Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, 200433, China.
Kiangnan Stem Cell Institute, Zhejiang, 311300, China.
Protein Cell. 2018 Mar;9(3):267-282. doi: 10.1007/s13238-018-0506-y. Epub 2018 Jan 17.
Irreversible destruction of bronchi and alveoli can lead to multiple incurable lung diseases. Identifying lung stem/progenitor cells with regenerative capacity and utilizing them to reconstruct functional tissue is one of the biggest hopes to reverse the damage and cure such diseases. Here we showed that a rare population of SOX9 basal cells (BCs) located at airway epithelium rugae can regenerate adult human lung. Human SOX9 BCs can be readily isolated by bronchoscopic brushing and indefinitely expanded in feeder-free condition. Expanded human SOX9 BCs can give rise to alveolar and bronchiolar epithelium after being transplanted into injured mouse lung, with air-blood exchange system reconstructed and recipient's lung function improved. Manipulation of lung microenvironment with Pirfenidone to suppress TGF-β signaling could further boost the transplantation efficiency. Moreover, we conducted the first autologous SOX9 BCs transplantation clinical trial in two bronchiectasis patients. Lung tissue repair and pulmonary function enhancement was observed in patients 3-12 months after cell transplantation. Altogether our current work indicated that functional adult human lung structure can be reconstituted by orthotopic transplantation of tissue-specific stem/progenitor cells, which could be translated into a mature regenerative therapeutic strategy in near future.
不可逆性的支气管和肺泡破坏可导致多种不可治愈的肺部疾病。鉴定具有再生能力的肺干/祖细胞，并利用它们来重建功能性组织，是逆转损伤和治疗此类疾病的最大希望之一。在这里，我们发现位于气道上皮皱襞的 SOX9 基底细胞 (BC) 这一稀有群体可使成人肺再生。通过支气管镜刷检可以轻易地分离出人 SOX9 BC，并在无饲养层的条件下无限扩增。扩增后的人 SOX9 BC 可在移植到受损的小鼠肺中后产生肺泡和细支气管上皮，重建气-血交换系统并改善受者的肺功能。用吡非尼酮对肺微环境进行操作以抑制 TGF-β 信号通路可进一步提高移植效率。此外，我们在两名支气管扩张症患者中进行了首例自体 SOX9 BC 移植临床试验。细胞移植后 3-12 个月，患者的肺组织修复和肺功能增强。总而言之，我们目前的工作表明，通过组织特异性干细胞/祖细胞的原位移植可以重建功能性成人肺结构，这可能在不久的将来转化为一种成熟的再生治疗策略。
