Engineering airway epithelium

Abstract

Airway epithelium is constantly presented with injurious signals, yet under healthy circumstances, the epithelium maintains its innate immune barrier and mucociliary elevator function. This suggests that airway epithelium has regenerative potential (I. R. Telford and C. F. Bridgman, 1990). In practice, however, airway regeneration is problematic because of slow turnover and dedifferentiation of epithelium thereby hindering regeneration and increasing time necessary for full maturation and function. Based on the anatomy and biology of the airway epithelium, a variety of tissue engineering tools available could be utilized to overcome the barriers currently seen in airway epithelial generation. This paper describes the structure, function, and repair mechanisms in native epithelium and highlights specific and manipulatable tissue engineering signals that could be of great use in the creation of artificial airway epithelium.

Figure 1

Examples of the tools of tissue engineering. Tools that manipulate the timing and appearance of chemical and mechanical signals offer opportunities to organize and direct the differentiation of developing tissue. Chemical signals can be immobilized, (a) in the form of covalently bonded growth factors that direct cell migration, or mobile in a hydrogel, (b) to create a chemotactic signal, through diffusion, for cells to respond to. Mechanical signals can be presented as a constant force, such as substrate stiffness, (c) to modulate cell spreading or as an inducible force, (d) such as shear flow, to organize cells in the direction parallel to flow.

Figure 2

Specialized exemplar tools of epithelial tissue engineering. Chemical signals can be presented as immobilized growth factors (a) that promote differentiation of airway basal cells to specific cell types in a pattern that is reminiscent of in vivo airway epithelium, or (b) a mobile chemokine gradient of CXCL12 that promotes airway epithelium polarity in the presence of Wnt5a, based on the work of Witze et al., 2008 [68]. Mechanical signals can be presented as a constant force that organizes epithelial cells cultured on nanogrooved and flat substrates (c) based on the work of Texeira et al., 2003 [90], or as a reversible force that mimics the transluminal pressure gradient applied to airway epithelium during normal tidal breathing to modulate ciliary beat frequency [3].