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Biomaterials. 2014 Jan;35(2):699-710. doi: 10.1016/j.biomaterials.2013.10.018. Epub 2013 Oct 19.

Alveolar epithelial differentiation of human induced pluripotent stem cells in a rotating bioreactor.

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Department of Anesthesiology, Yale University, New Haven, CT 06520, USA; Department of Biomedical Engineering, Yale University, New Haven, CT 06520, USA.


Traditional stem cell differentiation protocols make use of a variety of cytokines including growth factors (GFs) and inhibitors in an effort to provide appropriate signals for tissue specific differentiation. In this study, iPSC-derived type II pneumocytes (iPSC-ATII) as well as native isolated human type II pneumocytes (hATII) were differentiated toward a type I phenotype using a unique air-liquid interface (ALI) system that relies on a rotating apparatus that mimics in vivo respiratory conditions. A relatively homogenous population of alveolar type II-like cells from iPSC was first generated (iPSC-ATII cells), which had phenotypic properties similar to mature human alveolar type II cells. iPSC-ATII cells were then cultured in a specially designed rotating culture apparatus. The effectiveness of the ALI bioreactor was compared with the effectiveness of small molecule-based differentiation of type II pneumocytes toward type 1 pneumocytes. The dynamics of differentiation were examined by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), flow cytometry and immunocytochemistry. iPSC-ATII and hATII cells cultured in the ALI bioreactor had higher levels of type I markers, including aquaporin-5(AQ5), caveolin-1, and T1α, at both the RNA and protein levels as compared with the flask-grown iPSC-ATII and hATII that had been treated with small molecules to induce differentiation. In summary, this study demonstrates that a rotating bioreactor culture system that provides an air-liquid interface is a potent inducer of type I epithelial differentiation for both iPS-ATII cells and hATII cells, and provides a method for large-scale production of alveolar epithelium for tissue engineering and drug discovery.


ALI; Air–liquid interface; Alveolar epithelium; Bioreactor; Induced pluripotent stem (iPS); air–liquid interface; hATI; hATII; human alveolar type I; human alveolar type II; iPSC-ATII; iPSC-derived alveolar type II

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