Bioorthogonal microglia-inspired mesenchymal stem cell bioengineering system creates livable niches for enhancing ischemic stroke recovery via the hormesis  

作　　者：Jianpei Xu Yinzhe Sun Yang You Yuwen Zhang Dan Huang Songlei Zhou Yipu Liu Shiqiang Tong Fenfen Ma Qingxiang Song Chengxiang Dai Suke Li Jigang Lei Zhihua Wang Xiaoling Gao Jun Chen 

机构地区：[1]Shanghai Pudong Hospital&Department of Pharmaceutics,School of Pharmacy,Fudan University,Shanghai 201203,China [2]Key Laboratory of Smart Drug Delivery,Ministry of Education,School of Pharmacy,Fudan University,Shanghai 201203,China [3]Department of Pharmacology and Chemical Biology,State Key Laboratory of Oncogenes and Related Genes,Shanghai Universities Collaborative Innovation Center for Translational Medicine,Shanghai Jiao Tong University School of Medicine,Shanghai 200025,China [4]Department of Emergency,Shanghai Pudong Hospital,Fudan University Pudong Medical Center,Shanghai 201399,China [5]Institute of Science and Technology for Brain-Inspired Intelligence&Department of Neurology,Fudan University,Shanghai 201203,China [6]Department of Rehabilitation Medicine,Huashan Hospital,Fudan University,Shanghai 201203,China [7]Daxing Research Institute,University of Science and Technology Beijing,Biomedical Industry Base,Zhongguancun Science and Technology Park,Beijing 102600,China [8]Cellular Biomedicine Group Inc.,Shanghai 201210,China

出　　处：《Acta Pharmaceutica Sinica B》2024年第3期1412-1427,共16页药学学报（英文版）

基　　金：supported by National Natural Science Foundation of China(Nos.92068110,81973272 and 92068111);Shanghai Science and Technology Committee(Nos.20JC1411800,and 23S41900100,China);Programs of Shanghai Academic/Technology Research Leader(Nos.21XD1400200 and 21XD1422200,China);Innovation Program of Shanghai Municipal Education Commission(2023ZKZD21,China);the fund of Research Grant for Health Science and Technology of Shanghai Municipal Commission of Health Committee(No.20214Y0268,China);Science and Technology Development Fund of Shanghai Pudong New Area(No.PKJ2020-Y49,China);the Project of Key Medical Specialty and Treatment Center of Pudong Hospital of Fudan University(No.Zdzk2020-15,China)。

摘　　要：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 ROSscavenging and PC-absorbing layers effectively buffer the deleterious effects and establish a microlivable 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.

关 键 词：Ischemic stroke Mesenchymal stem cell Cell engineering Hormesis effect Bioorthogonal chemistry MICROGLIA Reactive oxygen spices Proinflammatory cytokines 

分 类 号：R743.3[医药卫生—神经病学与精神病学]