巨噬细胞共培养可促进细胞重编程并防止老化成纤维细胞中的铁蛋白沉积,从而治疗神经变性。

IF 4.8 3区 医学 Q1 GENETICS & HEREDITY
Journal of Molecular Medicine-Jmm Pub Date : 2025-03-01 Epub Date: 2025-02-01 DOI:10.1007/s00109-025-02518-z
Lunjie Ma, Fei Fang, Haonan Wang, Ping Zhao, Hongchi Yu, Xiaoheng Liu
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引用次数: 0

摘要

铁凋亡是一种与脂质过氧化和铁依赖性相关的程序性细胞死亡形式,在衰老相关的神经退行性疾病中对神经元功能的影响起关键作用。受这些变化影响的巨噬细胞在衰老神经疾病的进展中起着重要作用。诱导神经元重编程是一项先进的技术,可以直接将体细胞(如成纤维细胞)转化为神经元,并为纠正铁下垂和对抗衰老相关神经疾病的药物筛选提供了一种有前途的方法。然而,这种重编程过程的效率仍然是一个重大挑战。在这项研究中,我们的目的是操纵巨噬细胞表型,以增强成纤维细胞向神经元的直接转化。具体来说,我们试图通过使用老化成纤维细胞筛选天然化合物和利用巨噬细胞促进诱导的神经元(iN)重编程来纠正铁下垂。我们的研究结果表明,M2巨噬细胞有效地促进成纤维细胞直接重编程为iNs。在一种新的巨噬细胞-成纤维细胞共培养系统中,M2巨噬细胞通过降低成纤维细胞粘附力和促进不对称细胞分裂来促进In重编程。此外,我们发现操纵基质硬度可以诱导巨噬细胞向M2表型极化,从而增强成纤维细胞重编程为iNs。为了促进这些发现,我们开发了一种基于机械线索的药物筛选芯片,其中软水凝胶诱导并维持M2巨噬细胞的表型,并有效促进细胞重编程。使用36个这样的芯片组合方法,我们筛选了具有抗衰老特性的天然化合物,重点是逆转成纤维细胞老化并诱导其转化为神经元细胞。值得注意的是,维荆素是一种芹菜黄酮苷,具有血小板聚集抑制剂的作用,是实现我们治疗目标的有希望的候选者。这项研究强调了巨噬细胞介导的成纤维细胞重编程调节作为一种解决衰老相关神经疾病中铁中毒诱导的神经元功能障碍的策略的潜力。关键信息:该研究强调了巨噬细胞介导的成纤维细胞重编程调节作为解决衰老相关神经疾病中铁中毒诱导的神经元功能障碍的策略的潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Macrophage co-culture promotes cell reprogramming and prevents ferroptosis in aging fibroblasts for neurodegeneration therapy.

Ferroptosis, a form of programmed cell death associated with lipid peroxidation and iron dependency, plays a critical role in affecting neuronal function in the aging-related neurodegenerative diseases. Macrophages, influenced by these changes, contribute significantly to the progression of aging nerve diseases. Induced neuronal reprogramming is an advanced technology, which can direct convert somatic cells, such as fibroblasts, into neurons, and offers a promising approach for drug screening aimed at correcting ferroptosis and combating aging-related nerve diseases. However, the efficiency of this reprogramming process remains a significant challenge. In this study, we aimed to manipulate macrophage phenotypes to enhance the direct conversion of fibroblasts into neurons. Specifically, we sought to correct ferroptosis through screening natural compounds using aged fibroblasts and utilizing macrophages to promote induced neuronal (iN) reprogramming. Our findings demonstrate that M2 macrophages effectively promote the direct reprogramming of fibroblasts into iNs. In a novel macrophage-fibroblast co-culture system, M2 macrophages facilitate iN reprogramming by reducing fibroblast adhesion forces and promoting asymmetric cell division. Furthermore, we discovered that manipulating matrix stiffness can induce polarization of macrophages towards the M2 phenotype, thereby enhancing fibroblast reprogramming into iNs. To facilitate these findings, we developed a mechano-cue-based drug screening chip, where soft hydrogels induced and maintained the phenotype of M2 macrophages and effectively promoted cell reprogramming. Using a combinatorial approach with 36 such chips, we screened natural compounds for their anti-aging properties, focusing on reversing fibroblast aging and inducing their conversion into neuronal cells. Notably, Vitexin, an apigenin flavone glycoside with a role as a platelet aggregation inhibitor, emerged as a promising candidate to achieve our therapeutic goals. This study highlights the potential of macrophage-mediated modulation of fibroblast reprogramming as a strategy to address ferroptosis-induced neuronal dysfunction in aging-related nerve diseases. KEY MESSAGE: This study highlights the potential of macrophage-mediated modulation of fibroblast reprogramming as a strategy to address ferroptosis-induced neuronal dysfunction in aging-related nerve diseases.

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来源期刊
Journal of Molecular Medicine-Jmm
Journal of Molecular Medicine-Jmm 医学-医学:研究与实验
CiteScore
9.30
自引率
0.00%
发文量
100
审稿时长
1.3 months
期刊介绍: The Journal of Molecular Medicine publishes original research articles and review articles that range from basic findings in mechanisms of disease pathogenesis to therapy. The focus includes all human diseases, including but not limited to: Aging, angiogenesis, autoimmune diseases as well as other inflammatory diseases, cancer, cardiovascular diseases, development and differentiation, endocrinology, gastrointestinal diseases and hepatology, genetics and epigenetics, hematology, hypoxia research, immunology, infectious diseases, metabolic disorders, neuroscience of diseases, -omics based disease research, regenerative medicine, and stem cell research. Studies solely based on cell lines will not be considered. Studies that are based on model organisms will be considered as long as they are directly relevant to human disease.
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