![]() ![]() 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. Clinically, the ubiquitous nature of the cAMP pathway gives rise to therapeutic possibilities within the signal transduction system to fight against diseases such as cancer, diabetes, heart failure, inflammation, neurological disorders, myocardial atrophy, and mood disorders.Ĭopyright © 2023, StatPearls Publishing LLC.A bipotential organoid model of respiratory epithelium recapitulates high infectivity of SARS-CoV-2 Omicron variant Metabolism, gene regulation, regulation of neurotransmitter synthesis, growth factors, and immune function are some examples of the numerous biological processes that utilize cAMP. cAMP can trigger a cascade of events to influence cellular function through its interaction with protein effectors such as protein kinase A (PKA), exchange proteins activated by cAMP (EPACs), cyclic nucleotide-gated ion (CNG) channels, and hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. Cyclic adenosine monophosphate is a small, hydrophilic molecule commonly known as cyclic AMP or cAMP, which is an important intracellular second messenger molecule regulated in many physiological processes. Sutherland in 1958 for which he received a Nobel prize. ![]()
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