Li Mi, Zhang Tao, Li Pengfei, Luan Zhiwei, Liu Jingsong, Wang Yangyang, Zhang Yubo, Liu Yishu, Wang Yansong
Department of Orthopedic surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China; Department of Orthopedic Surgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, China; The Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, China.
Department of Orthopedic Surgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, China.
Life Sci. 2025 Mar 1;364:123441. doi: 10.1016/j.lfs.2025.123441. Epub 2025 Feb 3.
Spinal cord injury (SCI) represents a significant neurological disorder that profoundly impacts human life. Transplantation of extracellular vesicles (EVs) from human umbilical cord mesenchymal stem cells (hUC-MSCs) has emerged as a promising therapeutic strategy. microRNA (miRNA) containing EVs serve as crucial mediators of intercellular communication, playing vital roles in physiological and pathological processes. Research indicates that EVs from hUC-MSCs could attenuate inflammation and facilitate recovery from SCI. Nevertheless, their application in clinical treatment necessitates further investigation. We are actively pursuing an effective approach to modulate the intensity of the inflammatory response, thereby addressing secondary SCI. Initially, we activated hUC-MSCs with interleukin-4 (IL-4) and subsequently harvested their EVs. We investigated the influences of A-hUC-MSCs-EVs compared to routinely acquired EVs on macrophage polarization phenotypes both in vitro and in vivo. Our results show that EVs originating from A-hUC-MSCs are more effective at promoting macrophage polarization from the M1 phenotype to the M2 phenotype than those derived from hUC-MSCs. Notably, we found that A-hUC-MSCs-derived EVs had a superior impact on motor function recovery in mice with SCI. Importantly, we observed that IL-4 activation significantly upregulated the expression of miR-21-5p within these EVs. More specifically, our data demonstrate that A-hUC-MSCs-EVs depend on miR-21-5p to inhibit the effects of PDCD4 on macrophage polarization. This mechanism regulates inflammatory responses while simultaneously reducing apoptosis. In summary, EVs derived from IL-4 primed hUC-MSCs are enriched with miR-21-5p, which exerts a pivotal influence in shifting macrophage polarization, alleviating inflammatory responses following SCI, and facilitating recovery.
脊髓损伤（SCI）是一种严重的神经系统疾病，对人类生活产生深远影响。人脐带间充质干细胞（hUC-MSCs）来源的细胞外囊泡（EVs）移植已成为一种有前景的治疗策略。含微小RNA（miRNA）的EVs作为细胞间通讯的关键介质，在生理和病理过程中发挥着重要作用。研究表明，hUC-MSCs来源的EVs可减轻炎症并促进SCI恢复。然而，它们在临床治疗中的应用仍需进一步研究。我们正在积极寻求一种有效的方法来调节炎症反应的强度，从而解决继发性SCI问题。最初，我们用白细胞介素-4（IL-4）激活hUC-MSCs，随后收集其EVs。我们研究了与常规获取的EVs相比，A-hUC-MSCs-EVs在体外和体内对巨噬细胞极化表型的影响。我们的结果表明，源自A-hUC-MSCs的EVs在促进巨噬细胞从M1表型向M2表型极化方面比源自hUC-MSCs的EVs更有效。值得注意的是，我们发现A-hUC-MSCs来源的EVs对SCI小鼠的运动功能恢复有更好的影响。重要的是，我们观察到IL-4激活显著上调了这些EVs中miR-21-5p的表达。更具体地说，我们的数据表明，A-hUC-MSCs-EVs依赖miR-21-5p来抑制PDCD4对巨噬细胞极化的影响。这种机制调节炎症反应，同时减少细胞凋亡。总之，IL-4预处理的hUC-MSCs来源的EVs富含miR-21-5p，其在改变巨噬细胞极化、减轻SCI后的炎症反应和促进恢复方面发挥着关键作用。
