Department of Neurosurgery, The First Affiliated Hospital, Nanchang University, Nanchang, People's Republic of China.
Department of Pathology, The First Affiliated Hospital of Nanchang University, Nanchang, People's Republic of China.
Int J Nanomedicine. 2023 Jan 5;18:65-78. doi: 10.2147/IJN.S385395. eCollection 2023.
Cerebral ischemia-reperfusion (CI/R) injury is a subtype of complication after treatment of ischemic stroke. It has been reported that exosomes derived from BMSCs could play an important role in CI/R injury. However, whether BMSCs-derived exosomes could regulate CI/R injury via carrying miRNAs remains to be further explored.
RNA sequencing was performed to identify the differentially expressed miRNAs. To mimic CI/R in vitro, SH-SY5Y cells were exposed to oxygen glucose deprivation/reoxygenation (OGD/R). The viability of SH-SY5Y cells was tested by CCK8 assay, and TUNEL staining was performed to detect the cell apoptosis.
MiR-133a-3p was identified to be reduced in exosomes derived from the plasma of patients with IS. Upregulation of miR-133a-3p significantly reversed OGD/R-induced SH-SY5Y cell growth inhibition. Consistently, BMSCs-derived exosomal miR-133a-3p could restore OGD/R-decreased SH-SY5Y cell proliferation via inhibiting apoptosis. Meanwhile, DAPK2 was a direct target of miR-133a-3p. In addition, OGD/R notably upregulated the level of DAPK2 and weakened the expressions of p-Akt and p-mTOR in SH-SY5Y cells, whereas exosomal miR-133a-3p derived from BMSCs notably reversed these phenomena. Exosomal miR-133a-3p derived from BMSCs could reverse OGD/R-induced cell apoptosis via inhibiting autophagy. Furthermore, exosomal miR-133a-3p derived from BMSCs markedly alleviated the symptom of CI/R injury in vivo.
Exosomal miR-133a-3p derived from BMSCs alleviates CI/R injury via targeting DAPK2/Akt signaling. Thus, our study might shed new light on discovering new strategies against CI/R injury.
脑缺血再灌注（CI/R）损伤是缺血性脑卒中治疗后的一种并发症。有报道称，骨髓间充质干细胞衍生的外泌体在 CI/R 损伤中可能发挥重要作用。然而，骨髓间充质干细胞衍生的外泌体是否可以通过携带 miRNA 来调节 CI/R 损伤仍有待进一步探讨。
进行 RNA 测序以鉴定差异表达的 miRNA。为了在体外模拟 CI/R，将 SH-SY5Y 细胞暴露于氧葡萄糖剥夺/复氧（OGD/R）中。通过 CCK8 测定法检测 SH-SY5Y 细胞的活力，并用 TUNEL 染色法检测细胞凋亡。
发现来自 IS 患者血浆的外泌体中 miR-133a-3p 减少。miR-133a-3p 的上调显著逆转了 OGD/R 诱导的 SH-SY5Y 细胞生长抑制。一致地，BMSCs 衍生的外泌体 miR-133a-3p 可以通过抑制凋亡来恢复 OGD/R 降低的 SH-SY5Y 细胞增殖。同时，DAPK2 是 miR-133a-3p 的直接靶标。此外，OGD/R 明显上调了 SH-SY5Y 细胞中 DAPK2 的水平，并减弱了 Akt 和 mTOR 的磷酸化表达，而来自 BMSCs 的外泌体 miR-133a-3p 则明显逆转了这些现象。来自 BMSCs 的外泌体 miR-133a-3p 可以通过抑制自噬来逆转 OGD/R 诱导的细胞凋亡。此外，来自 BMSCs 的外泌体 miR-133a-3p 明显减轻了体内 CI/R 损伤的症状。
BMSCs 衍生的外泌体 miR-133a-3p 通过靶向 DAPK2/Akt 信号通路缓解 CI/R 损伤。因此，我们的研究可能为发现针对 CI/R 损伤的新策略提供新的思路。
