Research ArticleCILIOPATHIES

Multicellular modeling of ciliopathy by combining iPS cells and microfluidic airway-on-a-chip technology

See allHide authors and affiliations

Science Translational Medicine  07 Jul 2021:
Vol. 13, Issue 601, eabb1298
DOI: 10.1126/scitranslmed.abb1298

You are currently viewing the abstract.

View Full Text

Log in to view the full text

Log in through your institution

Log in through your institution

Modeling cilia

Understanding the mechanisms mediating mucociliary clearance in lungs is critical for understanding and treating ciliary disfunctions. Here, Sone et al. developed an airway-on-a-chip system using human-derived induced pluripotent stem cells (iPSCs) from healthy donors to study mucociliary flow. The authors show that fluid shear stress plays a major role in regulating the flow by regulating multicellular planar cell polarity and ciliogenesis. The airway-on-a-chip using iPSCs from two patients with primary ciliary dyskinesia replicated abnormal ciliary function, suggesting that the in vitro system developed here could be used to study ciliary dysfunction and for testing pharmacological targets.

Abstract

Mucociliary clearance is an essential lung function that facilitates the removal of inhaled pathogens and foreign matter unidirectionally from the airway tract and is innately achieved by coordinated ciliary beating of multiciliated cells. Should ciliary function become disturbed, mucus can accumulate in the airway causing subsequent obstruction and potentially recurrent pneumonia. However, it has been difficult to recapitulate unidirectional mucociliary flow using human-derived induced pluripotent stem cells (iPSCs) in vitro and the mechanism governing the flow has not yet been elucidated, hampering the proper humanized airway disease modeling. Here, we combine human iPSCs and airway-on-a-chip technology, to demonstrate the effectiveness of fluid shear stress (FSS) for regulating the global axis of multicellular planar cell polarity (PCP), as well as inducing ciliogenesis, thereby contributing to quantifiable unidirectional mucociliary flow. Furthermore, we applied the findings to disease modeling of primary ciliary dyskinesia (PCD), a genetic disease characterized by impaired mucociliary clearance. The application of an airway cell sheet derived from patient-derived iPSCs and their gene-edited counterparts, as well as genetic knockout iPSCs of PCD causative genes, made it possible to recapitulate the abnormal ciliary functions in organized PCP using the airway-on-a-chip. These findings suggest that the disease model of PCD developed here is a potential platform for making diagnoses and identifying therapeutic targets and that airway reconstruction therapy using mechanical stress to regulate PCP might have therapeutic value.

View Full Text

Stay Connected to Science Translational Medicine