Tractable human distal lung organoid model as a new efficient tool to study mesenchymal-epithelial interactions in COPD

易处理的人远端肺类器官模型作为研究慢性阻塞性肺病间充质-上皮相互作用的新有效工具

• 批准号: NC/Y500641/1
• 金额: $ 12.74万
• 依托单位: Queen's University Belfast
• 依托单位国家: 英国
• 项目类别: Training Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=NC%2FY500641%2F1
• 关键词: Tractable; human; distal; lung; organoid

Reduced lung regeneration capacity is a hallmark of chronic obstructive pulmonary disease (COPD), the third leading cause of death worldwide. Accumulating evidence suggests that alveolar epithelial regeneration is tightly regulated by signals from the mesenchymal niche. Therefore it is fundamentally important to better understand cellular and molecular mechanisms underpinning mesenchymal-epithelial interactions in the process of lung repair and regeneration. Current knowledge about mechanisms underpinning human lung regeneration is limited and in large based on mouse models. Given the significant differences between the human and mouse lung, especially in the distal airways, novel models based on primary human lung cells are needed. We have devised a novel organoid model system that better recapitulates normal distal lung complexity. This model is based on the self-aggregation of primary human small airway epithelial cells (SAECs), pulmonary microvascular endothelia cells (HPMECs) and lung mesenchymal stromal cells (LMSCs) in Matrigel. These organoids develop alveoli-like budding structures with a lumen and support the presence of endothelial cells for up to 21 days. We found that lung MSCs play a central role in organoid formation and growth of alveoli-like structures. More crucially, we found that MSCs derived from COPD lungs are not able to support alveoli formation and that is, at least partially, explained by aberrant epigenetic modifications (DNA methylation) in COPD MSCs.Further investigation of the mechanisms underpinning mesenchymal-epithelial interactions in COPD using this tractable organoid model will allow us to better understand mechanisms of lung alveolar epithelial regeneration, identify new therapeutic targets and will stimulate novel therapies aimed at the restoration of cellular organization of distal airways in lung disease.In summary, this research addresses the knowledge gap in understanding mechanisms of human lung regeneration by utilizing a novel organoid model. By investigating the role of LMSCs and DNA methylation, the study aims to uncover new therapeutic targets and contribute to advancements in COPD treatment and lung regenerative medicine. The potential to replace animal models and the broad applications of the organoid model further emphasize the significance of this timely research.

肺再生能力降低是慢性阻塞性肺疾病（COPD）的标志，COPD是全球第三大死亡原因。越来越多的证据表明，肺泡上皮细胞的再生受到来自间充质生态位的信号的严格调控。因此，更好地理解肺修复和再生过程中间充质-上皮相互作用的细胞和分子机制至关重要。目前关于人类肺再生机制的知识是有限的，并且大部分基于小鼠模型。鉴于人和小鼠肺之间的显著差异，特别是在远端气道中，需要基于原代人肺细胞的新模型。我们设计了一种新的类器官模型系统，可以更好地概括正常远端肺的复杂性。该模型基于原代人小气道上皮细胞（SAEC）、肺微血管内皮细胞（HPMEC）和肺间充质基质细胞（LMSC）在Matrigel中的自聚集。这些类器官发育出具有管腔的肺泡样出芽结构，并支持内皮细胞的存在长达21天。我们发现，肺间充质干细胞在类器官形成和肺泡样结构的生长中起着核心作用。更重要的是，我们发现来源于COPD肺的MSC不能支持肺泡形成，这至少部分是由异常的表观遗传修饰解释的（DNA甲基化）。使用这种易于处理的类器官模型进一步研究COPD中间充质-上皮相互作用的机制将使我们能够更好地了解肺泡上皮再生的机制，确定新的治疗靶点，并将刺激旨在恢复肺部疾病远端气道细胞组织的新疗法。总之，本研究通过利用新的类器官模型解决了人类肺再生机制的知识缺口。通过研究LMSC和DNA甲基化的作用，该研究旨在发现新的治疗靶点，并为COPD治疗和肺再生医学的进步做出贡献。替代动物模型的潜力和类器官模型的广泛应用进一步强调了这项及时研究的重要性。