Application of Embryonic stem cells in drug discovery

Ananya Ghosal, MAKAUT (WB)

Teratogenicity is tested for use in the patient with childbearing potential before marketing. Animal-free in-vitro models allow fast selection of lead compounds which further contribute to 3R’s principle i.e., Refine, Replace and reduce by smoothly selecting the compounds that are submitted for the regulatory studies in animals. Disorganized 3D structures and adherent monolayer cultures lack morphological and spatiotemporal context for the developing embryo in which in-vitro models are dependent. The 3D gastruloid model can predict teratogenicity by giving a robust recapitulation of gastrulation-like stages. The human and mouse gastruloids were studied to examine seven reference compounds, related to teratogenic risk and in-vivo data for evaluating in-vitro teratogenicity. Several gross morphological effects have been observed which also include reduced elongation or decreasing the size of gastruloids by exposing them to multiple reference compounds. Divergent gene expression has been observed by using fluorescent reporters which includes SOX17, BRA and SOX2, suggestive of disrupted axial patterning and multiple lineage differential defects. The gastruloids reiterate some in-vivo species-specific susceptibilities between human and mouse counterparts. 

Proof-of-concept study

According to a proof-of-concept study, demonstrations of 3D models made from embryonic stem cells have been shown which can be used as a part of the testing process assessing if the treatment and drugs are safe for developing embryos. Multiple stages of testing are followed before approving pharmaceuticals that are safe for pregnant women, which also includes testing of drugs to find if they are safe during pregnancy in animal trials. The experiments are supplemented as pharmaceutical companies have started to develop stem cell tests to predict before time outcomes in the drug development pipeline. Moreover, the stem cells are arranged in single layers instead of the complex 3D arrangement which is noticed in developing embryos. 

The predictive potential of 3D models of embryonic stem cells is known as Gastruloids. Under precise conditions, the models, when grown, arrange themselves into similar order as certain parts of developing embryos. Testing the effects of seven pharmaceutical compounds that includes penicillin, thalidomide and ibuprofen, on both human and mouse gastruloids. Observations were made that the gastruloids respond to the compounds which are similar to the known embryo reactions, which provide evidence of adoption in pharmaceutical testing in the end. This would help to establish if the compounds are safe or not and could also help to improve the selection of which compounds need to move forward into animal trials. The stem cell and human development laboratory’s leader Naomi Moris stated that “existing drug safety tests are robust and effective” whereas gastruloid offers a cell-based model which is similar to the structure of embryos, that could help to limit the number of compounds moving forward to the animal test. 

Advantages and disadvantages of using the cells for drug screening:

Advantages:

• Continuous in vitro propagation and sustaining the potential to generate embryonic stem cells.
• To achieve a desired biological effect compounds can regulate more than one target.
• Large quantity of stem cells.
• The available source of all cell types.

Disadvantages:

• Lineages are restricted and the expansion potential is limited.
• Expensive growth and maintenance.
• It takes more time to get fully differentiated cell types.
• It takes more effort to get a purified population.

Also read: Can Marine animals drown?

Reference:

1. APA: Mantziou, V., Baillie-Benson, P., Jaklin, M., Kustermann, S., Arias, A. M., & Moris, N. (2021). In vitro teratogenicity testing using a 3D, embryo-like gastruloid system. Reproductive Toxicology, S0890623821001301. https://doi.org/10.1016/j.reprotox.2021.08.003
2. Institute, T. F. C. (n.d.). How embryo-like stem cell models could be used in drug safety tests. Retrieved August 28, 2021, from https://phys.org/news/2021-08-embryo-like-stem-cell-drug-safety.html

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