Extracellular Vesicles Derived from Wharton's Jelly Mesenchymal Stem Cells Prevent and Resolve Programmed Cell Death Mediated by Perinatal Hypoxia-Ischemia in Neuronal Cells.
Extracellular Vesicles Derived from Wharton's Jelly Mesenchymal Stem Cells Prevent and Resolve Programmed Cell Death Mediated by Perinatal Hypoxia-Ischemia in Neuronal Cells.
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DOI：
10.1177/0963689717738256
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发表时间：
2018-01
影响因子：
3.3
通讯作者：
Schoeberlein A
中科院分区：
文献类型：
--
作者：
Joerger-Messerli MS;Oppliger B;Spinelli M;Thomi G;di Salvo I;Schneider P;Schoeberlein A
围产期缺氧缺血性损伤（HI）是新生儿发生脑病的高危因素。脑细胞经历凋亡，引发神经变性。到目前为止，冷却等治疗方法仍然有限。间充质干细胞（MSC）的移植尽管在宿主脑中存活时间短，但仍表现出治疗成功，这提供了强有力的证据，证明其有益作用主要基于分泌因子，包括细胞外囊泡（EV）。本研究的目的是研究人沃顿胶质MSC（hWJ-MSC）衍生的EV对神经保护和神经再生的影响，使用体外模型的氧-葡萄糖剥夺/复氧（OGD/R）模拟HI损伤小鼠神经母细胞瘤细胞系neuro 2a（N2 a）。通过多步离心从细胞培养上清液中分离hWJ-MSC衍生的EV，并通过内体标志物表达和电子显微镜鉴定。OGD/R显著增加了N2 a细胞的DNA片段化和caspase 3（Casp 3）转录。OGD/R介导的DNA断裂和Casp 3表达可以通过在OGD前后分别添加hWJ-MSC衍生的EV来防止和解决。当在OGD之前或之后加入时，hWJ-MSC衍生的EV也倾向于增加N2 a细胞中B细胞淋巴瘤2（Bcl 2）家族成员Bcl-2细胞死亡拮抗剂（BAD）的磷酸化，从而使BAD的促凋亡功能失活。荧光共聚焦显微镜显示hWJ-MSC衍生的EV紧密定位于N2 a细胞的细胞核。此外，EV将其RNA内容物释放到细胞中。已知的Casp 3调节因子microRNA（miRs）let-7a和let-7 e的表达水平与Casp 3呈负相关。我们的数据表明，hWJ-MSC衍生的EV具有预防和解决未成熟新生儿脑中神经元细胞中HI诱导的凋亡的潜力。它们的抗凋亡作用似乎是由EV衍生的let-7- 5 p miR的转移介导的。
Hypoxic-ischemic (HI) insult in the perinatal phase harbors a high risk of encephalopathy in the neonate. Brain cells undergo apoptosis, initiating neurodegeneration. So far, therapeutic approaches such as cooling remain limited. Transplantation of mesenchymal stem cells (MSCs) exhibits therapeutic success despite the short-time survival in the host brain, providing strong evidence that their beneficial effects are largely based on secreted factors, including extracellular vesicles (EVs). The aim of this study was to investigate the effects of human Wharton’s jelly MSC (hWJ-MSC)-derived EVs on neuroprotection and neuroregeneration, using an in vitro model of oxygen–glucose deprivation/reoxygenation (OGD/R) mimicking HI injury in the mouse neuroblastoma cell line neuro2a (N2a). hWJ-MSC-derived EVs were isolated from cell culture supernatants by multistep centrifugation and identified by endosomal marker expression and electron microscopy. OGD/R significantly increased DNA fragmentation and caspase 3 (Casp3) transcription in N2a cells relative to undamaged cells. OGD/R-mediated DNA fragmentation and Casp3 expression could be prevented as well as resolved by the addition of hWJ-MSC-derived EV before and after OGD, respectively. hWJ-MSC-derived EV also tended to increase the phosphorylation of the B cell lymphoma 2 (Bcl2) family member Bcl-2-antagonist of cell death (BAD) in N2a cells, when added prior or post OGD, thereby inactivating the proapoptotic function of BAD. Fluorescence confocal microscopy revealed the close localization of hWJ-MSC-derived EVs to the nuclei of N2a cells. Furthermore, EVs released their RNA content into the cells. The expression levels of the microRNAs (miRs) let-7a and let-7e, known regulators of Casp3, were inversely correlated to Casp3. Our data suggest that hWJ-MSC-derived EVs have the potential to prevent and resolve HI-induced apoptosis in neuronal cells in the immature neonatal brain. Their antiapoptotic effect seems to be mediated by the transfer of EV-derived let-7-5p miR.
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影响因子：
6
作者：
Doeppner, Thorsten R.;Herz, Josephine;Hermann, Dirk M.
通讯作者：
Hermann, Dirk M.
DOI：
10.1073/pnas.94.21.11657
发表时间：
1997-10-14
影响因子：
11.1
作者：
Du, YS;Bales, KR;Paul, SM
通讯作者：
Paul, SM
缺血性脑损伤的干细胞：批判性综述。
DOI：
10.1002/cne.22038
发表时间：
2009-07-01
期刊：
The Journal of comparative neurology
影响因子：
--
作者：
Burns TC;Verfaillie CM;Low WC
通讯作者：
Low WC
影响因子：
3.7
作者：
Lee JK;Park SR;Jung BK;Jeon YK;Lee YS;Kim MK;Kim YG;Jang JY;Kim CW
通讯作者：
Kim CW
影响因子：
9.7
作者：
Katakowski, Mark;Buller, Ben;Zheng, Xuguang;Lu, Yong;Rogers, Thomas;Osobamiro, Oyinkansola;Shu, Wayne;Jiang, Feng;Chopp, Michael
通讯作者：
Chopp, Michael