Functional human iPSC-derived alveolar-like cells cultured in a miniaturized 96‑Transwell air-liquid interface model

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2021
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Traub, Stefanie
Müller, Ann-Kathrin
Bitzer, Sarah
Schruf, Eva
Bammert, Marie-Therese
Garnett, James P.
Heilker, Ralf
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Scientific Reports. Springer Nature. 2021, 11(1), 17028. eISSN 2045-2322. Available under: doi: 10.1038/s41598-021-96565-4
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In order to circumvent the limited access and donor variability of human primary alveolar cells, directed differentiation of human pluripotent stem cells (hiPSCs) into alveolar-like cells, provides a promising tool for respiratory disease modeling and drug discovery assays. In this work, a unique, miniaturized 96-Transwell microplate system is described where hiPSC-derived alveolar-like cells were cultured at an air-liquid interface (ALI). To this end, hiPSCs were differentiated into lung epithelial progenitor cells (LPCs) and subsequently matured into a functional alveolar type 2 (AT2)-like epithelium with monolayer-like morphology. AT2-like cells cultured at the physiological ALI conditions displayed characteristics of AT2 cells with classical alveolar surfactant protein expressions and lamellar-body like structures. The integrity of the epithelial barriers between the AT2-like cells was confirmed by applying a custom-made device for 96-parallelized transepithelial electric resistance (TEER) measurements. In order to generate an IPF disease-like phenotype in vitro, the functional AT2-like cells were stimulated with cytokines and growth factors present in the alveolar tissue of IPF patients. The cytokines stimulated the secretion of pro-fibrotic biomarker proteins both on the mRNA (messenger ribonucleic acid) and protein level. Thus, the hiPSC-derived and cellular model system enables the recapitulation of certain IPF hallmarks, while paving the route towards a miniaturized medium throughput approach of pharmaceutical drug discovery.

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ISO 690BLUHMKI, Teresa, Stefanie TRAUB, Ann-Kathrin MÜLLER, Sarah BITZER, Eva SCHRUF, Marie-Therese BAMMERT, Marcel LEIST, Florian GANTNER, James P. GARNETT, Ralf HEILKER, 2021. Functional human iPSC-derived alveolar-like cells cultured in a miniaturized 96‑Transwell air-liquid interface model. In: Scientific Reports. Springer Nature. 2021, 11(1), 17028. eISSN 2045-2322. Available under: doi: 10.1038/s41598-021-96565-4
BibTex
@article{Bluhmki2021-08-23Funct-54772,
  year={2021},
  doi={10.1038/s41598-021-96565-4},
  title={Functional human iPSC-derived alveolar-like cells cultured in a miniaturized 96‑Transwell air-liquid interface model},
  number={1},
  volume={11},
  journal={Scientific Reports},
  author={Bluhmki, Teresa and Traub, Stefanie and Müller, Ann-Kathrin and Bitzer, Sarah and Schruf, Eva and Bammert, Marie-Therese and Leist, Marcel and Gantner, Florian and Garnett, James P. and Heilker, Ralf},
  note={Article Number: 17028}
}
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