Project 461948

Cancer, trauma and narrowing of long segments of the airway are very difficult to reconstruct and require novel solutions. Attempts at transplantation of donor airway and tissue engineered constructs have faced two major challenges: (1) inability to produce cells which resemble the native airway therefore leading to further narrowing and (2) rejection of these transplants leading to their failure. Thus, there is a clinical need for functional airway grafts that do not induce rejection and do not require patients to be on anti-rejection medication. Genetic engineering of a specific type of stem cells called induced pluripotent stem cells (IPS) has allowed for the development of a population which can both be safe and prevent rejection. This population of cells, which we term safe cells, has multiple applications. Herein we propose to use safe cells to generate transplantable airway grafts. We have previously shown that smaller airway patches made with human safe cells are well accepted in a preclinical animal model. We will further characterize the cells and the airway patches for immunological properties and ensure that they are non-immunogenic. We hypothesize that larger tracheal grafts can be repopulated with the non-immunogenic human safe cells and will not induce an immune response. These will be evaluated in a preclinical pig tracheal transplantation model. These animals will be allowed to survive both short term and long term. The short term survival will indicate whether these grafts are rejected while the long term survival will indicate how they behave and how they integrate with our native airway. The use of universal non-immunogenic airway grafts has vast clinical implications not only for the trachea but also for other organs involved in breathing, voice production and swallowing.