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The cover article! Sichuan University Ding Qisen team revealed the formation mechanism of RHOJ endothelial cells in the pulmonary vascular microenvironment!

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Lung regeneration after fibrosis requires the formation of a functional neovasculature, which is critical for gas exchange and cellular crosstalk with other lung cells. It is not clear how the pulmonary blood vessels regenerate in the absence of fibrosis.

August 28, 2024, Sichuan UniversityDing Qisen, Cao Zhongwei,Harbin Medical University Yang liming et alInScience Translational Medicine(cover article)Published online entitled“Inhibiting endothelial Rhoj blocks profibrotic vascular intussusception and angiocrine factors to sustain lung regeneration”The research paper,The study foundinhibition of endothelialRhoj canBlockade of fibrotic vascular intussusception and vascular secreted factors to maintain lung regeneration.

In addition, the enlarged endothelial cells need to go through multiple steps to fill the new lumen to prevent extravasation of inflammatory cells and maintain blood perfusion. Thus, angiogenesis during regeneration requires the formation of endothelial tight junctions, the alignment of the endothelial parietal lumen, and the alignment of the basolateral side in juxtaposition with alveolar epithelial cells.In addition, vascular endothelial cells exhibit taxonomic and specialized functions within the organ. However, the cellular and molecular mechanisms underlying pulmonary neovascularization are largely unknown.

Lung scarring or fibrosis is the result of failure to regenerate after injury. Compared with parenchymal cells, vascular endothelial cells are less prone to genetic mutations during injury. Thus, epigenetic changes such as RNA modifications in endothelial cells may be crucial for regulating angiogenesis in damaged lungs.m6A modification is a major mRNA modification within mammals. It is involved in the regulation of many aspects of the mRNA life cycle, including pre-mRNA splicing, mRNA export, stability, and translation.methyltransferase-like 3 (METTL3), METTL14 andWilms tumor1-related proteins form a core methyltransferase complex with the addition of methyl groups. Fat mass and obesity associated protein (FTO) and Alkb homolog 5 (ALKBH5) act as demethylases to reverse methylation. Deletion of METTL3 or METTL14 (or its homologs in other species) prevents embryonic stem cell self-renewal and differentiation, leading to defective embryonic development, sex reversal, and impaired gametogenesis.In addition, M6A modifications have different roles in regulating cell proliferation. Gene ablation of METTL3 blocks tumor cell proliferation, but in some cases, METTL3 inhibits cell proliferation.

Here, the authors found that endothelial cell (EC)-specific knockout methyltransferase-like 3 (Mettl3) andFoxo1This results in non-productive intestinal nesting angiogenesis (IA), which impairs regeneration and enhances fibrosis. This nonproductive IA is characterized by enhanced endothelial cell proliferation, increased vascular division, and an increased number of columnar endothelial cells. Mouse Endothelial Selective KnockoutMettl3The upregulation of profibrotic factors after stimulation of nonproductive IA and PNX promotes the transition of regeneration to fibrosis.MiceFoxo1Gene m6EC-specific mutations at the site of A modification suggest that endothelialMettl3The A504 and A2035 sites in Foxo1 mRNA were modified to maintain pro-regenerative endothelial glycolysis, ensuring the generation of IA and lung regeneration without fibrosis.
Mettl3-Foxo1Inhibition of signaling stimulates high glycolysis and proliferation of 6-phosphofructose-2 kinase/fructose -2, 6-bisphosphatase 3 in human and mouse fibrotic lungs(Pfkfb3)+, Ras homologous family member j (Rhode) +and platelet-derived growth factor subunit B (Pdgfb)+ECs subgroup. InhibitPfkfb3+Rhode+Pdgfb+EC subpopulations normalize IA, attenuate fibrosis, and restore bleomycin (BLM) regeneration of injured mouse lung.In conclusion, the study found that the pulmonary vascular microenvironmentRhode+The mechanism of endothelial cell formation and reveals the role of endothelial cells in the process of pulmonary fibrosisRhode+Abnormal endothelial cell composition of Pillar Cell can promote pulmonary fibrosis through Angiocrine transformation.
Ma Jie and Zhang Liyin, doctoral students of Sichuan University, Zhang Xu, graduate student of Harbin Medical University, and Dr. Zhang Lanlan of West China Hospital of Sichuan University are the co-first authors of the thesis. The corresponding authors are Ding Kesen, Cao Zhongwei, Pu Qiang, Chen Lu and Professor Yang Liming of Harbin Medical University.

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