How insulin shapes lung development in a new human stem cell organoid model

Respiratory diseases are one of the leading causes of mortality. Despite the efforts to understand lung development, physiology, and pathology, this field remains in its early stages. In vitro models can replicate lung physiology to comprehend development, function, and pathology. Lung organoids (LOs) are 3D models that emulate the diverse developmental stages of the lung and its 3D architecture and functional characteristics. We adopted an organoid model derived from hESCs with transient overexpression of the lung/thyroid transcription factor NKX2.1. Insulin plays a role in LO generation, and airway, alveolar, and mesenchymal cell types were identified. Transcriptomic analysis reveals insulin's role in enhancing lung progenitors’ differentiation, glycolysis, and PI3K pathway activation. Insulin's indispensability throughout lung development is evident, as its removal at different stages disrupts LO generation and maturation. The protocol adopted is under the International Patent (WO/2023/099526). Our research emphasizes insulin's pivotal role in transforming NKX2.1 endodermal cells into LOs and aims to unveil the intricate dynamics behind it. Finally, this method has been applied to model idiopathic pulmonary fibrosis (IPF). IPF is a chronic lung condition associated with alterations in glucose metabolism and characterized by fibrosis accumulation in alveolar cells, leading to breathing difficulties.