Aims Pulmonary arterial hypertension (PAH) is characterized by extensive pulmonary arterial remodelling. Although mesenchymal stem cell (MSC)-derived exosomes provide protective effects in PAH, MSCs exhibit limited senescence during in vitro expansion compared with the induced pluripotent stem cells (iPSCs). Moreover, the exact mechanism is not known. Methods and results In this study, we used murine iPSCs generated from mouse embryonic fibroblasts with triple factor (Oct4, Klf4, and Sox2) transduction to determine the efficacy and action mechanism of iPSC-derived exosomes (iPSC-Exo) in attenuating PAH in rats with monocrotaline (MCT)-induced pulmonary hypertension. Both early and late iPSC-Exo treatment effectively prevented the wall thickening and muscularization of pulmonary arterioles, improved the right ventricular systolic pressure, and alleviated the right ventricular hypertrophy in MCT-induced PAH rats. Pulmonary artery smooth muscle cells (PASMC) derived from MCT-treated rats (MCT-PASMC) developed more proliferative and pro-migratory phenotypes, which were attenuated by the iPSC-Exo treatment. Moreover, the proliferation and migration of MCT-PASMC were reduced by iPSC-Exo with suppression of PCNA, cyclin D1, MMP-1, and MMP-10, which are mediated via the HIF-1α and P21-activated kinase 1/AKT/Runx2 pathways. Conclusion IPSC-Exo are effective at reversing pulmonary hypertension by reducing pulmonary vascular remodelling and may provide an iPSC-free therapy for the treatment of PAH.

中文翻译：

---

诱导多能干细胞衍生的外泌体通过靶向 HIF-1α 和 Runx2 减弱肺动脉高压的血管重塑

目的 肺动脉高压（PAH）的特点是广泛的肺动脉重塑。尽管间充质干细胞 (MSC) 衍生的外泌体对 PAH 具有保护作用，但与诱导多能干细胞 (iPSC) 相比，MSC 在体外扩增过程中表现出有限的衰老。此外，确切的机制尚不清楚。方法和结果在本研究中，我们使用由小鼠胚胎成纤维细胞产生的小鼠 iPSC，通过三因子（Oct4、Klf4 和 Sox2）转导来确定 iPSC 衍生的外泌体 (iPSC-Exo) 在减轻大鼠 PAH 方面的功效和作用机制野百合碱（MCT）引起的肺动脉高压。早期和晚期iPSC-Exo治疗均有效防止MCT诱导的PAH大鼠的肺小动脉壁增厚和肌化，改善右心室收缩压，减轻右心室肥厚。来自 MCT 治疗大鼠 (MCT-PASMC) 的肺动脉平滑肌细胞 (PASMC) 产生了更多的增殖和促迁移表型，但 iPSC-Exo 治疗减弱了这种表型。此外，iPSC-Exo 通过抑制 PCNA、细胞周期蛋白 D1、MMP-1 和 MMP-10 来减少 MCT-PASMC 的增殖和迁移，这些作用是通过 HIF-1α 和 P21 激活激酶 1/AKT/ 介导的。 Runx2 途径。结论 IPSC-Exo 可通过减少肺血管重塑有效逆转肺动脉高压，并可能为 PAH 的治疗提供一种无 iPSC 的疗法。