![]() ![]() Organoids derived from pluripotent stem cells (PSCs), such as embryonic stem cells and induced pluripotent stem cells, as well as organ-specific adult stem cells (ASCs), can simulate key structural and functional properties of tissues of interest 13. However, the limited proliferative capacity of primary cells 12 in vitro restricts their utility in routine experimentation for in-depth characterization of SARS-CoV-2 infection. Thus, the in vitro cultivated primary airway and alveolar epithelial cells are harnessed to delineate SARS-CoV-2 infection 9, 10, 11. However, these homogeneous cell lines are unable to simulate the multicellular complexity and functional diversity of human respiratory epithelia, let alone model respiratory infections. Currently, immortalized cell lines such as A549 or Calu3 are commonly utilized to study respiratory viruses, including SARS-CoV-2. AT1 cells are involved in gas exchange, while AT2 cells synthesize, secrete, and recycle surfactants to regulate the alveolar surface tension and maintain alveolar stability. The human alveolar sac, the basic unit of oxygen exchange, is lined with alveolar epithelium, which is composed of flat type I alveolar epithelial (AT1) cells and cuboidal type II alveolar epithelial (AT2) cells. The former lines the airways from the nasal cavity (except nasal vestibule) to the terminal bronchiole, and consists of four major types of epithelial cells, i.e., ciliated, goblet, club, and basal cells. The human respiratory tract is lined with two distinct types of epithelium, i.e., airway and alveolar epithelium. Indeed, airway ciliated cells and alveolar epithelial cells are the target cells in COVID-19 patients and SARS-CoV-2-infected nonhuman primates 5, 6, 7, 8. Yet, viral pneumonia suggests that alveoli in the distal respiratory tract are also susceptible to the virus. ![]() The respiratory epithelium, particularly the airway epithelium, is the primary infection site of SARS-CoV-2. COVID-19 patients develop a broad spectrum of symptoms, ranging from mild upper respiratory illness to fatal pneumonia 3, 4. Compelling evidence indicated its notably increased transmission rate 2. The recently emerged Omicron variant (B.1.1.529) surged quickly and produced a tsunami of COVID-19 cases worldwide. SARS-CoV-2 has evolved constantly since late 2020. The COVID-19 pandemic caused by SARS-CoV-2 has posed an unprecedented threat to public health globally 1. In conclusion, we have established a bipotential organoid culture system able to reproducibly expand the entire human respiratory epithelium in vitro for modeling respiratory diseases, including COVID-19. Notably, the higher infectivity and replicative fitness of the Omicron variant than an ancestral strain were accurately recapitulated in these optimized airway organoids. Upon differentiation under a slightly acidic pH, the 2D airway organoids exhibit enhanced viral replication, representing an optimal in vitro correlate of respiratory epithelium for modeling the high infectivity of SARS-CoV-2. We further optimized 2-dimensional (2D) airway organoids. ![]() Moreover, alveolar organoids sustain a productive SARS-CoV-2 infection, albeit a lower replicative fitness was observed compared to that in airway organoids. AT2 cells maintained in lung organoids serve as progenitor cells from which alveolar organoids derive. The alveolar organoids consisting of type I and type II alveolar epithelial cells (AT1 and AT2, respectively) functionally simulate the alveolar epithelium. Here we defined a ‘distal’ differentiation approach to generate alveolar organoids from the same source for the derivation of airway organoids. However, a respiratory organoid system with bipotential of the airway and alveolar differentiation remains elusive. We previously established long-term expanding human lung epithelial organoids from lung tissues and developed a ‘proximal’ differentiation protocol to generate mucociliary airway organoids. The airways and alveoli of the human respiratory tract are lined by two distinct types of epithelium, which are the primary targets of respiratory viruses. A bipotential organoid model of respiratory epithelium recapitulates high infectivity of SARS-CoV-2 Omicron variant ![]()
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