Brain-derived neurotropic factor mediates neuroprotection of mesenchymal stem cell-derived extracellular vesicles against severe intraventricular hemorrhage in newborn rats.
Brain-derived neurotropic factor mediates neuroprotection of mesenchymal stem cell-derived extracellular vesicles against severe intraventricular hemorrhage in newborn rats.
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脑源性神经营养因子介导间充质干细胞来源的细胞外小泡对新生大鼠严重脑室出血的神经保护作用。
DOI：
10.1002/sctm.20-0301
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发表时间：
2021-03
影响因子：
6
通讯作者：
Park WS
中科院分区：
文献类型：
--
作者：
Ahn SY;Sung DK;Kim YE;Sung S;Chang YS;Park WS
由间充质干细胞（MSC）分泌的脑源性神经营养因子（BDNF）可防止严重脑室内出血（IVH）诱导的脑损伤。虽然MSC的旁分泌保护作用主要由细胞外囊泡（EV）介导，但MSC衍生的EV的治疗功效和BDNF在EV中的作用尚未研究。本研究旨在确定MSC衍生的EV是否能减轻严重的IVH诱导的脑损伤，如果是，这种保护是否由BDNF转移介导。我们比较了MSC、有或没有BDNF敲低的MSC衍生EV和成纤维细胞衍生EV在体外用凝血酶激发的大鼠皮质神经元细胞中的治疗效果，以及通过在出生后第4天（P）注射200 μL血液和在P6移植1 × 105 MSC或20 μg EV在新生大鼠体内的治疗效果。MSC和MSC衍生的EV，但不是源自BDNF敲除MSC或成纤维细胞的EV，显著减弱了体外凝血酶诱导的神经元细胞死亡和体内严重IVH诱导的脑损伤，如神经元细胞死亡增加、星形胶质细胞增生和炎症反应;髓鞘碱性蛋白和神经发生减少;导致出血后脑积水进展;以及行为测试表现受损。我们的数据表明，MSC衍生的EV在减轻严重IVH诱导的脑损伤方面与亲本MSC一样有效，并且这种神经保护主要由通过EV的BDNF转移介导。近年来的研究表明，干细胞移植可有效改善新生大鼠严重脑室内出血（IVH）所致的脑损伤。作为下一步，由于干细胞分泌生物活性细胞外囊泡（EV），作者试图证明EV作为下一代治疗候选药物对新生儿IVH的治疗效果。脑室内移植干细胞分泌的EV通过转移脑源性神经营养因子有效减轻新生大鼠严重IVH的脑损伤。
Brain‐derived neurotropic factor (BDNF), which is secreted by mesenchymal stem cells (MSCs), protects against severe intraventricular hemorrhage (IVH)‐induced brain injuries. Although the paracrine protective effects of MSCs are mediated primarily by extracellular vesicles (EVs), the therapeutic efficacy of MSC‐derived EVs and the role of the BDNF in the EVs have not been studied. This study aimed to determine whether MSC‐derived EVs attenuate severe IVH‐induced brain injuries, and if so, whether this protection is mediated by BDNF transfer. We compared the therapeutic efficacy of MSCs, MSC‐derived EVs with or without BDNF knockdown, and fibroblast‐derived EVs in vitro in rat cortical neuronal cells challenged with thrombin and in vivo in newborn rats by injecting 200 μL of blood at postnatal day (P) 4 and transplanting 1 × 105 MSCs or 20 μg of EVs at P6. The MSCs and MSC‐derived EVs, but not the EVs derived from BDNF‐knockdown MSCs or fibroblasts, significantly attenuated in vitro thrombin‐induced neuronal cell death and in vivo severe IVH‐induced brain injuries such as increased neuronal cell death, astrogliosis, and inflammatory responses; reduced myelin basic protein and neurogenesis; led to progression of posthemorrhagic hydrocephalus; and impaired behavioral test performance. Our data indicate that MSC‐derived EVs are as effective as parental MSCs in attenuating severe IVH‐induced brain injuries, and this neuroprotection is primarily mediated by BDNF transfer via EVs. Recent reports showed that stem cells transplantation was effective on improving brain injury from severe intraventricular hemorrhage (IVH) in newborn rats. As a next step, because stem cells secrete bioactive extracellular vesicles (EVs), the authors tried to prove the therapeutic effects of EVs as next‐generation therapeutic candidates against newborn IVH. Intracerebroventricular transplantation of EVs secreted from stem cells effectively attenuated brain injury from severe IVH via transferring brain‐derived neurotrophic factor in newborn rats.
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影响因子：
20.1
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