Department of Geriatric Endocrinology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, People's Republic of China.
Department of Endocrinology, the First Affiliated Hospital of Zhengzhou University, No. 1, Jianshe East Road, Zhengzhou, 450052, People's Republic of China.
Cell Biol Toxicol. 2023 Dec;39(6):2647-2663. doi: 10.1007/s10565-023-09793-x. Epub 2023 Feb 15.
Splicing factor proline/glutamine-rich (SFPQ) is expressed in induced pluripotent stem cells (iPSCs), which are reported to orchestrate hypoxic injury responses and release extracellular vesicles (EVs). Therefore, this study sought to explore the role of iPSC-derived EVs carrying SFPQ in hypoxia-induced injury to retinal Müller cells. We induced oxygen-glucose deprivation/reoxygenation (OGD/R) in Müller cells. SFPQ was overexpressed or knocked down in iPSCs, from which EVs were extracted. Müller cells were co-cultured with EVs, and the results indicated that SFPQ protein was transferred into retinal Müller cells by iPSC-derived EVs. We identified an interaction of SFPQ with HDAC1 in retinal Müller cells. Specifically, SFPQ recruited HDAC1 to downregulate HIF-2α by regulating its acetylation. The in vitro studies suggested that iPSC-derived EVs, SFPQ or HDAC1 overexpression, or HIF-2α silencing diminished cell injury and apoptosis but elevated proliferation in retinal Müller cells. The in vivo studies indicated that iPSC-derived EVs containing SFPQ curtailed apoptosis of retinal Müller cells, thus alleviating retinal ischemia/reperfusion (I/R) injury of rat model. Taken together, iPSC-derived EVs containing SFPQ upregulated HDAC1 to attenuate OGD/R-induced Müller cell injury via downregulation of HIF-2α.
拼接因子脯氨酸/谷氨酰胺丰富（SFPQ）在诱导多能干细胞（iPSC）中表达，据报道，iPSC 可以协调缺氧损伤反应并释放细胞外囊泡（EV）。因此，本研究旨在探讨携带 SFPQ 的 iPSC 衍生 EV 在缺氧诱导的视网膜 Müller 细胞损伤中的作用。我们诱导 Müller 细胞氧葡萄糖剥夺/复氧（OGD/R）。在 iPSC 中转染 SFPQ 过表达或敲低，提取 EV。Müller 细胞与 EV 共培养，结果表明 iPSC 衍生的 EV 将 SFPQ 蛋白转移到视网膜 Müller 细胞中。我们在视网膜 Müller 细胞中鉴定到 SFPQ 与 HDAC1 的相互作用。具体而言，SFPQ 通过调节其乙酰化来募集 HDAC1 下调 HIF-2α。体外研究表明，iPSC 衍生的 EV、SFPQ 或 HDAC1 过表达或 HIF-2α 沉默可减轻视网膜 Müller 细胞的损伤和凋亡，但可促进增殖。体内研究表明，含有 SFPQ 的 iPSC 衍生 EV 可减少视网膜 Müller 细胞的凋亡，从而减轻大鼠模型的视网膜缺血/再灌注（I/R）损伤。总之，含有 SFPQ 的 iPSC 衍生 EV 通过下调 HIF-2α 上调 HDAC1 来减轻 OGD/R 诱导的 Müller 细胞损伤。
