Prospects and challenges in engineering functional respiratory epithelium for in vitro and in vivo applications

Respiratory diseases are amongst the leading causes of morbidity and mortality worldwide. There is therefore significant interest in developing more efficient treatment strategies for respiratory diseases particularly where there is irreversible tissue damage and loss of function. Despite recent advances in tissue engineering and stem cell technologies the reconstruction of large defects of upper airway and similar pathologies in respiratory system remains an unmet clinical need. The complex organisation of respiratory epithelium still has not been completely recapitulated in vitro. Therefore, novel strategies for the regeneration of functional ciliated respiratory epithelium are required to address the need for the treatment of life threatening respiratory diseases as well as developing biomimetic in vitro models that can be used in drug discovery and disease modelling. This review primarily focuses on current cell based approaches including available cell sources which have shown potential for developing biomimetic models/replacements of upper respiratory epithelium. Most of the tissue engineering approaches for the development of airway epithelium use epithelial basal cells, autologous or allogenic adult stem cells, induced pluripotent stem cells (iPSCs), embryonic stem cells (ESCs) or other stromal cells to induce the organised epithelial differentiation. However, the viability and function of injected/implanted cells could suffer from the host immune response and fail to perform the desired therapeutic functions. Also, given the key role of immune cells in the respiratory epithelium in maintaining defense against external insults, the importance of immune-competency of engineered respiratory epithelia is also discussed. To this end, modulation of immune system and application of biomaterials could play an important role in improving the therapeutic value of cell based respiratory epithelium regeneration. Overall, efforts for reconstruction of functional airway epithelium can be further improved by using optimal cell sources, biomaterials and modulation of immune response. The ability to engineer organised, functional respiratory epithelium can not only provide a remedy for several debilitating diseases but also provide a strong tool for in vitro drug assessment and disease modelling.