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

Table 3 Applications of lung organoids in evaluating stem cell therapy

Disease type	Source/organoid type	Stem cell/EV therapy	Evaluation metrics	Key findings	Study design/sample size	Ref.
Pulmonary fibrosis	-	-	-	No published studies have been identified that directly evaluate MSC- or MSC-EV-based therapy in pulmonary fibrosis lung organoid models; current evidence is primarily derived from animal models and 2D culture experiments	-	-
COPD/emphysema	Mouse-derived/Lung epithelial progenitor cell-derived organoids	hUC-MSC-EVs; hUC-MSCs	Number/size of organoids; AT2/AT1 marker balance; collagen deposition; inflammatory infiltration	hUC-MSC-EVs reduce inflammatory infiltration and collagen deposition, restore the normal number and size of organoids, and rebalance the AT2/AT1 ratio	Murine organoids; n = 3-5 mice per group; single exposure model	[58]
Acute lung injury	Mouse-derived/Lung organoid-macrophage co-culture model	MSCs (bone marrow origin)	Macrophage pro-inflammatory function; organoid morphology	MSCs mitigate LPS-induced acute lung injury by inhibiting the pro-inflammatory function of macrophages	Murine organoid-macrophage co-culture; n = 3 independent experiments; 2 organoid donors + ≥ 3 MSC donors	[18]
Lung cancer	Human-derived/iPSCs-derived bronchial organoids (BLO); patient-derived LCOs	PSC-MSC-derived EVs (loaded with cisplatin)	LDH release; CCK8 metabolic activity; apoptosis-related genes (e.g., P53)	The empty EVs themselves exhibit cytotoxicity toward both LCO and BLO, suggesting that MSC-EVs may exert non-specific effects	Human iPSCs-derived organoids; n = 3-4 technical replicates; 2 independent differentiations	[33]

Except for the pulmonary fibrosis row (for which no published studies were identified), all other therapies involving stem cells or stem cell-derived extracellular vesicles listed in this table have been directly validated within lung organoid systems. EV: Extracellular vesicle; MSC: Mesenchymal stromal cell; 2D: Two-dimensional; COPD: Chronic obstructive pulmonary disease; hUC-MSC-EVs: Human umbilical cord mesenchymal stem cell-derived extracellular vesicles; hUC-MSCs: Human umbilical cord mesenchymal stem cell; AT2: Alveolar type 2; LPS: Lipopolysaccharide; iPSCs: Induced pluripotent stem cells; BLO: Branched lung organoid; LCO: Lung cancer organoid; PSC: Pluripotent stem cell; LDH: Lactate dehydrogenase.