Long noncoding RNA MALAT1 in exosomes drives regenerative function and modulates inflammation-linked networks following traumatic brain injury.
Long noncoding RNA MALAT1 in exosomes drives regenerative function and modulates inflammation-linked networks following traumatic brain injury.
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DOI：
10.1186/s12974-018-1240-3
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发表时间：
2018-07-12
影响因子：
9.3
通讯作者：
Bickford PC
中科院分区：
文献类型：
--
作者：
Patel NA;Moss LD;Lee JY;Tajiri N;Acosta S;Hudson C;Parag S;Cooper DR;Borlongan CV;Bickford PC
神经炎是创伤性脑损伤(TBI)的常见治疗靶点，因为它导致延迟性继发性细胞死亡，并有可能在最初的损伤后持续数年。来自脂肪干细胞(HASCs)的外体含有长非编码RNA MALAT1，是一种新的、无细胞的再生方法，可用于创伤性脑损伤(TBI)后的长期恢复，具有在基因组水平调节炎症的潜力。长的非编码RNA MALAT1是hASCs分泌组的重要组成部分。我们从HASC中分离出含有或缺失MALAT1的外体。然后，在轻度受控皮质撞击(CCI)后，将HASC衍生的外切体静脉注射给大鼠。我们对大鼠进行了行为学、活体成像、组织学和RNA测序(RNA Seq)的跟踪。使用活体成像，我们发现外切体会在给药后1小时内迁移到脾内，并在脑外伤后几小时后进入大脑。在使用外切体治疗的大鼠脑损伤后，观察到运动行为功能的显著恢复以及皮质脑损伤的减少。无论是耗尽MALAT1的外切体还是耗尽外切体的条件培养液处理，再生效果都有限，证明了MALAT1在外切体介导的恢复中的重要性。使用RNA Seq对大脑和脾转录组的分析表明，MALAT1依赖于炎症相关途径、细胞周期、细胞死亡和再生分子途径的调节。重要的是，我们的数据表明，MALAT1调节包括snoRNAs在内的其他非编码RNA的表达。我们证明了HASC来源的外切体中的MALAT1调节包括炎症在内的多个治疗靶点，并具有治疗脑外伤的巨大潜力。
Neuroinflammation is a common therapeutic target for traumatic brain injury (TBI) due to its contribution to delayed secondary cell death and has the potential to occur for years after the initial insult. Exosomes from adipose-derived stem cells (hASCs) containing the long noncoding RNA MALAT1 are a novel, cell-free regenerative approach to long-term recovery after traumatic brain injury (TBI) that have the potential to modulate inflammation at the genomic level. The long noncoding RNA MALAT1 has been shown to be an important component of the secretome of hASCs. We isolated exosomes from hASC containing or depleted of MALAT1. The hASC-derived exosomes were then administered intravenously to rats following a mild controlled cortical impact (CCI). We followed the rats with behavior, in vivo imaging, histology, and RNA sequencing (RNA Seq). Using in vivo imaging, we show that exosomes migrate into the spleen within 1 h following administration and enter the brain several hours later following TBI. Significant recovery of function on motor behavior as well as a reduction in cortical brain injury was observed after TBI in rats treated with exosomes. Treatment with either exosomes depleted of MALAT1 or conditioned media depleted of exosomes showed limited regenerative effects, demonstrating the importance of MALAT1 in exosome-mediated recovery. Analysis of the brain and spleen transcriptome using RNA Seq showed MALAT1-dependent modulation of inflammation-related pathways, cell cycle, cell death, and regenerative molecular pathways. Importantly, our data demonstrates that MALAT1 regulates expression of other noncoding RNAs including snoRNAs. We demonstrate that MALAT1 in hASC-derived exosomes modulates multiple therapeutic targets, including inflammation, and has tremendous therapeutic potential for treatment of TBI.
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影响因子：
3.7
作者：
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通讯作者：
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1.7
作者：
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