Enhanced neoangiogenesis and balance of the immune response mediated by the Wilms' tumor suppressor WT1 favor repair after myocardial infarction.

IF 12.4 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Theranostics Pub Date : 2025-06-09 eCollection Date: 2025-01-01 DOI:10.7150/thno.104329
Nicole Wagner, Ana Vukolic, Delphine Baudouy, Sophie Pagnotta, Jean-Francois Michiels, Kay-Dietrich Wagner
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引用次数: 0

Abstract

Rationale: Cardiac repair and regeneration are severely constrained in adult mammals. Several cell types have been identified as playing a role in cardiac repair. However, our understanding of the regulatory proteins common to these cell types and implicated in cardiac repair remains limited. Methods: Experimental myocardial infarctions (MI) were induced in mice by ligation of the left coronary artery. WT1 expression in different cell types was determined by immunofluorescent double-labelling. VE-cadherin-CreERT2 (VE-CreERT2) mice were crossed with Wt1lox/lox animals to generate the VE-CreERT2;Wt1lox/lox strain to knockout WT1 in endothelial cells. Wt1lox/lox and Tie2-CreERT2 animals were crossed to generate Tie2-CreERT2;Wt1lox/lox mice to delete WT1 in endothelial and myeloid-derived cells. Results: We show that the Wilms' tumor suppressor WT1 is expressed in progenitor cell populations, endothelial cells, and myeloid-derived suppressor cells (MDSCs) in mice following MI. Endothelial-specific knockout of WT1 results in reduced vascular density after MI but does not affect functional recovery. Conversely, combined knockout of WT1 in endothelial and myeloid-derived cells increases infarct size, cardiac hypertrophy, fibrosis, hypoxia, and lymphocyte infiltration. Notably, angiogenesis, infiltration of MDSCs, and cellular proliferation were diminished, and importantly, cardiac function was reduced. Mechanistically, in addition to the previously established role of WT1 in promoting the expression of angiogenic molecules, this transcription factor positively regulates the expression of Cd11b and Ly6G, which are crucial for MDSC invasion, migration and function thereby preventing overactivation of the immune response. Conclusions: Several molecules have been identified that are implicated in distinct aspects of cardiac repair following MI. The identification of WT1 as a transcription factor that is essential for repair mechanisms involving various cell types within the heart may potentially enable the future development of a coordinated repair process following myocardial infarction.

Wilms肿瘤抑制因子WT1介导的新血管生成和免疫反应平衡的增强有利于心肌梗死后的修复。
理由:成年哺乳动物的心脏修复和再生受到严重限制。几种细胞类型已被确定在心脏修复中起作用。然而,我们对这些细胞类型共同的调节蛋白和涉及心脏修复的理解仍然有限。方法:采用左冠状动脉结扎法诱导小鼠实验性心肌梗死。免疫荧光双标记法检测WT1在不同细胞类型中的表达。将VE-cadherin-CreERT2 (VE-CreERT2)小鼠与Wt1lox/lox动物杂交,产生VE-CreERT2;Wt1lox/lox菌株,敲除内皮细胞中的WT1。将Wt1lox/lox与Tie2-CreERT2动物杂交,生成Tie2-CreERT2;将Wt1lox/lox小鼠杂交,删除内皮细胞和髓源性细胞中的WT1。结果:我们发现Wilms肿瘤抑制因子WT1在心肌梗死小鼠的祖细胞群、内皮细胞和髓源性抑制细胞(MDSCs)中表达。内皮特异性敲除WT1导致心肌梗死后血管密度降低,但不影响功能恢复。相反,联合敲除内皮细胞和髓源性细胞中的WT1会增加梗死面积、心肌肥厚、纤维化、缺氧和淋巴细胞浸润。值得注意的是,血管生成、MDSCs浸润和细胞增殖减少,重要的是,心功能降低。在机制上,除了WT1在促进血管生成分子表达方面的作用外,该转录因子还积极调节Cd11b和Ly6G的表达,而Cd11b和Ly6G对于MDSC的侵袭、迁移和功能至关重要,从而防止免疫反应的过度激活。结论:已经确定了与心肌梗死后心脏修复的不同方面有关的几个分子。鉴定WT1作为一种转录因子,对涉及心脏内各种细胞类型的修复机制至关重要,可能有助于心肌梗死后协调修复过程的未来发展。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Theranostics
Theranostics MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
25.40
自引率
1.60%
发文量
433
审稿时长
1 months
期刊介绍: Theranostics serves as a pivotal platform for the exchange of clinical and scientific insights within the diagnostic and therapeutic molecular and nanomedicine community, along with allied professions engaged in integrating molecular imaging and therapy. As a multidisciplinary journal, Theranostics showcases innovative research articles spanning fields such as in vitro diagnostics and prognostics, in vivo molecular imaging, molecular therapeutics, image-guided therapy, biosensor technology, nanobiosensors, bioelectronics, system biology, translational medicine, point-of-care applications, and personalized medicine. Encouraging a broad spectrum of biomedical research with potential theranostic applications, the journal rigorously peer-reviews primary research, alongside publishing reviews, news, and commentary that aim to bridge the gap between the laboratory, clinic, and biotechnology industries.
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