Lung organoids: a new frontier in neonatology and paediatric respiratory medicine

Abstract

Great strides have been made in pre-clinical research in recent decades using animal models and cell lines. However, traditional models may fail to translate to humans, resulting in substantial failure rates in drug development. Recent three-dimensional organoid models have borne a good resemblance to the architecture, development and function of tissues, especially for organs with complex cell interactions and dynamics such as the lungs. In 2022, the role of organoids as alternative to animal testing was recognised by the US Food and Drug Administration. We searched Medline and ClinicalTrials.gov for studies on the experimental use of lung organoids to model disease pathogenesis and test treatments for paediatric and neonatal respiratory diseases. We comprehensively review the translational value of organoids for paediatric and neonatal respiratory conditions, with current limitations and future expectations, while glancing at other in vitro respiratory models. Combinations of organoid models varying in derivation and differentiation have been used to test interventions for conditions such as infectious/inflammatory diseases, abnormalities of the lung vasculature, surfactant deficiency and genetic diseases. Even multifactorial diseases such as congenital diaphragmatic hernia and bronchopulmonary dysplasia are benefiting from new options for patient-specific sampling and organoid derivation. Microscale technologies and engineering contribute to further advancements in lung-on-chip and microfluidic environments. Overall, organoids show great potential as a bridge between basic research and clinical applications, with versatile adaptability to research purposes. Patient-derived organoids carry exciting possibilities for both personalised medicine and clinical research. Rapid advances in regenerative medicine and engineering have opened up new avenues for neonatology and paediatric respiratory medicine.

FIGURE 1

Lung organoid types. Schematic representation of the major cell types found on different lung organoids with representative mouse-derived bright field images for each type of organoid. a) Depiction of an airway organoid (AO) in which goblet cells (MUC5AC-expressing cells) can be found in more abundance in human AOs compared to mice. Basal cells, which in mice are only present in trachea and in the main stem bronchi. Presence of ciliated and club cells in different proportions depending on maturation time [119, 124]. b) Bronchioalveolar organoids formed by cell types from both proximal and distal regions. Only a few ciliated cells are present while most are lung progenitor cells and alveolar epithelial cell type II (AT2) cells that give rise to epithelial cell type I (AT1). c) Depiction of an alveolar organoid (AlvO) with the two major epithelial cell types AT2 and AT1 present as is known for the distal lung region. Scale bar: 100 µm.