Alveolar wars: The rise of in vitro models to understand human lung alveolar maintenance, regeneration, and disease

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.

Progenitor identification and SARS-CoV-2 infection in human distal lung organoids

“…The presence and/or roles of facultative progenitors in human lung is unknown. Human AT2 cells can be differentiated into AT1 cells but cultures are short-lived, neither demonstrating long-term self-renewal nor enabling expansion for disease modeling 4,10,11 , while requirements for feeder cells impede definition of specific niche components 12,13 . Here, we established long-term organoid culture of distal human lung, including AT2 and basal stem cells, which was applied to functional progenitor validation and SARS-CoV-2 modeling.…”

Prospects for RNAi Therapy of COVID-19

“…Our studies on synthetic lipophilic carriers ( Incani et al, 2010 ) showed that these two domains could be engineered to obtain effective siRNA delivery agents to a variety of cells. It may be possible to set-up ECM mimics of pulmonary tissue ( Evans and Lee, 2020 ) to better understand the mediators of siRNA delivery into the cells, given the implication of this process on the potency of siRNAs agents for anti-viral activity.…”

InnovativeIn VitroModels for the Study of Lung Diseases

“…There is strong need to understand the mechanisms of alveolar maintenance and repair because damage to this region underlies many chronic adult lung diseases, such as chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, acute respiratory failure in pneumonia, and acute respiratory distress syndrome. Additionally, insufficient development of alveoli results in various neonatal and childhood diseases including bronchopulmonary dysplasia [1]. Despite the pivotal role of the alveoli in the development of lung diseases, the pathogenesis of these various conditions is still largely unknown, and treatment options for patients remain limited.…”