肺气道干细胞促进支气管胸膜瘘闭合的临床前研究

支气管胸膜瘘(BPF)是胸外科术后严重并发症，是临床上的较为棘手的问题。文献和我们发表的结果均显示间充质干细胞（MSCs）能够促进BPF闭合。然而MSCs缺乏肺组织细胞的定向分化能力，需依靠其旁分泌作用促进BPF瘘口处胶原纤维的增生，从而达到闭合瘘口的治疗目的，因而其临床治疗BPF的有效性低，急需建立一个有效的肺组织干细胞治疗方法。本项目将在国际上首先制备兔自体“无突变无外源性编程因子”的诱导性多能干细胞（riPSCs），然后借助我们课题组已经建立基因筛选-定向分化技术的优势，分别诱导riPSCs定向分化出Nkx2.1+肺内胚层早期干细胞和Nkx2.1+p63+气管基底细胞，继而通过兔BPF模型首次探讨肺内胚层早期干细胞和肺气管基底干细胞治疗BPF的有效性，为研发严重性BPF的干细胞治疗开辟新途径，为临床转化提供实验依据。

Bronchial pleural fistula (BPF) is a serious complication after thoracic surgery. Both the literature and our published results show that mesenchymal stem cells (MSCs) can promote BPF closure. However, due to MSCs lack the ability to differentiate into lung tissue cells, they need to rely on their paracrine effect to promote the proliferation of collagen fibers at the BPF, so as to achieve the purpose of closing the fistula. Therefore, the effectiveness of clinical treatment of BPF is low, and there is a pressing need to establish a novel treatment of BPF with lung stem cells. This project will be the first to prepare rabbit autologous “random-integration-free and exogenous reprogramming-factor-free” induced pluripotent stem cells (riPSCs) internationally, and then take advantage of the gene selection strategy that we have established to direct the riPSC differentiation into Nkx2.1 + early lung endoderm stem cells or Nkx2.1 + p63 + tracheal basal cells. By using the rabbit BPF model, for the first time we will explore the effectiveness of early lung endoderm stem cells and lung tracheal basal stem cells in the treatment of BPF, opening a new way for the development of stem cell treatment of severe BPF, and providing experiments for clinical transformation in accordance with.