Human induced pluripotent stem cell-derived salivary gland organoids model SARS-CoV-2 infection and replication

Abstract

Salivary glands act as virus reservoirs in various infectious diseases and have been reported to be targeted by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, the mechanisms underlying infection and replication in salivary glands are still enigmatic due to the lack of proper in vitro models. Here, we show that human induced salivary glands (hiSGs) generated from human induced pluripotent stem cells can be infected with SARS-CoV-2. The hiSGs exhibit properties similar to those of embryonic salivary glands and are a valuable tool for the functional analysis of genes during development. Orthotopically transplanted hiSGs can be engrafted at a recipient site in mice and show a mature phenotype. In addition, we confirm SARS-CoV-2 infection and replication in hiSGs. SARS-CoV-2 derived from saliva in asymptomatic individuals may participate in the spread of the virus. hiSGs may be a promising model for investigating the role of salivary glands as a virus reservoir.Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and spreads quickly worldwide. The main target organs of SARS-CoV-2 are considered to belong to the respiratory system, including the lungs and upper respiratory tract, but accumulating evidence has shown that multiple organs, such as the heart, kidneys, liver, spleen and gastrointestinal tract, can be affected 1 . SARS-CoV-2-infected individuals are a potential source of virus transmission, which occurs through aerosol droplets, close contact and facial-oral transmission 2 . The majority of infected individuals (approximately 80%) are asymptomatic and have the ability to spread the virus 3 . It was recently reported that saliva from asymptomatic individuals with COVID-19 can be a potential source of viral transmission 4 . SARS-CoV-2 has been identified in the oral mucosa and salivary glands of patients with COVID-19. The viral entry factors

Bioengineered Salivary Gland Microtissues─A Review of 3D Cellular Models and their Applications

“…It was only recently that iPSC-derived SG organoids were developed for use as in vitro models to study viral replication in SG organoids and for in vivo transplantation. 75 In an effort to gain deeper insights into the niche requirements of embryonic SMGs, Hosseini et al conducted experiments where E16 SMG cells were cultured under various conditions, including co-culture with fibroblast cells, mesenchymal cell derived condition media, or embryonic SG mesenchyme. 76 Their findings indicate that E16 epithelial cells cultured with their mesenchymal counterparts in the presence of FGF2 signaling exhibited robust expression of progenitor markers, including Kit proteins, and acinar marker AQP5 in SG organoids.…”

Development trends of human organoid‐based COVID‐19 research based on bibliometric analysis

“…Reproduced with permission. 92 Copyright 2022, Springer Nature. facilitated SARS-CoV-2 entry into host cells by promoting viral spike fusogenic activity.…”

“…(F) SARS‐CoV‐2 infected salivary gland organoids. Reproduced with permission 92 . Copyright 2022, Springer Nature.…”

“…It was recently reported that saliva could be a potential source of SARS‐CoV‐2 transmission due to the virus being identified in the salary glands of COVID‐19 patients 60 . Indeed, salivary glands express ACE2 and TMPRSS2 and serve as reservoirs of viruses 60,92,118 . Tanaka and colleagues generated salivary gland organoids (SGOs) from hiPSCs to model SARS‐CoV‐2 infection of salary glands (Figure 5F).…”

Angiotensin Converting Enzyme 2 (ACE2) - A macromolecule and its impact on human reproduction during COVID-19 pandemic

“…Many on-going and completed research works on ACE2 and its expression studies on the prostate shows that the prostate is most susceptible to COVID 19 infection (Song et al 2020;Abdolmaleki et al 2022). The double-positive cells with both ACE2 and TMPRSS2 expression can act as a medium or reservoir of COVID 19 infection (Singh et al 2020;Tanaka et al 2022). This, in turn, damages the prostate gland to some extent.…”