Department of Clinical Medicine, School of Medicine, Zhejiang University City College, China.
Biomedical Research (Therapy) Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, China.
Oxid Med Cell Longev. 2022 Jul 4;2022:1282362. doi: 10.1155/2022/1282362. eCollection 2022.
The low survival rate of endothelial progenitor cells (EPCs) in vivo which are susceptible to adverse microenvironments including inflammation and oxidative stress has become one primary challenge of EPCs transplantation for regenerative therapy. Recent studies reported functional expression of toll-like receptor (TLR) 4 on EPCs and dose-dependent effects of lipopolysaccharide (LPS) on cellular oxidative stress and angiogenic properties. However, the involved mechanism has not yet been elucidated well, and the influence of TLR4 signaling on EPCs survival and function is unknown. In the present study, we observed the effects of LPS and TLR4/SIRT3 on EPCs mitochondrial permeability and intracellular mitochondrial superoxide. We employed the monocrotaline-induced pulmonary arteriolar injury model to observe the effects of TLR4/SIRT3 on the recruitment and survival of transplanted EPCs. We found the destructive effects of 10 g/mL LPS on mitochondrial homeostasis, and cellular viability was mediated by TLR4/SIRT3 signals at least partially, and the TLR4 mediates the early-stage recruitment of transplanted EPCs in pulmonary arteriolar inflammation injury; however, SIRT3 has more contribution to the survival of incorporated EPCs and ameliorated arteriolar remodeling in lung vascular tissue. The study provides insights for the critical role of TLR4/SIRT3 in LPS-induced oxidative stress and mitochondrial disorder in EPCs and . The TLR4/SIRT3 signaling is important for EPCs resistance against inflammation and oxidative stress and may represent a new manipulating target for developing efficient cell therapy strategy.
内皮祖细胞 (EPCs) 在体内的存活率较低，容易受到炎症和氧化应激等不利微环境的影响，这成为 EPCs 移植再生治疗的主要挑战之一。最近的研究报道了 TLR4 在 EPCs 上的功能性表达，以及脂多糖 (LPS) 对细胞氧化应激和血管生成特性的剂量依赖性影响。然而，其涉及的机制尚未得到很好的阐明，TLR4 信号对 EPCs 存活和功能的影响也尚不清楚。在本研究中，我们观察了 LPS 和 TLR4/SIRT3 对 EPCs 线粒体通透性和细胞内线粒体超氧阴离子的影响。我们采用单环素来诱导肺动脉小动脉损伤模型，观察 TLR4/SIRT3 对移植 EPCs 募集和存活的影响。我们发现 10μg/mL LPS 对线粒体稳态具有破坏作用，TLR4/SIRT3 信号至少部分介导了细胞活力，TLR4 介导了移植 EPCs 在肺动脉炎症损伤中的早期募集；然而，SIRT3 对整合 EPCs 的存活和肺血管组织中小动脉重塑的改善有更大的贡献。该研究为 TLR4/SIRT3 在 LPS 诱导的 EPCs 氧化应激和线粒体紊乱中的关键作用提供了新的见解。TLR4/SIRT3 信号对 EPCs 抵抗炎症和氧化应激非常重要，可能代表开发有效细胞治疗策略的新的调控靶点。
