Bioengineering of Pulmonary Epithelium With Preservation of the Vascular Niche

Abstract

The shortage of transplantable donor organs directly affects patients with end-stage lung disease, for which transplantation remains the only definitive treatment. With the current acceptance rate of donor lungs of only 20%, rescuing even one half of the rejected donor lungs would increase the number of transplantable lungs threefold, to 60%. We review recent advances in lung bioengineering that have potential to repair the epithelial and vascular compartments of the lung. Our focus is on the long-term support and recovery of the lung ex vivo, and the replacement of defective epithelium with healthy therapeutic cells. To this end, we first review the roles of the lung epithelium and vasculature, with focus on the alveolar-capillary membrane, and then discuss the available and emerging technologies for ex vivo bioengineering of the lung by decellularization and recellularization. While there have been many meritorious advances in these technologies for recovering marginal quality lungs to the levels needed to meet the standards for transplantation -many challenges remain, motivating further studies of the extended ex vivo support and interventions in the lung. We propose that the repair of injured epithelium with preservation of quiescent vasculature will be critical for the immediate blood supply to the lung and the lung survival and function following transplantation.

Advances in lung bioengineering: Where we are, where we need to go, and how to get there

“…One of the ways to overcome the challenge of repopulating the lung with so many cell types is to de-epithelialize instead of fully decellularize the lung. In diseases that primarily affect the conducting airways, de-epithelialization may allow for autologous lung transplantation after specific removal of diseased cell populations (39). Dorrello et al describes a method of deepithelization through infusing a CHAPS detergent solution through the airways while using low tidal volume ventilation to optimize distribution of the solution through the airways which was tested and successful in rat lungs (40).…”

Advanced In Vitro Lung Models for Drug and Toxicity Screening: The Promising Role of Induced Pluripotent Stem Cells

“…[341] As an alternative, it is possible to selectively remove the epithelial component of the pulmonary airways, which can then be reseeded with iPSC-derived epithelium, while preserving a viable vasculature and basement membrane. [342,343] While, to the best of our knowledge, the latter procedure has only been tested in a rodent lung model, such a chimeric approach could allow the maintenance of iPSC-derived epithelial cells in an in vivo-like environment and the occurrence of gas and nutrient exchange between alveolar and vascular compartments, thereby constituting a potentially valuable platform to study pulmonary physiology and disease. However, the ability to bioengineer whole lungs would have incredible applications not only in in vitro modelling, where, for instance, cell-ECM communication could be more accurately represented and investigated, [188] but especially in regenerative medicine, as the only solution for serious pulmonary damage and disfunction is lung transplantation.…”

Advances in bioreactors for lung bioengineering: From scalable cell culture to tissue growth monitoring

“…It is worth mentioning that another approach to recover lungs with poor gas exchange function and prepare them for transplantation is XC with a living host. In this approach, the recovered lung is put into an EVLP‐like organ chamber, ventilated in a normothermic, humidified environment, and connected to the blood perfusion with an animal recipient, for example, swine (Dorrello & Vunjak‐Novakovic, 2020; O'Neill et al, 2017). Two important features make XC superior to EVLP: the unique physiological conditions and the length of lung support.…”