Department of Anesthesiology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, 83301, Taiwan, ROC.
Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, 83301, Taiwan, ROC.
Stem Cell Res Ther. 2022 Jun 21;13(1):265. doi: 10.1186/s13287-022-02939-4.
This study tested whether two doses of human umbilical-derived mesenchymal stem cells (hUC-MSCs) were superior to one dose for protecting the brain against intracranial hemorrhage (ICH) induced by intracranial injection collagenase and the capacity of ironic-magnetic-nanoparticles (Ir-MNa) coated hUC-MSCs tracked by MRI.
Adult male SD rats (n = 40) were equally categorized into group 1 (sham-operated-control), group 2 (ICH), group 3 [ICH + Ir-MNa-coated hUC-MSCs/1.2 × 10 cells with an extracorporeal magnet over rat head (eCMag)/administered by left internal carotid artery (LICA) at post-3 h ICH], and group 4 (ICH + Ir-MNa-coated hUC-MSCs/1.2 × 10 cells with an eCMag/administered post-3 h ICH by LICA and 24 h by IV) and euthanized by day 28. The result showed that by day 28 after ICH induction the neurological function was severely impaired in group 2 than in group 1 that was significantly improved in group 3 and further significantly improved in group 4, whereas ICH volume exhibited an opposite pattern of neurological impairment among the groups (all p < 0.0001). Brain MRI demonstrated that by 4 h after ICH, Ir-MNa-coated hUC-MSCs were abundantly identified in ischemic area in group 4. The protein expressions of inflammatory (TNF-α/MMP-9/IL-1ß/iNOS)/oxidative-stress (NOX-1/NOX-2/oxidized protein)/apoptotic (caspase-3/mitochondrial Bax/PARP)/fibrotic (Smad3/TGF-ß)/mitochondrial-damaged (cytosolic-cytochrome-C) biomarkers displayed an identical pattern of neurological impairment among the groups (all p < 0.0001). The cellular expressions of inflammation (CD68+/CD11b+)/brain edema (AQP4+) biomarkers exhibited an identical pattern, whereas the neuronal-myelin (Doublecortin+/NeuN/nestin) biomarkers displayed an opposite pattern of neurological impairment (all p < 0.0001).
Two doses of hUC-MSCs were superior to just one dose for protecting the brain against ICH-induced damage and Ir-MNa-coated hUC-MSCs offered a well adopted method for tracking hUC-MSCs homing into the brain.
本研究旨在测试两剂人脐带来源的间充质干细胞（hUC-MSCs）是否优于一剂，以保护大脑免受胶原酶颅内注射引起的颅内出血（ICH）的影响，以及 MRI 追踪的铁磁纳米粒子（Ir-MNa）涂层 hUC-MSCs 的能力。
成年雄性 SD 大鼠（n=40）平均分为 4 组：1 组（假手术对照）、2 组（ICH）、3 组[ICH+Ir-MNa 涂层 hUC-MSCs/1.2×10 个细胞，用体外磁铁（eCMag）置于大鼠头部（eCMag），于 ICH 后 3 小时通过左颈内动脉（LICA）给药]和 4 组（ICH+Ir-MNa 涂层 hUC-MSCs/1.2×10 个细胞，用 eCMag 于 ICH 后 3 小时通过 LICA 给药，24 小时通过 IV 给药），并于第 28 天处死。结果显示，ICH 诱导后第 28 天，2 组大鼠的神经功能明显受损，而 1 组大鼠的神经功能明显改善，3 组和 4 组大鼠的神经功能进一步明显改善，而各组大鼠的 ICH 体积则呈现出相反的神经损伤模式（均 p<0.0001）。脑 MRI 显示，ICH 后 4 小时，4 组缺血区可大量鉴定出 Ir-MNa 涂层 hUC-MSCs。炎症（TNF-α/MMP-9/IL-1ß/iNOS）/氧化应激（NOX-1/NOX-2/氧化蛋白）/细胞凋亡（caspase-3/线粒体 Bax/PARP）/纤维化（Smad3/TGF-ß）/线粒体损伤（细胞溶质细胞色素 C）标志物的蛋白表达在各组中呈现出与神经损伤相同的模式（均 p<0.0001）。炎症（CD68+/CD11b+）/脑水肿（AQP4+）标志物的细胞表达呈现出与神经损伤相同的模式，而神经元-髓鞘（Doublecortin+/NeuN/nestin）标志物的表达则呈现出与神经损伤相反的模式（均 p<0.0001）。
两剂 hUC-MSCs 比一剂更能保护大脑免受 ICH 损伤，Ir-MNa 涂层 hUC-MSCs 为追踪 hUC-MSCs 归巢到大脑提供了一种很好的方法。
