Chen Jiaqi, Liang Xiaoting, Han Qian, He Haiwei, Huang Xinran, Shen Ying, Qiu Jie, Lin Fang, Mai Cong, Li Ziqi, Ma Kexin, Hu Bei, Li Xin, Zhang Yuelin
Department of Emergency Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China.
Translational Medical Center for Stem Cell Therapy & Institute for Regenerative Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
Stem Cell Res Ther. 2025 Jun 3;16(1):282. doi: 10.1186/s13287-025-04390-7.
NOD-like receptor thermal protein domain associated protein 3 (NLRP3)-mediated pyroptosis of cardiomyocytes is a key contributor to the progression of myocardial infarction (MI). This study aimed to investigate whether exosomes derived from human induced pluripotent stem cell-derived mesenchymal stem cells (iPSC-MSC-EXOs) could protect against MI by inhibiting cardiomyocyte pyroptosis and explore the underlying mechanisms.
Exosomes from human bone marrow-MSCs (BM-MSC-EXOs) and iPSC-MSCs (iPSC-MSC-EXOs) were collected and intramuscularly injected into the peri-infarct region of a mouse MI model. Cardiac function was assessed four weeks post-injection. Myocardial pyroptosis was evaluated using TUNEL staining and measurement of associated factors. Neonatal mouse cardiomyocytes (NMCMs) exposed to serum deprivation and hypoxia (SD/H) were treated with BM-MSC-EXOs or iPSC-MSC-EXOs. A loss-of-function approach was employed to examine the role of iPSC-MSC-exosomal-miR-202-5p in regulating cardiomyocyte pyroptosis.
Compared to BM-MSC-EXOs, iPSC-MSC-EXOs demonstrated superior improvement in cardiac function in MI mice. Both BM-MSC-EXOs and iPSC-MSC-EXOs reduced cardiomyocyte pyroptosis by downregulating proteins NLRP3, ASC, Caspase-1, and gasdermin D-NT, as well as inflammatory factors in MI mice and SD/H-treated NMCMs. iPSC-MSC-EXOs exhibited greater protective effects. MicroRNA sequencing revealed higher levels of miR-202-5p in iPSC-MSC-EXOs than in BM-MSC-EXOs. The protective effect of iPSC-MSC-EXOs against cardiomyocyte pyroptosis was partially reversed by miR-202-5p knockdown. Mechanistically, miR-202-5p in iPSC-MSC-EXOs inhibited cardiomyocyte pyroptosis by downregulating the TRAF3IP2/JNK pathway.
iPSC-MSC-EXOs protect against MI by inhibiting cardiomyocyte pyroptosis via miR-202-5p-mediated suppression of the TRAF3IP2/JNK axis. These findings suggest a promising therapeutic approach for MI.
NOD样受体热蛋白结构域相关蛋白3（NLRP3）介导的心肌细胞焦亡是心肌梗死（MI）进展的关键因素。本研究旨在探讨人诱导多能干细胞来源的间充质干细胞外泌体（iPSC-MSC-EXOs）是否能通过抑制心肌细胞焦亡来预防MI，并探索其潜在机制。
收集人骨髓间充质干细胞（BM-MSC-EXOs）和iPSC-MSCs（iPSC-MSC-EXOs）的外泌体，并肌肉注射到小鼠MI模型的梗死周边区域。注射后四周评估心脏功能。使用TUNEL染色和相关因子测量来评估心肌焦亡。用BM-MSC-EXOs或iPSC-MSC-EXOs处理暴露于血清剥夺和缺氧（SD/H）的新生小鼠心肌细胞（NMCMs）。采用功能丧失方法来研究iPSC-MSC-外泌体-miR-202-5p在调节心肌细胞焦亡中的作用。
与BM-MSC-EXOs相比，iPSC-MSC-EXOs在MI小鼠心脏功能改善方面表现更优。BM-MSC-EXOs和iPSC-MSC-EXOs均通过下调MI小鼠和SD/H处理的NMCMs中的NLRP3、ASC、Caspase-1和gasdermin D-NT蛋白以及炎症因子来减少心肌细胞焦亡。iPSC-MSC-EXOs表现出更大的保护作用。微小RNA测序显示iPSC-MSC-EXOs中miR-202-5p的水平高于BM-MSC-EXOs。miR-202-5p敲低部分逆转了iPSC-MSC-EXOs对心肌细胞焦亡的保护作用。机制上，iPSC-MSC-EXOs中的miR-202-5p通过下调TRAF3IP2/JNK途径抑制心肌细胞焦亡。
iPSC-MSC-EXOs通过miR-202-5p介导的对TRAF3IP2/JNK轴的抑制来抑制心肌细胞焦亡，从而预防MI。这些发现为MI提供了一种有前景的治疗方法。
