Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, PR China.
Department of Medical Psychology and Ethics, School of Basic Medicine Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong, PR China.
J Control Release. 2020 Dec 10;328:13-27. doi: 10.1016/j.jconrel.2020.08.037. Epub 2020 Aug 26.
We previously reported that preconditioning of mesenchymal stem cells (MSCs) with hydrogen sulfide (HS) improved their therapeutic potential in cerebral ischemia. However, the mechanisms involved with this effect have not been determined. As one approach to address this issue, we focused on a neuroprotective role of modification of MSCs-derived extracellular vesicles (EVs) with HS treatment, and further examined the underlying mechanisms during hypoxia-ischemia (HI) injury in neonatal mice. At 24 h following HI insult, neonatal mice received either systemically administered EVs (derived from MSCs) or HS-EVs (derived from NaHS-preconditioned MSCs). Both treatments reached the injured region of the ipsilateral hemisphere within 2 h after administration and were incorporated into microglia and neurons. Mice receiving HS-EVs exhibited substantially lower amounts of brain tissue loss, decreased levels of pro-inflammatory mediators, and a skewed distribution of CD45 microglia and CD45 brain mononuclear phagocytes toward a more anti-inflammatory condition as compared with that in mice receiving only EVs. Moreover, these neuroprotective and anti-inflammatory effects of HS-EVs were accompanied with long-term preservation of cognitive and memory functions, in contrast to the functional deficits observed in mice receiving only EVs. This HS preconditioning upregulated miR-7b-5p levels in EVs as determined with next-generation sequencing, while knockdown analyses revealed that inducing miR-7b-5p expression and targeting FOS in the ipsilateral cortex were essential for the neuroprotective and anti-inflammatory effects of HS-EVs following HI exposure. Taken together, these results demonstrate that miR-7b-5p transferred by HS-EVs into the ipsilateral hemisphere further induced miR-7b-5p expression, which promoted CD45 microglia and CD45 brain mononuclear phagocytes toward a beneficial phenotype and improved HI-induced cognitive impairments in neonatal mice.
我们之前报道过，用硫化氢（HS）预处理间充质干细胞（MSCs）可提高其在脑缺血中的治疗潜能。然而，这种效应的相关机制尚未确定。为了解决这个问题，我们专注于研究 HS 处理对 MSCs 衍生的细胞外囊泡（EVs）的神经保护作用，并进一步研究了其在新生小鼠缺氧缺血（HI）损伤中的潜在机制。在 HI 损伤后 24 小时，新生小鼠接受了系统给予的 EVs（来自 MSCs）或 HS-EVs（来自 NaHS 预处理的 MSCs）。两种治疗方法在给药后 2 小时内均到达对侧半球的损伤区域，并被整合到小胶质细胞和神经元中。与仅接受 EVs 的小鼠相比，接受 HS-EVs 的小鼠脑组织结构丢失明显减少，促炎介质水平降低，CD45 小胶质细胞和 CD45 脑单核吞噬细胞的分布向抗炎状态倾斜。此外，与仅接受 EVs 的小鼠相比，HS-EVs 的这些神经保护和抗炎作用伴随着认知和记忆功能的长期保存，而不是观察到的功能缺陷。与 EVs 相比，HS 预处理可通过下一代测序确定上调 EVs 中的 miR-7b-5p 水平，而敲低分析表明，诱导 miR-7b-5p 表达并靶向同侧皮质中的 FOS 对于 HS-EVs 暴露于 HI 后的神经保护和抗炎作用至关重要。综上所述，这些结果表明，HS-EVs 转移到对侧半球的 miR-7b-5p 进一步诱导了 miR-7b-5p 的表达，促进了 CD45 小胶质细胞和 CD45 脑单核吞噬细胞向有益的表型发展，并改善了新生小鼠 HI 诱导的认知障碍。
