TSP1-CD47 Signaling Limits Restoration of Decellularized and Synthetic Tracheal Transplants

 描述(由申请人提供)：气管损伤和缺陷虽然不常见，但在许多情况下是致命的或致残性疾病的来源。尽管制定了修复方案，如滑动气管成形术，但仍有一批患者没有可用的治疗方法。这些患者包括先天性气管发育不全(有或没有食管瘘)的儿童患者，以及患有气管肿瘤的成年人。在这些患者中，气管移植或用生物工程移植物替代将是一种拯救生命的疗法。分泌的基质-细胞蛋白凝血酶敏感蛋白-1(TSP1)是细胞在应激状态下沉积在细胞外基质中。它与其高亲和力细胞受体CD47连接。CD7的TSP1激活通过影响血管生成和自我更新而冗余地抑制组织的存活。因此，TSP1(1)保留在细胞外基质中，或(2)由迁移到移植物中并重新填充的细胞分泌，可限制移植物和整个移植物的存活。我假设 TSP1通过细胞表面受体CD47抑制脱细胞气管移植物的细胞存活、植入和血运重建。我的目标是检验以下三个假设：(1)TSP1-CD47信号被诱导抑制脱细胞和合成气管移植的细胞恢复；(2)TSP1通过CD47抑制自我更新途径，从而限制损伤后呼吸道上皮的恢复和气道血管的形成；(3)干扰TSP1-CD47信号轴(通过使用突变的小鼠模型或治疗性阻断)可以改善原位气管移植的结果。这些目标的成功完成将为深入了解细胞-基质相互作用限制脱细胞和合成气管移植物的细胞存活和重建的新机制提供洞察力。这项提议产生的知识将支持使用CD47阻断疗法来改善组织工程移植的结果。

 DESCRIPTION (provided by applicant): 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.