Abstract
Diseases such as idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, and bronchopulmonary dysplasia injure the gas‐exchanging alveoli of the human lung. Animal studies have indicated that dysregulation of alveolar cells, including alveolar type II stem/progenitor cells, is implicated in disease pathogenesis. Due to mouse‐human differences, there has been a desperate need to develop human‐relevant lung models that can more closely recapitulate the human lung during homeostasis, injury repair, and disease. Here we discuss how current single‐cell RNA sequencing studies have increased knowledge of the cellular and molecular composition of human lung alveoli, including the identification of molecular heterogeneity, cellular diversity, and previously unknown cell types, some of which arise specifically during disease. For functional analysis of alveolar cells, in vitro human alveolar organoids established from human pluripotent stem cells, embryonic progenitors, and adult tissue from both healthy and diseased lungs have modeled aspects of the cellular and molecular features of alveolar epithelium. Drawbacks of such systems are highlighted, along with possible solutions. Organoid‐on‐a‐chip and ex vivo systems including precision‐cut lung slices can complement organoid studies by providing further cellular and structural complexity of lung tissues, and have been shown to be invaluable models of human lung disease, while the production of acellular and synthetic scaffolds hold promise in lung transplant efforts. Further improvements to such systems will increase understanding of the underlying biology of human alveolar stem/progenitor cells, and could lead to future therapeutic or pharmacological intervention in patients suffering from end‐stage lung diseases.
Highlights
The primary function of the lungs is gas exchange and the site for this is the alveoli that are arranged by acini found in the lung parenchyma regions
There is a significant need to understand the mechanisms of alveolar maintenance and damage repair because damage to the alveolar region is a component of chronic adult lung diseases such as chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis
Alveolar macrophages (AMs) are located on the luminal epithelial surface of the alveoli, making up more than 95% of phagocytes in the alveoli at steady state, and act as the first line of defense against invading pathogens and clear the surfactant.[28,29,30] scRNA-seq data have identified proliferating and nonproliferating AMs in healthy human lungs, while AM heterogeneity has been observed in disease settings such as IPF, where a subset of monocyte-derived AMs express profibrotic genes.[1,14,31]
Summary
The primary function of the lungs is gas exchange and the site for this is the alveoli that are arranged by acini found in the lung parenchyma regions. Despite the pivotal role of alveoli in lung function and disease, and their clinical burden, the pathogenesis of these diverse diseases is incompletely understood and treatment options for patients remain limited. This is partly due to the lack of model systems that allow us to understand human lung biology and disease. We summarize our current knowledge of human lung alveoli from decades of animal studies and recent single-cell RNA sequencing analysis (scRNA-seq) (Figure 1). We highlight recent advances in the available in vitro and ex vivo human lung alveolar model systems and discuss their potential applications and limitations in therapeutic aspects
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