Alveolar Macrophages in a Dish: A Human iPSC Platform for Translational Pediatric Lung Research

Alveolar macrophages (AMs) play a critical role in maintaining lung immunity and homeostasis. Dysfunctional AMs can contribute not only to infectious respiratory diseases but also to inflammatory and chronic lung disorders, such as bronchopulmonary dysplasia, interstitial lung disease and asthma. Because primary human AMs – especially from children – are scarce and animal models do not fully reflect human pediatric physiology, scalable human-specific systems are needed to study these mechanisms. To address this gap and reduce reliance on animal experimentation, we generate AM-like cells from human induced pluripotent stem cells (iPSC-AMs) using a standardized and scalable differentiation protocol. These iPSC-AMs recapitulate key features of human AMs, providing a valuable platform for in vitro disease modeling, environmental exposure studies, and the development of cell-based therapies. Our approach allows the production of iPSC-AMs not only under laboratory-scale conditions but can also be applied on iPSC-macrophages from a stirred-tank bioreactor, demonstrating feasibility for large-scale generation. Differentiation into AMs was optimized by mimicking the alveolar microenvironment through surfactant supplementation. Morphologically, iPSC-AMs displayed the characteristic rounded shape of primary AMs. qPCR analysis confirmed the acquisition of an AM-like transcriptional signature, including upregulation of SPI1, PPARG, and MRC1, and downregulation of mmP7 and mmP9. Preliminary functional assays demonstrated intact ROS production and efficient phagocytic activity. Together, these findings indicate that iPSC-AMs faithfully recapitulate key molecular and functional traits of human alveolar macrophages. Our scalable iPSC-AM platform provides a reproducible and ethically sustainable system that goes beyond traditional animal-based models by offering a more biologically relevant human model of alveolar macrophages. Importantly, this model creates new opportunities for pediatric pulmonary research, allowing mechanistic studies of childhood lung diseases and evaluation of potential therapeutic strategies relevant to pediatric patients. Publication History Article published online: 26 February 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany