Tracheal injuries and defects though uncommon are in many instances fatal or a source of crippling morbidity. Despite the development of reparative protocols such as slide tracheoplasty, there remains a population of patients for which there are no therapies available. These include pediatric patients with congenital tracheal agenesis (with or without an esophageal fistula), and adults with tracheal tumors. In these patients, tracheal transplantation or replacement with a bioengineered graft would be a life-saving therapy. The secreted matrix-cellular protein thrombospondin-1 (TSP1) is deposited in the extracellular matrix by cells under stress. It ligates with its high affinity cell receptor, CD47. TSP1 activation of CD7 redundantly inhibits tissue survival through effects on angiogenesis and self-renewal. Thus, TSP1 which is (1) retained in the extracellular matrix, or (2) is secreted by cells migrating into and repopulating such grafts, can limit the survival of grafts and whole transplants. I hypothesize that TSP1, via cell-surface receptor CD47, inhibits cellular survival, engraftment, and revascularization within decellularized tracheal grafts.
I aim to test the following three sub-hypothesis: (1) that TSP1-CD47 signaling is induced to inhibit cellular restoration of decellularized and synthetic tracheal transplants, (2) that TSP1, via CD47, inhibits self-renewal pathways to limit recovery of the airway epithelium and airway angiogenesis after injury, and (3) that interference with the TSP1-CD47 signaling axis (via the use of mutant mouse models or therapeutic blockade) can improve outcomes in orthotopic tracheal transplantation. Successful completion of these aims will provide insight into a novel mechanism by which cell-matrix interactions limit cell survival and reconstitution of decellularized and synthetic tracheal grafts The knowledge generated by this proposal will support the use of CD47-blocking therapeutics to improve outcomes in tissue engineered transplants.
Tracheal insufficiency represents a chronic and potentially fatal process. There exists a cohort of patients for whom tracheal transplant or tracheal replacement with a tissue engineered graft could be a life-saving therapy. Bioengineered tracheal transplants could potentially fill this void but initial results via this technology have een uniformly unsuccessful for reasons yet to be determined. The studies described in this proposal will further elucidate the role of TSP1-CD47 signaling in limiting cell and composite tissue survival through its effects on angiogenesis and self-renewal. Insights gained will be applied to bioengineered tracheal transplants. Further, these studies will likely provide applicable insight t multiple engineered transplants.
