Breathing on chip: Dynamic flow and stretch accelerate mucociliary maturation of airway epithelium in vitro

Materials Today Bio, vol. 21, pp. 100713

Abstract

Human lung function is intricately linked to blood flow and breathing cycles, but it remains unknown how these dynamic cues shape human airway epithelial biology. Here we report a state-of-the-art protocol for studying the effects of dynamic medium and airflow as well as stretch on human primary airway epithelial cell differentiation and maturation, including mucociliary clearance, using an organ-on-chip device. Perfused epithelial cell cultures displayed accelerated maturation and polarization of mucociliary clearance, and changes in specific cell-types when compared to traditional (static) culture methods. Additional application of airflow and stretch to the airway chip resulted in an increase in polarization of mucociliary clearance towards the applied flow, reduced baseline secretion of interleukin-8 and other inflammatory proteins, and reduced gene expression of matrix metalloproteinase (MMP) 9, fibronectin, and other extracellular matrix factors. These results indicate that breathing-like mechanical stimuli are important modulators of airway epithelial cell differentiation and maturation and that their fine-tuned application could generate models of specific epithelial pathologies, including mucociliary (dys)function.

Authors 13

1. Janna C. Nawroth

   University of Southern California · Helmholtz Munich · Emulate (United States) · Institute of Biological and Medical Imaging · Technical University of Munich

   Affiliation as printed

   Chair of Biological Imaging at the Central Institute for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Munich, Germany

   Emulate Inc., Boston, MA, USA

   Hastings Center for Pulmonary Research, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Southern California, Los Angeles, CA, USA

   Helmholtz Pioneer Campus and Institute for Biological and Medical Imaging, Helmholtz Zentrum München (GmbH), Neuherberg, Germany

2. Doris Roth

   Emulate (United States)

   Affiliation as printed

   Emulate Inc., Boston, MA, USA

3. Annemarie M. van Schadewijk Aachen PulmoScience Lab Dept of Pulmonology, Leiden University Medical Center

   Leiden University Medical Center

   Affiliation as printed

   PulmoScience Lab, Department of Pulmonology, Leiden University Medical Center, Leiden, the Netherlands

4. Abilash Ravi Aachen PulmoScience Lab Dept of Pulmonology, Leiden University Medical Center

   Leiden University Medical Center

   Affiliation as printed

   PulmoScience Lab, Department of Pulmonology, Leiden University Medical Center, Leiden, the Netherlands

5. Tengku Ibrahim Maulana

   Emulate (United States)

   Affiliation as printed

   Emulate Inc., Boston, MA, USA

6. Christiana N. Senger

   University of Southern California

   Affiliation as printed

   Hastings Center for Pulmonary Research, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Southern California, Los Angeles, CA, USA

7. Sander van Riet Aachen PulmoScience Lab Dept of Pulmonology, Leiden University Medical Center

   Leiden University Medical Center

   Affiliation as printed

   PulmoScience Lab, Department of Pulmonology, Leiden University Medical Center, Leiden, the Netherlands

8. Dennis K. Ninaber Aachen PulmoScience Lab Dept of Pulmonology, Leiden University Medical Center

   Leiden University Medical Center

   Affiliation as printed

   PulmoScience Lab, Department of Pulmonology, Leiden University Medical Center, Leiden, the Netherlands

9. Amy M. de Waal Aachen Department of Infectious Diseases

   Leiden University Medical Center

   Affiliation as printed

   Department of Infectious Diseases, Leiden University Medical Center, Leiden, the Netherlands

10. Dorothea Kraft

    Helmholtz Munich · Institute of Biological and Medical Imaging

    Affiliation as printed

    Helmholtz Pioneer Campus and Institute for Biological and Medical Imaging, Helmholtz Zentrum München (GmbH), Neuherberg, Germany

11. Pieter Sicco Hiemstra Aachen PulmoScience Lab Dept of Pulmonology, Leiden University Medical Center

    Leiden University Medical Center

    Affiliation as printed

    PulmoScience Lab, Department of Pulmonology, Leiden University Medical Center, Leiden, the Netherlands

12. Amy L. Ryan

    University of Southern California

    Affiliation as printed

    Department of Stem Cells and Regenerative Medicine, University of Southern California, Los Angeles, CA, USA

    Hastings Center for Pulmonary Research, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Southern California, Los Angeles, CA, USA

13. Anne M. van der Does corresponding Aachen PulmoScience Lab Dept of Pulmonology, Leiden University Medical Center

    Leiden University Medical Center

    Affiliation as printed

    PulmoScience Lab, Department of Pulmonology, Leiden University Medical Center, Leiden, the Netherlands