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Cellular and Molecular Bioengineering

Cellular and Molecular Bioengineering - Poster Session E

Poster V1 - Human Alveolar Organoids for Modeling Idiopathic Pulmonary Fibrosis and Evaluating Drug Efficacy

Saturday, October 26, 2024
10:00 AM – 11:00 AM EST
Location: Exhibit Hall E, F & G

Introduction:  Idiopathic pulmonary fibrosis (IPF) is a grave and progressively lethal lung disease characterized by the thickening and fibrosis of lung tissue, resulting in a continuous and irreversible deterioration of lung function. Despite the critical nature of the disease, treatment options remain limited, and effective preclinical models are notably absent. Traditional animal models employed in preclinical studies and drug screening often exhibit distinct drug responses from humans due to physiological dissimilarities. As a result, these models fail to accurately replicate the disease patterns observed in human patients. To address this shortcoming, we have devised a robust preclinical platform that utilizes alveolar organoids derived from human induced pluripotent stem cells (iPSCs) for modeling IPF and evaluating drug responses.

Materials and

Methods:  Human lung progenitor organoids were cultured through a series of differentiation processes. Shortly, hiPSCs were differentiated into definitive endoderm and subsequently into anterior foregut endoderm. The protruding cell spheroids were encapsulated in Matrigel and treated with a cytokine cocktail for differentiation into lung progenitor organoids. After differentiation, the lung progenitor organoids were further differentiated into alveolar organoids.
For IPF modeling, human alveolar organoids were treated with a fibrosis-inducing factor. To confirm the occurrence of IPF, morphological changes of organoid were observed. Immunostaining and qPCR analysis for the fibrosis-specific markers were also performed.
Drug response evaluation was conducted by treating IPF-induced human alveolar organoids with Nintedanib. After treatment, the organoids were analyzed for fibrosis characteristics. The fibrosis marker-positive area was quantified from immunostaining images, and relative gene expressions were measured by qPCR analysis.

Results, Conclusions, and Discussions: In this research, human iPSCs were effectively differentiated into human lung progenitor organoids, which were subsequently developed into human alveolar organoids. These organoids exhibited key alveolar markers, confirming their correct identity as human alveoli mimetics. When exposed to a fibrosis-inducing factor, the alveolar organoids displayed typical features of IPF, including significant morphological shrinkage and elevated expression of fibrotic markers, thereby reflecting the pathological characteristics of IPF. To evaluate the drug response of our IPF model, we treated alveolar organoids with Nintedanib, an FDA-approved antifibrotic drug for IPF. This treatment significantly alleviated fibrotic features in the IPF organoids: the morphology of the organoids was preserved to be comparable to that of non-fibrotic organoids, accompanied by a substantial decrease in the expression of fibrosis markers. These results demonstrate the functionality and reliability of our IPF organoid model for preclinical drug screening. Due to the rising severity of pulmonary fibrotic diseases, it is crucial to investigate their underlying causes and identify therapeutic agents. The human iPSC-derived alveolar organoid platform developed in this study accurately reproduces the pathological features of IPF and allows precise evaluation of the drug efficacy, offering significant promise for developing novel therapeutics for pulmonary fibrotic diseases.

Acknowledgements (Optional):  This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Ministry of Science and ICT (2021R1A2C3004262). The work was supported in part by Brain Korea 21(BK21) FOUR program.