ESC-sEVs Rejuvenate Aging Hippocampal NSCs by Transferring SMADs to Regulate the MYT1-Egln3-Sirt1 Axis
ESC-sEVs Rejuvenate Aging Hippocampal NSCs by Transferring SMADs to Regulate the MYT1-Egln3-Sirt1 Axis
复制标题
ESC-sEV 通过转移 SMAD 来调节 MYT1-Egln3-Sirt1 轴，使衰老的海马 NSC 恢复活力
DOI：
10.1016/j.ymthe.2020.09.037
复制
发表时间：
2021-01-06
影响因子：
12.4
通讯作者：
Deng, Zhifeng
中科院分区：
文献类型：
--
作者：
Hu, Guowen;Xia, Yuguo;Deng, Zhifeng
组织干细胞衰老导致干细胞衰竭，导致组织内环境平衡失衡，再生能力下降。然而，神经干细胞(NSC)在衰老过程中是否发生衰老并导致神经发生减少尚不清楚。本研究以不同年龄的小鼠为实验对象，检测了衰老相关的海马神经干细胞(H-NSC)的衰老情况，以及胚胎干细胞衍生的小细胞外小泡(ESC-SEV)在延缓H-NSC衰老中的作用及其机制。我们在小鼠中发现了进行性认知障碍，以及与年龄相关的H-NSC衰老。ESC-SEV治疗可显著缓解H-NSC衰老，恢复受损的自我更新和神经再生能力，逆转认知功能障碍。转录组分析表明，髓鞘转录因子1(MYT1)在衰老的H-NSCs中表达下调，但在ESC-SEV治疗后上调。此外，在年轻的H-NSCs中，MYT1基因的敲除加速了与年龄相关的表型，并损害了增殖和分化能力。机制上，ESC-SEV通过转移SMAD家族成员4(Smad4)和5(Smad5)激活MYT1，进而下调EGL-9家族低氧诱导因子3(Egln3)，随后依次激活低氧诱导因子2亚单位α(HIF-2α)、烟酰胺磷酸核糖基转移酶(NAMPT)和sirtuin 1(Sirt1)，从而部分恢复衰老的H-NSCs。综上所述，我们的结果表明，在衰老过程中，H-NSC衰老导致细胞衰竭、神经发生减少和认知功能障碍，而ESC-SEV可以逆转这一现象。因此，ESC-SEV可能是治疗年龄相关疾病的有前途的候选药物。
Tissue stem cell senescence leads to stem cell exhaustion, which results in tissue homeostasis imbalance and a decline in regeneration capacity. However, whether neural stem cell (NSC) senescence occurs and causes neurogenesis reduction during aging is unknown. In this study, mice at different ages were used to detect age-related hippocampal NSC (H-NSC) senescence, as well as the function and mechanism of embryonic stem cell-derived small extracellular vesicles (ESC-sEVs) in rejuvenating H-NSC senescence. We found a progressive cognitive impairment, as well as age-related H-NSC senescence, in mice. ESC-sEV treatment significantly alleviated H-NSC senescence, recovered compromised self-renewal and neurogenesis capacities, and reversed cognitive impairment. Transcriptome analysis revealed that myelin transcription factor 1 (MYT1) is downregulated in senescent H-NSCs but upregulated by ESC-sEV treatment. In addition, knockdown of MYT1 in young H-NSCs accelerated age-related phenotypes and impaired proliferation and differentiation capacities. Mechanistically, ESC-sEVs rejuvenated senescent H-NSCs partly by transferring SMAD family members 4 (SMAD4) and 5 (SMAD5) to activate MYT1, which downregulated egl-9 family hypoxia inducible factor 3 (Egln3), followed by activation of hypoxia inducible factor 2 subunit alpha (HIF-2 alpha), nicotinamide phosphoribosyl transferase (NAMPT), and sirtuin 1 (Sirtl) successively. Taken together, our results indicated that H-NSC senescence caused cellular exhaustion, neurogenesis reduction, and cognitive impairment during aging, which can be reversed by ESC-sEVs. Thus, ESC-sEVs may be promising therapeutic candidates for age-related diseases.