Induced pluripotent stem cell-derived extracellular vesicles overexpressing SFPQ protect retinal Muller cells against hypoxia-induced injury

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 Muller cells. We induced oxygen-glucose deprivation/reoxygenation (OGD/R) in Muller cells. SFPQ was overexpressed or knocked down in iPSCs, from which EVs were extracted. Muller cells were co-cultured with EVs, and the results indicated that SFPQ protein was transferred into retinal Muller cells by iPSC-derived EVs. We identified an interaction of SFPQ with HDAC1 in retinal Muller cells. Specifically, SFPQ recruited HDAC1 to downregulate HIF-2 alpha by regulating its acetylation. The in vitro studies suggested that iPSC-derived EVs, SFPQ or HDAC1 overexpression, or HIF-2 alpha silencing diminished cell injury and apoptosis but elevated proliferation in retinal Muller cells. The in vivo studies indicated that iPSC-derived EVs containing SFPQ curtailed apoptosis of retinal Muller 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 Muller cell injury via downregulation of HIF-2 alpha.