Progenitor Cells in Airway Repair

描述(由申请人提供)：肺移植通常是终末期肺部疾病唯一可行的治疗选择。不幸的是，肺移植伴随着许多严重的并发症，包括急性排斥反应和闭塞性细支气管炎综合征(BOS)。研究表明，免疫介导的呼吸道上皮细胞损伤和丢失在BOS的发病机制中起关键作用。因此，以这种生物学为靶点可以为开发预防肺移植排斥反应的新治疗策略提供重大突破。我们已经确定了循环上皮祖细胞(CEPC)，它们被招募到受损的呼吸道并帮助修复上皮。这些细胞表达细胞角蛋白5，这是呼吸道内祖细胞基底上皮细胞的标志，并通过CXCR4/CXCL12生物轴进行运输。与CEPC在呼吸道修复中的重要性一致，用CXCL12中和抗体阻断CEPC的募集导致鳞状化生的表型。这意味着循环和驻留在气道壁龛的祖细胞之间的相互作用对正常的呼吸道修复至关重要。我们推测，肺移植后促进受体CEPC植入供体呼吸道上皮将改善上皮修复，减少对供体肺的同种异体识别，最终减少BOS。这项建议的目的是：1)通过选择性地消除驻留和循环上皮祖细胞在BOS发展中的作用；2)检测CEPC的增强动员对BOS发展的影响；3)使用患者肺移植的血液样本来确定CEPC是否与患者的预后相关。拟议的研究将有助于进一步了解上皮祖细胞在呼吸道中的作用，并将能够利用CEPC的治疗潜力。与公共卫生相关：成人干细胞对肺的修复有着很大的希望，我们已经在血液中发现了有助于肺修复的成人干细胞。许多终末期肺部疾病患者接受肺移植，但与许多并发症相关。我们推测，肺移植后动员成人干细胞将促进受损供体肺的修复，减少肺移植的并发症。我们计划在临床前模型和肺移植患者样本中测试这一假设。

DESCRIPTION (provided by applicant): Lung transplantation is often the only viable therapeutic option for end-stage pulmonary disorders. Unfortunately, lung transplantation is associated with numerous serious complications including acute rejection and bronchiolitis obliterans syndrome (BOS). Studies have indicated that immune-mediated injury and loss of airway epithelial cells is critical in the pathogenesis of BOS. Targeting this biology could therefore provide a major breakthrough for developing new therapeutic strategies for preventing rejection in lung transplantation. We have identified circulating epithelial progenitor cells (CEPC) that are recruited to the injured airway and aid in repair of the epithelium. These cells express cytokeratin 5, a marker of progenitor basal epithelial cells in the airway, and traffic via the CXCR4/CXCL12 biological axis. Consistent with the importance of CEPC in airway repair, blocking the recruitment of CEPC with neutralizing antibodies to CXCL12 resulted in the phenotype of squamous metaplasia. This implies that the interaction between circulating and resident progenitor epithelial cells in the airway niche is critical for normal airway repair. We hypothesize that enhancing engraftment of recipient CEPC into donor airway epithelium after lung transplantation will improve epithelial repair, result in less allo-recognition of the donor lung and ultimately reduce BOS. The goal of this proposal is to: 1) investigate the role of resident and circulating epithelial progenitor cell populations in the development of BOS by selectively eliminating these cell populations, 2) examine the effect of enhanced mobilization of CEPC on the development of BOS and 3) use patient lung transplant blood samples to determine whether CEPC correlate with patient outcome. The proposed studies will allow further understanding of the role of epithelial progenitor cells in the airway and will enable the harnessing of the therapeutic potential of CEPC. PUBLIC HEALTH RELEVANCE: Adult stem cells hold great promise for repair of the lungs and we have discovered adult stem cells in the blood that contribute to repair of the lungs. Lung transplants are performed for many patients with end stage lung diseases, but are associated with many complications. We hypothesize that mobilizing adult stem cells after lung transplantation will improve the repair of the injured donor lungs and reduce the complications of lung transplantation. We plan to test this hypothesis in preclinical models and in lung transplant patient samples.