Yu Ma
Xiaotian Dai
Tao Ren
Yingjie Fu
Wenbin Liu
Yufei Han
Yingchuan Wu
Yu Cheng
Ting Zhang
Wei Zuo
1 Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai 200433, China;
2 Southwest Hospital, Third Military Medical University of PLA, Chongqing 400038, China;
3 Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China;
4 The Institute for Biomedical Engineering and Nano Science, School of Medicine, Tongji University, Shanghai 200029, China;
5 Kiangnan Stem Cell Institute, Zhejiang 311300, China;
6 Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China
Funds: This work was funded by The National Key Research and Development Program of China (2017YFA0104600), Youth 1000 Talent Plan of China to W. Zuo, Tongji University (Basic Scientific Research-Interdisciplinary Fund and 985 Grant to W. Zuo), Shanghai Pulmonary Hospital (Annual Grant to W. Zuo), National Science Fund Committee of China (81570091 and 81770073 to W. Zuo), Academic Leadership Fund of Shanghai (16XD1403100 to T. Ren), Postdoc Grant of China (2016M601651 to Y. Ma and 2016M591716 to Q. Ma) and Kiangnan Stem Cell Institute.
Received Date: 2017-12-08
Rev Recd Date:2017-12-24
Abstract
Abstract
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.Keywords: lung,
regeneration,
transplantation,
stem cell,
bronchiectasis,
alveoli
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