Recent Advances of COVID-19 Modeling Based on Regenerative Medicine

Abstract

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) has caused a pandemic since December 2019 that originated in Wuhan, China. Soon after that, the world health organization declared Coronavirus disease-2019 a global health concern. SARS-CoV-2 is responsible for a lethal respiratory infection as well as the involvement of other organs due to its large tropism spectrum such as neurologic, cardiovascular, endocrine, gastrointestinal, and renal systems. Since the behavior of the virus is not fully understood, a new manifestation of the infection is revealed every day. In order to be able to design more efficient drugs and vaccines to treat the infection, finding out the exact mechanism of pathogenicity would be necessary. Although there have been some big steps toward understanding the relevant process, there are still some deficiencies in this field. Accordingly, regenerative medicine (RM), can offer promising opportunities in discovering the exact mechanisms and specific treatments. For instance, since it is not always possible to catch the pathophysiology mechanisms in human beings, several modeling methods have been introduced in this field that can be studied in three main groups: stem cell-based models, organoids, and animal models. Regarding stem cell-based models, induced pluripotent stem cells are the major study subjects, which are generated by reprogramming the somatic stem cells and then directing them into different adult cell populations to study their behavior toward the infection. In organoid models, different cell lines can be guided to produce a 3D structure including liver, heart, and brain-like platforms. Among animal models, mice are the most common species in this field. However, in order for mice models to be permissive to the virus, angiotensin-converting enzyme 2 receptors, the main receptor involved in the pathogenicity of the virus, should be introduced to the host cells through different methods. Here, the current known mechanism of SARS-CoV-2 infection, different suggested models, the specific response toward different manipulation as well as challenges and shortcomings in each case have been reviewed. Finally, we have tried to provide a quick summary of the present available RM-based models for SARS-CoV-2 infection, as an essential part of developing drugs, for future therapeutic goals.

Induced pluripotent stem cells: Generation methods and a new perspective in COVID-19 research

“…Table 1 indicates a summary of cellular models of COVID-19 using pluripotent stem cells. Two-dimensional cell cultures of various cell line models such as Caco-2, Calu-3, HEK293T, Vero, and Huh7 appear to more accurately simulate the pathophysiology of SARS-CoV-2 infection in the apical membrane of cells (where SARS-CoV-2 infection occurs), compared to 3D cultures such as organoids (Takayama, 2020;Larijani et al, 2021). Higher virus titers have been observed in 2D constructs compared to 3D organoids, hence, they appear more useful for testing antiviral agents.…”

“…The problem with using mice to model SARS-CoV-2 is that they show resistance to SARS-CoV-2, which can be overcome by introducing the human ACE2 receptor (hACE2) into the cells via an adenovirus. Ferrets, dogs, and cats that are susceptible to SARS-CoV-2 have also been used to model SARS-CoV-2 ( Larijani et al, 2021 ). Modeling of SARS-CoV-2 infection has also been performed with golden Syrian hamsters which developed clinical symptoms of the disease, transmitted the virus through aerosols to other animals, and induced neutralizing antibody responses, which led to the identification of therapeutic strategies against SARS-CoV-2 infection.…”

“…Higher virus titers have been observed in 2D constructs compared to 3D organoids, hence, they appear more useful for testing antiviral agents. Moreover, because the apical portion of the cells is exposed to air in 2D cultures (in contrast to organoids where the cellular apex is inside), 2D cultures are more suitable for studying virus pathogenesis ( Larijani et al, 2021 ).…”

“…On the contrary, organoids have a higher advantage in disease modeling compared to in vitro as well as in vivo models, which can be attributed to the higher speed of this modeling strategy. Organoids enable the comparison of different SAR-CoV-2 strains and their susceptibility to vaccines and drugs ( Larijani et al, 2021 ). Finally, another advantage of organoids is their ability to provide reliable molecular assessment of differences in viral susceptibility in different individuals and races ( Larijani et al, 2021 ).…”

“…Organoids enable the comparison of different SAR-CoV-2 strains and their susceptibility to vaccines and drugs ( Larijani et al, 2021 ). Finally, another advantage of organoids is their ability to provide reliable molecular assessment of differences in viral susceptibility in different individuals and races ( Larijani et al, 2021 ).…”