临床转化和促进中风恢复的潜力。
Mesenchymal stem cells (MSCs) experience substantial viability issues in the stroke infarct region, limiting their therapeutic efficacy and clinical translation. High levels of deadly reactive oxygen radicals (ROS) and proinflammatory cytokines (PC) in the infarct milieu kill transplanted MSCs, whereas low levels of beneficial ROS and PC stimulate and improve engrafted MSCs' viability. Based on the intrinsic hormesis effects in cellular biology, we built a microglia-inspired MSC bioengineering system to transform detrimental high-level ROS and PC into vitality enhancers for strengthening MSC therapy. This system is achieved by bioorthogonally arming metabolic glycoengineered MSCs with microglial membrane-coated nanoparticles and an antioxidative extracellular protective layer. In this system, extracellular ROS-scavenging and PC-absorbing layers effectively buffer the deleterious effects and establish a micro-livable niche at the level of a single MSC for transplantation. Meanwhile, the infarct's inanimate milieu is transformed at the tissue level into a new living niche to facilitate healing. The engineered MSCs achieved viability five times higher than natural MSCs at seven days after transplantation and exhibited a superior therapeutic effect for stroke recovery up to 28 days. This vitality-augmented system demonstrates the potential to accelerate the clinical translation of MSC treatment and boost stroke recovery.