Intranasal delivery of exosomes from human adipose derived stem cells at forty-eight hours post injury reduces motor and cognitive impairments following traumatic brain injury.
Intranasal delivery of exosomes from human adipose derived stem cells at forty-eight hours post injury reduces motor and cognitive impairments following traumatic brain injury.
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DOI：
10.1016/j.neuint.2021.105173
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发表时间：
2021-11
影响因子：
4.2
通讯作者：
Bickford PC
中科院分区：
文献类型：
--
作者：
Moss LD;Sode D;Patel R;Lui A;Hudson C;Patel NA;Bickford PC
人类脂肪源性干细胞（hASCs）的神经保护作用由于其调节周围环境的能力而引起了再生医学的极大兴趣。我们的研究小组已经证明，来自hASC的外泌体（hASCexo）是创伤性脑损伤（TBI）后长期恢复的无细胞再生方法。之前，我们在大鼠脑外伤后3小时静脉给药证明了外泌体治疗的有效性。在这里，我们展示了外泌体在小鼠脑外伤后48小时经鼻给药的有效性，延长了治疗的治疗窗口期，从而增加了转化为临床研究的可能性。我们的研究结果表明，与不含MALAT1外泌体和MALAT1缺失外泌体的TBI小鼠相比，接受含有MALAT1外泌体治疗的小鼠，通过升高的身体摆动试验评估了运动障碍的显著恢复。在含有MALAT1的外泌体治疗小鼠的8臂桡臂水迷宫逆转试验中，观察到显著的认知改善。此外，用含有MALAT1的外泌体处理的小鼠皮质损伤显著减轻，小胶质细胞的MHCII+染色也降低。没有外泌体或用MALAT1缺失的外泌体治疗的小鼠没有表现出类似的恢复。结果表明，炎症相关基因和NRTK3 （TrkC）都是hASC外泌体调节的靶基因，hASC外泌体中的MALAT1调节全长TrkC的表达，从而激活MAPK通路，促进恢复。外泌体是一种很有前途的治疗方法，治疗窗口至少为48小时，含有长链非编码RNA，特别是在作用机制中起重要作用的MALAT1。
The neuroprotective role of human adipose-derived stems cells (hASCs) has raised great interest in regenerative medicine due to their ability to modulate their surrounding environment. Our group has demonstrated that exosomes derived from hASC (hASCexo) are a cell-free regenerative approach to long term recovery following traumatic brain injury (TBI). Previously, we demonstrated the efficacy of exosome treatment with intravenous delivery at 3 h post TBI in rats. Here, we show efficacy of exosomes through intranasal delivery at 48 h post TBI in mice lengthening the therapeutic window of treatment and therefore increasing possible translation to clinical studies. Our findings demonstrate significant recovery of motor impairment assessed by an elevated body swing test in mice treated with exosomes containing MALAT1 compared to both TBI mice without exosomes and exosomes depleted of MALAT1. Significant cognitive improvement was seen in the reversal trial of 8 arm radial arm water maze in mice treated with exosomes containing MALAT1. Furthermore, cortical damage was significantly reduced in mice treated with exosomes containing MALAT1 as well as decreased MHCII+ staining of microglial cells. Mice without exosomes or treated with exosomes depleted of MALAT1 did not show similar recovery. Results demonstrate both inflammation related genes and NRTK3 (TrkC) are target genes modulated by hASC exosomes and further that MALAT1 in hASC exosomes regulates expression of full length TrkC thereby activating the MAPK pathway and promoting recovery. Exosomes are a promising therapeutic approach following TBI with a therapeutic window of at least 48 h and contain long noncoding RNA’s, specifically MALAT1 that play a vital role in the mechanism of action.
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影响因子：
5.6
作者：
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通讯作者：
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影响因子：
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作者：
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影响因子：
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作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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影响因子：
9.3
作者：
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通讯作者：
Van Eldik LJ