Inhibiting endothelial Rhoj blocks profibrotic vascular intussusception and angiocrine factors to sustain lung regeneration

IF 15.8 1区 医学 Q1 CELL BIOLOGY Science Translational Medicine Pub Date : 2024-08-28 DOI:10.1126/scitranslmed.ado5266
Jie Ma, Liyin Zhang, Xu Zhang, Lanlan Zhang, Hua Zhang, Yulei Zhu, Xingming Huang, Ting Zhang, Xiangdong Tang, Yuan Wang, Lu Chen, Qiang Pu, Liming Yang, Zhongwei Cao, Bi-Sen Ding
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Abstract

Lung regeneration after fibrosis requires formation of functional new vasculature, which is essential for gas exchange and cellular cross-talk with other lung cells. It remains unknown how the lung vasculature can be regenerated without fibrosis. Here, we tested the role of N6-methyladenosine (m6A) modification of forkhead box protein O1 (Foxo1) mRNA in lung regeneration after pneumonectomy (PNX) in mice, a model for lung regrowth after surgical resection. Endothelial cell (EC)–specific knockout of methyltransferase-like 3 (Mettl3) and Foxo1 caused nonproductive intussusceptive angiogenesis (IA), which impaired regeneration and enhanced fibrosis. This nonproductive IA was characterized by enhanced endothelial proliferation and increased vascular splitting with increased numbers of pillar ECs. Endothelial-selective knockout of Mettl3 in mice stimulated nonproductive IA and up-regulation of profibrotic factors after PNX, promoting regeneration to fibrotic transition. EC-specific mutation of m6A modification sites in the Foxo1 gene in mice revealed that endothelial Mettl3 modified A504 and A2035 sites in the Foxo1 mRNA to maintain pro-regenerative endothelial glycolysis, ensuring productive IA and lung regeneration without fibrosis. Suppression of Mettl3-Foxo1 signaling stimulated a subset of hyperglycolytic and hyperproliferative 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (Pfkfb3)+, Ras homolog family member J (Rhoj)+, and platelet-derived growth factor subunit B (Pdgfb)+ ECs in both human and mouse lungs with fibrosis. Inhibiting this Pfkfb3+Rhoj+Pdgfb+ EC subset normalized IA, alleviated fibrosis, and restored regeneration in bleomycin (BLM)–injured mouse lungs. We found that m6A modification of Foxo1 in the mouse vasculature promoted lung regeneration over fibrosis after PNX and BLM injury.
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抑制内皮 Rhoj 可阻断凋亡性血管闭塞和血管内分泌因子,从而维持肺再生。
纤维化后的肺再生需要形成功能性的新血管,这对气体交换和与其他肺细胞的细胞间交流至关重要。肺血管如何在不发生纤维化的情况下再生仍是一个未知数。在这里,我们测试了叉头盒蛋白 O1(Foxo1)mRNA 的 N6-甲基腺苷(m6A)修饰在小鼠肺切除术(PNX)后肺再生中的作用,这是一种手术切除后肺再生的模型。内皮细胞(EC)特异性敲除甲基转移酶样3(Mettl3)和Foxo1会导致非生产性闭锁性血管生成(IA),从而影响再生并加重纤维化。这种非生产性肠内血管生成的特点是内皮增殖增强,血管分裂加剧,柱状 EC 数量增加。小鼠内皮选择性敲除 Mettl3 会刺激非生产性内膜增生,并在 PNX 后上调促纤维化因子,促进再生向纤维化转变。小鼠内皮细胞特异性突变 Foxo1 基因中的 m6A 修饰位点后发现,内皮细胞 Mettl3 修饰了 Foxo1 mRNA 中的 A504 和 A2035 位点,以维持促进再生的内皮细胞糖酵解,从而确保有成效的内脏损伤和肺再生,而不发生纤维化。抑制Mettl3-Foxo1信号传导可刺激人和小鼠肺纤维化的高糖酵解和高增殖性6-磷酸果糖-2-激酶/果糖-2,6-二磷酸酶3(Pfkfb3)+、Ras同源家族成员J(Rhoj)+和血小板衍生生长因子亚基B(Pdgfb)+内皮细胞亚群。抑制这种 Pfkfb3+Rhoj+Pdgfb+ EC 亚群可使 IA 正常化、减轻纤维化并恢复博来霉素(BLM)损伤小鼠肺的再生。我们发现,小鼠血管中 Foxo1 的 m6A 修饰促进了肺再生,而不是 PNX 和 BLM 损伤后的纤维化。
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来源期刊
Science Translational Medicine
Science Translational Medicine CELL BIOLOGY-MEDICINE, RESEARCH & EXPERIMENTAL
CiteScore
26.70
自引率
1.20%
发文量
309
审稿时长
1.7 months
期刊介绍: Science Translational Medicine is an online journal that focuses on publishing research at the intersection of science, engineering, and medicine. The goal of the journal is to promote human health by providing a platform for researchers from various disciplines to communicate their latest advancements in biomedical, translational, and clinical research. The journal aims to address the slow translation of scientific knowledge into effective treatments and health measures. It publishes articles that fill the knowledge gaps between preclinical research and medical applications, with a focus on accelerating the translation of knowledge into new ways of preventing, diagnosing, and treating human diseases. The scope of Science Translational Medicine includes various areas such as cardiovascular disease, immunology/vaccines, metabolism/diabetes/obesity, neuroscience/neurology/psychiatry, cancer, infectious diseases, policy, behavior, bioengineering, chemical genomics/drug discovery, imaging, applied physical sciences, medical nanotechnology, drug delivery, biomarkers, gene therapy/regenerative medicine, toxicology and pharmacokinetics, data mining, cell culture, animal and human studies, medical informatics, and other interdisciplinary approaches to medicine. The target audience of the journal includes researchers and management in academia, government, and the biotechnology and pharmaceutical industries. It is also relevant to physician scientists, regulators, policy makers, investors, business developers, and funding agencies.
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