Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
Department of Cardiovascular and Thoracic Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
Am J Physiol Heart Circ Physiol. 2021 May 1;320(5):H1959-H1974. doi: 10.1152/ajpheart.00855.2020. Epub 2021 Mar 26.
In this study, we investigated whether human umbilical cord mesenchymal stem cell (hUCMSC) fibrin patches loaded with nerve growth factor (NGF) poly(lactic--glycolic acid) (PLGA) nanoparticles could enhance the therapeutic potency of hUCMSCs for myocardial infarction (MI). In vitro, NGF significantly improved the proliferation of hUCMSCs and mitigated cytotoxicity and apoptosis under hypoxic injury. NGF also promoted the paracrine effects of hUCMSCs on angiogenesis and cardiomyocyte protection. The tyrosine kinase A (TrkA) and phosphoinositide 3-kinase (PI3K)-serine/threonine protein kinase (Akt) signaling pathways in hUCMSCs were involved in the NGF-induced protection. NGF PLGA nanoparticles continued to release NGF for at least 1 mo and also exerted a protective effect on hUCMSCs, the same with free NGF. In vivo, we treated MI mice with nothing (MI group), a cell-free fibrin patch with blank PLGA nanoparticles (MI + OP group), a cell-free fibrin patch with NGF nanoparticles (MI + NGF group), and hUCMSC fibrin patches with blank PLGA nanoparticles (MI + MSC group) or NGF PLGA nanoparticles (MSC + NGF group). Among these groups, the MSC + NGF group exhibited the best cardiac contractile function, the smallest infarct size, and the thickest ventricular wall. The application of NGF PLGA nanoparticles significantly improved the retention of transplanted hUCMSCs and enhanced their ability to reduce myocardial apoptosis and promote angiogenesis in the mouse heart after MI. These findings demonstrate the promising therapeutic potential of hUCMSC fibrin cardiac patches loaded with NGF PLGA nanoparticles. NGF PLGA nanoparticles can exert a protective effect on hUCMSCs and promote the paracrine effects of hUCMSCs on angiogenesis and cardiomyocyte protection through TrkA-PI3K/Akt signaling pathway, the same with free NGF. The application of NGF PLGA nanoparticles in the hUCMSC fibrin cardiac patches can significantly improve the retention of transplanted hUCMSCs and enhance their ability to reduce myocardial apoptosis and promote angiogenesis in the mouse heart after MI.
在这项研究中，我们研究了负载神经生长因子（NGF）聚乳酸-羟基乙酸共聚物（PLGA）纳米颗粒的人脐带间充质干细胞（hUCMSC）纤维蛋白贴剂是否可以增强 hUCMSC 治疗心肌梗死（MI）的疗效。在体外，NGF 显著促进了 hUCMSC 的增殖，并减轻了缺氧损伤下的细胞毒性和细胞凋亡。NGF 还促进了 hUCMSC 的旁分泌作用，促进血管生成和心肌细胞保护。hUCMSC 中的酪氨酸激酶 A（TrkA）和磷酸肌醇 3-激酶（PI3K）-丝氨酸/苏氨酸蛋白激酶（Akt）信号通路参与了 NGF 诱导的保护作用。NGF-PLGA 纳米颗粒至少能持续释放 NGF 达 1 个月，并对 hUCMSC 产生保护作用，与游离 NGF 相同。在体内，我们用什么都不做（MI 组）、无细胞纤维蛋白贴剂与空白 PLGA 纳米颗粒（MI + OP 组）、无细胞纤维蛋白贴剂与 NGF 纳米颗粒（MI + NGF 组）、负载空白 PLGA 纳米颗粒的 hUCMSC 纤维蛋白贴剂（MI + MSC 组）或负载 NGF-PLGA 纳米颗粒的 hUCMSC 纤维蛋白贴剂（MSC + NGF 组）处理 MI 小鼠。在这些组中，MSC + NGF 组表现出最佳的心脏收缩功能、最小的梗死面积和最厚的心室壁。应用 NGF-PLGA 纳米颗粒显著提高了移植 hUCMSC 的保留率，并增强了它们减少心肌细胞凋亡和促进 MI 后小鼠心脏血管生成的能力。这些发现表明负载 NGF-PLGA 纳米颗粒的 hUCMSC 纤维蛋白心脏贴剂具有有前景的治疗潜力。NGF-PLGA 纳米颗粒通过 TrkA-PI3K/Akt 信号通路对 hUCMSC 发挥保护作用，并促进 hUCMSC 的旁分泌作用，促进血管生成和心肌细胞保护，与游离 NGF 相同。在 hUCMSC 纤维蛋白心脏贴剂中应用 NGF-PLGA 纳米颗粒可显著提高移植 hUCMSC 的保留率，并增强其减少 MI 后小鼠心脏心肌细胞凋亡和促进血管生成的能力。
