Cell replacement in human lung bioengineering

Background: As the number of patients with end-stage lung disease continues to rise, there is a growing need to increase the limited number of lungs available for transplantation. Unfortunately, attempts at engineering functional lung de novo have been unsuccessful, and artificial mechanical devices have limited utility as a bridge to transplant. This difficulty is largely due to the size and inherent complexity of the lung; however, recent advances in cell-based therapeutics offer a unique opportunity to enhance traditional tissue-engineering approaches with targeted site- and cell-specific strategies.

Methods: Human lungs considered unsuitable for transplantation were procured and supported using novel cannulation techniques and modified ex-vivo lung perfusion. Targeted lung regions were treated using intratracheal delivery of decellularization solution. Labeled mesenchymal stem cells or airway epithelial cells were then delivered into the lung and incubated for up to 6 hours.

Results: Tissue samples were collected at regular time intervals and detailed histologic and immunohistochemical analyses were performed to evaluate the effectiveness of native cell removal and exogenous cell replacement. Regional decellularization resulted in the removal of airway epithelium with preservation of vascular endothelium and extracellular matrix proteins. After incubation, delivered cells were retained in the lung and showed homogeneous topographic distribution and flattened cellular morphology.

Conclusions: Our findings suggest that targeted cell replacement in extracorporeal organs is feasible and may ultimately lead to chimeric organs suitable for transplantation or the development of in-situ interventions to treat or reverse disease, ultimately negating the need for transplantation.