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

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.

The objectives of the study are the following:

1) to investigate the role of lung MSCs in the alveoli formation in the organoid using cells isolated from lungs of COPD and non-COPD patients.

2) decipher the impact of DNA methylation on LMSCs' ability to support alveoli formation.

3) assess whether FDA-approved epigenetic drugs can restore regenerative ability of COPD LMSCs.

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.