A novel coronavirus SARS-CoV-2 was identified in Wuhan, Hubei Province, China in December of 2019. According to WHO report, this new coronavirus has resulted in 76,392 confirmed infections and 2,348 deaths in China by 22 February, 2020, with additional patients being identified in a rapidly growing number internationally. SARS-CoV-2 was reported to share the same receptor, Angiotensin-converting enzyme 2 (ACE2), with SARS-CoV. Here based on the public database and the state-of-the-art single-cell RNA-Seq technique, we analyzed the ACE2 RNA expression profile in the normal human lungs. The result indicates that the ACE2 virus receptor expression is concentrated in a small population of type II alveolar cells (AT2). Surprisingly, we found that this population of ACE2-expressing AT2 also highly expressed many other genes that positively regulating viral entry, reproduction and transmission. This study provides a biological background for the epidemic investigation of the COVID-19, and could be informative for future anti-ACE2 therapeutic strategy development.

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.

Idiopathic pulmonary fibrosis is characterized by loss of lung epithelial cells and inexorable progression of fibrosis with no effective and approved treatments. The distal airway stem/progenitor cells (DASCs) have been shown to have potent regenerative capacity after lung injury. In this work, we aimed to define the role of mouse DASCs (mDASCs) in response to bleomycin-induced lung fibrosis in mice. The mDASCs were isolated, expanded in vitro, and labeled with GFP by lentiviral infection. The labeled mDASCs were intratracheally instilled into bleomycin-induced pulmonary fibrosis mice on day 7. Pathological change, collagen content, α-SMA expression, lung function, and mortality rate were assessed at 7, 14, and 21 days after bleomycin administration. Tissue section and direct fluorescence staining was used to show the distribution and differentiation of mDASCs in lung. The transplanted mDASCs could incorporate, proliferate, and differentiate into type I pneumocytes in bleomycin-injured lung. They also inhibited fibrogenesis by attenuating the deposition of collagen and expression of α-SMA. In addition, mDASCs improved pulmonary function and reduce mortality in bleomycin-induced pulmonary fibrosis mice. The data strongly suggest that mDASCs could ameliorate bleomycin-induced pulmonary fibrosis by promotion of lung regeneration and inhibition of lung fibrogenesis.

Adult lung resident stem/progenitor cells, including P63 ⁺ progenitor cells, have demonstrated the capacity for regeneration of lung epithelium in preclinical models. Here, we report a clinical trial of intrapulmonary P63 ⁺ progenitor cell transplantation in 28 participants with stage II to IV chronic obstructive pulmonary disease (COPD). Autologous P63 ⁺ progenitor cells were isolated from the airway basal layer of participants in the intervention group via bronchoscopic brushing, cultured for 3 to 5 weeks, and then transplanted back into the lungs via bronchoscopy at 0.7 × 10 ⁶ to 5.2 × 10 ⁶ cells per kilogram of body weight. Twenty patients were evaluable at the end of the study (intervention group, n = 17; control group, n = 3). No grade 3 to 5 adverse events (AEs) or serious AEs occurred. Although bronchoscopy-associated AEs were recorded in participants in the intervention group, other AEs were not substantial different between groups. Twenty-four weeks after transplantation, participants in the intervention group displayed improvement in gas transfer capacity [diffusing capacity of the lung for carbon monoxide (DLCO) change from baseline: +18.2%], whereas the control group experienced a decrease (DLCO change from baseline: −17.4%; P = 0.008). Furthermore, participants in the intervention group showed >30-meter increase in walking distance within 6 minutes. Transcriptomic analysis of progenitor cells isolated from responding and nonresponding individuals in the intervention group showed that higher expression of P63 was associated with treatment efficacy. In conclusion, transplantation of cultured P63 ⁺ lung progenitor cells was safe and might represent a potential therapeutic strategy for COPD.