Dear Editor, The global pandemic COVID-19 caused by SARS-CoV-2 virus has infected over 6.5 million individuals and claimed over 350,000 lives worldwide within six months. The respiratory epithelial cells covering the airways and alveoli are the major targets of the virus. Moreover, damage to the epithelium can be exacerbated by mechanical ventilation. It is expected that many of the infected individuals that survived the acute phase will develop pulmonary diseases (eg fibrosis) if the epithelium fails to regenerate properly.

Multiple stem/progenitor cells have been implicated in the regeneration of the respiratory epithelium. The human trachea and intrapulmonary airways are lined by three major cell types, basal, club and ciliated cells, and the alveolar epithelium includes type 1 (AT1) and type 2 (AT2) cells. The trachea basal cells have been shown to serve as progenitor cells to self-renew and differentiate into other cell types including club, ciliated cells and minor cell populations (eg, tuft cells). 1, 2 Club cells can also dedifferentiate into basal cells to regenerate the tracheal epithelium in a mouse model where basal cells are ablated prior to injury. 3 In the intrapulmonary airways, basal cells have been postulated to serve as progenitor cells for epithelial regeneration in humans (reviewed by 4). In mice, however, club cells are responsible for repopulating the intrapulmonary airway epithelium upon injury due to their lack of basal cells in the intrapulmonary airways. 5 The cell of origin for regenerating the alveolar epithelium remains controversial. Multiple cell types have been implicated in the regeneration of the alveolar epithelium depending on injury models. These cells include AT1 and AT2 cells, bronchial-alveolar ductal cells (BASCs), distal airway stem cells (DASCs), lineage negative epithelial precursor (LNEP) cells, bronchial epithelial stem cells (BESCs), and different AT2 subpopulation cells (reviewed by 6). Although histology analysis has been performed, it remains unknown which stem/progenitor cell (s) proliferate in response to viral challenges in COVID-19 patients. Cellular entry of SARS-CoV-2 depends on the extracellular receptor Angiotensin Converting Enzyme 2 (ACE2) and the serine protease transmembrane serine protease 2 (TMPRSS2). ACE2 and TMPRSS2 are expressed in both nasal and bronchial epithelium as detected by immunohistochemistry. 7 Single cell RNA-sequencing analysis confirmed that ACE2 is enriched in the human airway epithelium including club, ciliated and goblet cells, AT1 and AT2 cells. 8, 9 ACE2 and TMPRSS2 are also co-expressed in a subpopulation of ciliated cells and AT2 cells. 8 Consistently, histology characterization revealed that SARS-CoV-2 infection induces severe damages in the intrapulmonary airways and alveoli. 10 However, detailed characterization of different respiratory cell types remains lacking for COVID-19 patients. In this report we showed that ciliated, club, AT1 and AT2 cells are the major cell types damaged by SARS-CoV-2 infection. More importantly, we