Abstract Objectives The high mortality of severe 2019 novel coronavirus disease (COVID‐19) cases is mainly caused by acute respiratory distress syndrome (ARDS), which is characterized by increased permeability of the alveolar epithelial barriers, pulmonary oedema and consequently inflammatory tissue damage. Some but not all patients showed full functional recovery after the devastating lung damage, and so far there is little knowledge about the lung repair process. We focused on crucial roles of lung progenitor cells in alveolar cell regeneration and epithelial barrier re‐establishment and aimed to uncover a possible mechanism of lung repair after severe SARS‐CoV‐2 infection. Materials and methods Bronchoalveolar lavage fluid (BALF) of COVID‐19 patients was analysed by single‐cell RNA‐sequencing (scRNA‐seq). Transplantation of a single KRT5+ cell‐derived cell population into damaged mouse lung and time‐course scRNA‐seq analysis was performed. Results In severe (or critical) COVID‐19 patients, there is a remarkable expansion of TM4SF1+ and KRT5+ lung progenitor cells. The two distinct populations of progenitor cells could play crucial roles in alveolar cell regeneration and epithelial barrier re‐establishment, respectively. The transplanted KRT5+ progenitors could long‐term engraft into host lung and differentiate into HOPX+ OCLN+ alveolar barrier cell which restored the epithelial barrier and efficiently prevented inflammatory cell infiltration. Conclusions This work uncovered the mechanism by which various lung progenitor cells work in concert to prevent and replenish alveoli loss post‐severe SARS‐CoV‐2 infection. The high mortality of severe 2019 novel coronavirus disease (COVID‐19) cases is mainly caused by acute respiratory distress syndrome (ARDS), which is characterized by increased permeability of the alveolar epithelial barriers, pulmonary oedema and consequently inflammatory tissue damage. Some but not all patients showed full functional recovery after the devastating lung damage, and so far there is little knowledge about the lung repair process. Here, by analysing the bronchoalveolar lavage fluid (BALF) of COVID‐19 patients through single cell RNA‐sequencing (scRNA‐Seq), we found that in severe (or critical) cases, there is remarkable expansion of TM4SF1+ and KRT5+ lung progenitor cells. The two distinct populations of progenitor cells could play crucial roles in alveolar cell regeneration and epithelial barrier re‐establishment, respectively. In order to understand the function of KRT5+ progenitors in vivo, we transplanted a single KRT5+ cell‐derived cell population into damaged mouse lung. Time‐course single‐cell transcriptomic analysis showed that the transplanted KRT5+ progenitors could long‐term engraft into host lung and differentiate into HOPX+ OCLN+ alveolar barrier cell which restored the epithelial barrier and efficiently prevented inflammatory cell infiltration. Similar barrier cells were also identified in some COVID‐19 patients with massive leukocyte infiltration. Altogether, this work uncovered the mechanism by which various lung progenitor cells work in concert to prevent and replenish alveoli loss post severe SARS‐CoV‐2 infection
【저자키워드】 COVID‐19, lung progenitor cells, scRNA‐seq, regeneration, transplantation, 【초록키워드】 ARDS, knowledge, lung, Population, COVID‐19, 2019 novel coronavirus, Bronchoalveolar lavage fluid, Patient, Single Cell, transcriptomic analysis, in vivo, disease, epithelial, BALF, Critical, mechanism, acute respiratory distress, Analysis, Inflammatory, lung damage, tissue damage, COVID‐19 patients, syndrome, high mortality, SARS‐CoV‐2 infection, material, progenitor cells, oedema, leukocyte infiltration, alveolar, inflammatory cell infiltration, cell population, Host, objective, Prevent, Cell, Result, caused, was performed, analysed, characterized, functional, alveolar cell, prevented, restored, damaged, barrier cell, COVID‐19 patient, progenitor cell, 【제목키워드】 lung, Analysis, COVID‐19 patient, progenitor cell,