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.Electronic supplementary materialThe online version of this article (10.1007/s13238-018-0506-y) contains supplementary material, which is available to authorized users.

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Pseudomonas aeruginosa strain 10265 was recovered from a patient with pneumonia in a Chinese public hospital, and it displays the carbapenem resistance phenotype due to the acquisition of a non-conjugative but mobilizable IncP-6-type plasmid p10265-KPC. p10265-KPC carries a Tn 5563 -borne defective mer locus, and a novel ΔIS Ec33 -associated bla KPC-2 gene cluster without paired inverted repeats and paired direct repeats at both ends. Mobilization of this ΔIS Ec33 -associated element in p10265-KPC would be attributed to homologous recombination-based insertion of a foreign structure Tn 3- IS Apu1 - orf7 -IS Apu2 - IS Kpn27- Δ bla TEM-1 -bla KPC-2 - ΔIS Kpn6- korC-orf6 - klcA- Δ repB into a pre-existent intact IS Ec33 , making IS Ec33 truncated at the 3′ end. The previously reported pCOL-1 represents the first sequenced KPC-producing IncP-6 plasmid, while p10265-KPC is the second one. These two plasmids carry two distinct bla KPC-2 gene clusters, which are inserted into the different sites of the IncP-6 backbone and have different evolutionary histories of assembly and mobilization. This is the first report of identification of the IncP-6-type resistance plasmid in China.

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