Conditional reprogramming of pediatric airway epithelial cells: A new human model to investigate early‐life respiratory disorders

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Excerpt

The airway epithelium is a crucial cellular interface that shapes airway immune responses in humans.1 Airway epithelial cells (AEC) have evolutionary conserved innate receptors that control airway immune responses to viruses, allergens, and other environmental challenges.1 Thus, the epithelium is in a unique position to translate gene‐environment interactions linked to the pathogenesis of respiratory conditions. In susceptible individuals, altered AEC function can make the airways vulnerable to viral infections and facilitate the establishment of the asthmatic phenotype.1 Studies using AEC derived from adults with asthma have led to the discovery of novel therapies and companion biomarkers based on epithelial‐derived cytokines.4 In contrast, the airway epithelium of infants has been remarkably understudied, despite compelling evidence showing that asthma and other chronic respiratory disorders often begin in early life.6
One of the main limitations of studying the human infant airway epithelium is the lack of robust AEC culture systems. Prior studies have demonstrated that the use of human infant AEC cultures is a powerful strategy to investigate early‐life respiratory disorders7; however, airway sampling in this age group is a major challenge. Here we present a strategy to optimize nasal and bronchial infant AEC cultures using conditionally reprogrammed cells (CRC).11 The purpose of generating CRC is to enhance proliferative and survival capacity as primary AEC cannot survive multiple passages.11 The CRC method combines exposure to a Rho kinase (ROCK) inhibitor Y‐27632 and a fibroblast‐derived feeder layer or conditioned medium (medium from irradiated fibroblasts) to reprogram primary AEC into progenitor cells.11 The induction of CRC results from reprogramming of the entire cell population rather than the selection of a minor subpopulation11; thus, CRC are life‐extended preserving the AEC phenotype. Although CRC generation has been described in human adult bronchial and nasal epithelium,12 our study is the first to adapt CRC technology to develop a human‐based model of the newborn and infant airway epithelium. The impact of this work is that it presents a clinically and scientifically relevant human‐based approach to investigate the developmental immunobiology of the airway epithelium and the pathogenesis of respiratory disorders that begin in early life.
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