Pulmonary diseases encompass a wide array of disorders affecting the respiratory system, often characterized by inflammation, impaired gas exchange, tissue remodeling, and compromised lung function. Understanding the cellular mechanisms underlying these diseases is essential for developing targeted therapies. Primary pulmonary cells, isolated directly from human lung tissue or derived from pluripotent stem cells, provide physiologically relevant models that closely mimic the in vivo lung environment, offering critical insights into disease pathogenesis and therapeutic responses.
Primary Pulmonary Cell Types and Their Roles
The respiratory system comprises diverse primary cell types, including airway epithelial cells (basal, goblet, ciliated), alveolar epithelial cells (type I and II), pulmonary fibroblasts, smooth muscle cells, endothelial cells, and various immune cells such as alveolar and interstitial macrophages. Airway basal cells serve as progenitors critical for airway epithelium regeneration and are implicated in chronic obstructive pulmonary disease (COPD) pathology, exhibiting molecular heterogeneity and altered gene expression profiles in disease states. Alveolar epithelial type II (AT2) cells, responsible for surfactant production and alveolar repair, can be cultured as organoids that model lung regeneration and disease processes, including fibrosis and viral infections such as SARS-CoV-2.
Macrophages in the lung, including tissue-resident alveolar macrophages (AMs) and interstitial macrophages (IMs), are pivotal in maintaining lung homeostasis and mediating immune responses. These cells exhibit distinct ontogeny, transcriptional profiles, and functions, adapting dynamically during inflammation and infection. AMs regulate surfactant turnover and defend against pathogens but can contribute to disease progression when dysregulated.
Advances in lung disease modeling using primary cells
Recent advancements in stem cell biology have enabled the generation of lung organoids from human pluripotent stem cells (PSCs), including embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). These 3D organoid models recapitulate lung development and architecture, comprising multiple epithelial and mesenchymal cell types, and serve as powerful platforms for studying lung diseases and screening therapeutics. Protocols involving sequential modulation of signaling pathways (e.g., TGF-β, BMP, Wnt, FGF) guide PSC differentiation into lung progenitors and mature epithelial cells, enabling disease modeling of cystic fibrosis, pulmonary fibrosis, and infectious diseases.
Primary pulmonary cells and organoids facilitate the investigation of cellular interactions, immune responses, and regenerative mechanisms under pathological conditions. For example, cytokine stimulation of lung organoids has elucidated the role of IL-1β in alveolar epithelial cell differentiation and fibrosis, highlighting potential therapeutic targets. Additionally, primary airway basal cells from COPD patients reveal gene expression changes linked to stress responses and hypoxia, underscoring their relevance in disease progression and regenerative capacity.