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

Abstract 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...

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Autores principales:	Teresa Bluhmki, Stefanie Traub, Ann-Kathrin Müller, Sarah Bitzer, Eva Schruf, Marie-Therese Bammert, Marcel Leist, Florian Gantner, James P Garnett, Ralf Heilker
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/09338b009eba44b382db553973d27bc2
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spelling	oai:doaj.org-article:09338b009eba44b382db553973d27bc22021-12-02T19:02:32ZFunctional human iPSC-derived alveolar-like cells cultured in a miniaturized 96‑Transwell air–liquid interface model10.1038/s41598-021-96565-42045-2322https://doaj.org/article/09338b009eba44b382db553973d27bc22021-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-96565-4https://doaj.org/toc/2045-2322Abstract 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.Teresa BluhmkiStefanie TraubAnn-Kathrin MüllerSarah BitzerEva SchrufMarie-Therese BammertMarcel LeistFlorian GantnerJames P GarnettRalf HeilkerNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-19 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Teresa Bluhmki Stefanie Traub Ann-Kathrin Müller Sarah Bitzer Eva Schruf Marie-Therese Bammert Marcel Leist Florian Gantner James P Garnett Ralf Heilker Functional human iPSC-derived alveolar-like cells cultured in a miniaturized 96‑Transwell air–liquid interface model
description	Abstract 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.
format	article
author	Teresa Bluhmki Stefanie Traub Ann-Kathrin Müller Sarah Bitzer Eva Schruf Marie-Therese Bammert Marcel Leist Florian Gantner James P Garnett Ralf Heilker
author_facet	Teresa Bluhmki Stefanie Traub Ann-Kathrin Müller Sarah Bitzer Eva Schruf Marie-Therese Bammert Marcel Leist Florian Gantner James P Garnett Ralf Heilker
author_sort	Teresa Bluhmki
title	Functional human iPSC-derived alveolar-like cells cultured in a miniaturized 96‑Transwell air–liquid interface model
title_short	Functional human iPSC-derived alveolar-like cells cultured in a miniaturized 96‑Transwell air–liquid interface model
title_full	Functional human iPSC-derived alveolar-like cells cultured in a miniaturized 96‑Transwell air–liquid interface model
title_fullStr	Functional human iPSC-derived alveolar-like cells cultured in a miniaturized 96‑Transwell air–liquid interface model
title_full_unstemmed	Functional human iPSC-derived alveolar-like cells cultured in a miniaturized 96‑Transwell air–liquid interface model
title_sort	functional human ipsc-derived alveolar-like cells cultured in a miniaturized 96‑transwell air–liquid interface model
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/09338b009eba44b382db553973d27bc2
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Functional human iPSC-derived alveolar-like cells cultured in a miniaturized 96‑Transwell air–liquid interface model

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