Abstract

Conventional cancer and transformed cell lines are widely used in cancer biology and other fields within biology. These cells usually have abnormalities from the original tumor itself, but may also develop abnormalities due to genetic manipulation, or genetic and epigenetic changes during long‐term passages. Primary cultures may maintain lineage functions as the original tissue types, yet they have a very limited life span or population doubling time because of the nature of cellular senescence. Primary cultures usually have very low yields, and the high variability from any original tissue specimens, largely limiting their applications in research. Animal models are often used for studies of virus infections, disease modeling, development of antiviral drugs, and vaccines. Human viruses often need a series of passages in vivo to adapt to the host environment because of variable receptors on the cell surface and may have intracellular restrictions from the cell types or host species. Here, we describe a long‐term cell culture system, conditionally reprogrammed cells (CRCs), and its applications in modeling human viral diseases and drug discovery. Using feeder layer coculture in presence of Y‐27632 (conditional reprogramming, CR), CRCs can be obtained and rapidly propagated from surgical specimens, core or needle biopsies, and other minimally invasive or noninvasive specimens, for example, nasal cavity brushing. CRCs preserve their lineage functions and provide biologically relevant and physiological conditions, which are suitable for studies of viral entry and replication, innate immune responses of host cells, and discovery of antiviral drugs. In this review, we summarize the applications of CR technology in modeling host‐virus interactions and human viral diseases including severe acute respiratory syndrome coronavirus‐2 and coronavirus disease‐2019, and antiviral discovery.

Highlights

  • We focus on the applications of conditionally reprogrammed cells (CRCs) in modeling host‐virus interactions and human viral diseases, and antiviral discovery

  • The results demonstrated that these CRCs were sensitive to conventional agents and standard bladder cancer (BC) chemotherapy drugs.[114]

  • Baric lab at UNC has used for ALI cultures of human airway epithelial cells (HAEs) for functional drug screening of SARS‐CoV and SARS‐CoV‐2.137,138 To overcome the difficulties with stable source and expense of primary human normal cells and variability of donors, CRCs from airway, GI, FIGURE 3 Proposed diagram of SARS‐CoV‐2 replication and immunopathogenic injuries for COVID‐19 patients

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Summary

LIU AND MONDAL

Response to a virus infection and exposure to different environmental factors To answer this question, we need to make the difficult transition from the study of cancer cells and all the research tools that have been developed in cell biology and disease modeling to normal cells. Typical epithelial cell colonies are surrounded by feeder cells that can be visualized within 18 to 36 hours after initial plating from single‐cell suspension We termed this cell technology as “conditional reprogramming (CR),” and the resulting cells as “conditionally reprogrammed cells (CRC),” respectively.[1,3,4,5,6] As normal CRCs maintain their lineages and differentiation functions under in vitro three‐dimensional (3D) or in vivo conditions, the CR technology has been widely used in basic and translational cancer biology, disease modeling, tissue regeneration, evaluation of drug toxicity, virus infections, and so on. Organoids[7,8,9,10,11] and CR technologies have been both recognized as the key new technologies by NIH precision oncology,[12,13] and have been used

Genetic manipulation
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