Lung organoids for preclinical evaluation of stem cell therapies: Opportunities, evidence, and translational challenges

Abstract

Pulmonary diseases impose a substantial global burden and remain major causes of morbidity and mortality. Despite advances in disease-modifying therapies, effective regenerative treatments remain limited for several chronic lung diseases, including idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease. Stem cell-based therapies have shown promise in preclinical studies and early-phase clinical trials for lung tissue repair; however, substantial obstacles remain before clinical translation, including incomplete understanding of therapeutic mechanisms, safety concerns regarding tumorigenicity and immunogenicity, and a lack of standardized evaluation platforms. Lung organoids are three-dimensional, in vitro tissue constructs derived from pluripotent or adult stem cells that may bridge basic stem cell research and clinical application. This review introduces the sources and isolation methods of stem cells for lung organoid generation, describes preparation processes, and evaluates the utility of lung organoids in building pulmonary disease models. Importantly, we distinguish between current validated applications and proposed future capabilities. Organoid-based evidence offers new directions for investigating pathological mechanisms in stem cell treatment and suggests the exploratory potential of organoids in drug screening and early toxicity testing. However, direct evidence for the validation of stem cell therapies using human lung organoids is limited; most supporting data come from small-scale animal studies or proof-of-concept experiments. In addition, much of the evidence remains preclinical and model-dependent, with current organoid systems lacking vascularization, innervation, systemic circulation, and a complete immune context. Finally, we summarize the validated applications of lung organoids in stem cell therapy assessment (mechanistic elucidation and donor-specific screening), identify the remaining experimental gaps (clinical predictive validity, long-term safety surrogates), and propose the evidence needed to address these limitations.

Keywords: Stem cell therapy; Lung organoids; Pulmonary fibrosis; Chronic obstructive pulmonary disease; Extracellular vesicles; Disease modeling

Core Tip: Lung organoids are emerging human-relevant ex vivo models that may complement conventional preclinical systems in studying lung disease mechanisms and evaluating selected responses to stem cell-based therapeutic products. Current evidence does not support their use as clinically validated predictors of transplantation outcomes or as independent tools for comprehensive assessment of local safety-related responses. Standardized protocols and prospective studies linking organoid responses with animal and clinical outcomes are needed to establish their translational value.