Monday Article #12: Organoids

By definition, an organoid is a three-dimensional construct composed of multiple cell types that originates from stem cells by means of self-organisation and is capable of simulating the architecture and functionality of native organs. To study disease, human development and drug therapies, investigators have traditionally used either 2-dimensional cell cultures, or animal models - both of which have limitations. Hence, organoids are a new research tool derived from human pluripotent or adult stem cells, or somatic cells in vitro to form small, self organising three-dimensional structures that simulate many of the functions of native organs. However, this article will focus more on stem-cell organoids and less on somatic-cell organoids due to its limited availability, expandability, and throughput of tissues needed.


Intestinal, hepatic, endometrial, renal and other organoids have been created from adult stem and progenitor cells, and cortical brain organoids among other organoids have been created from pluripotent stem cells. Successful organoid formation requires the careful orchestration of spatial temporal cues from growth factors and supportive matrices to stimulate the niches particular to each organ type.


Advantages


There are a few advantages in regards to using the resulting organoids. For instance, as compared with traditional 2-dimensional cell cultures, the 3-dimensional nature of organoids can more closely mimic natural and physiological processes, including stem- cell differentiation, cellular movement, and cell-cell interactions. They can also display near-physiologic cellular composition and behaviours. In addition, most organoids can undergo extensive expansion and culture while maintaining the genomic stability, making long term storage (biobanking) and high-throughput screening possible.





Fig 1. High through-put screening








Fig 2. Biobanking





As compared with animal models, organoids reduce experimental complexity, are amenable to live imaging techniques and can, in some instances, provide a more accurate model of human development and disease. For example, renal organoids have been used to demonstrate how high-throughput screening of chemicals can reveal new pathways involved in cyst formation in polycystic kidney disease. Researchers have also created organoids from various primary tumour types, which can be used to study the tumour niche and have the potential for use in anticancer drug screening. Organoids, combined with other technologies, such as testing drug toxicity through organs on a chip system, or testing genes and cell therapies like transplanting organoids are two further applications in development.



Current challenges


Despite these advances, many challenges to the use of organoids in research remain. These include limited standardisation of growth methods, limitations in the physiological accuracy of the tissue architecture, lack of vascular and neural inputs in the resulting organoids, absence of increased interstitial pressure characteristic of tumours in vivo. Researchers are seeking to overcome such challenges, and with time, standardised protocol should be feasible hence a more accurate simulation of human physiology with organoids technology may become a reality.




Identifying Drug Toxicity


Organ toxicity is the primary reason for failures in drug development and postapproval withdrawals. Current toxicology screens that use cell lines and animal models often do not predict adverse effects in humans, in whom renal and hepatic toxicities are among the most common. Three-dimensional organoids may offer more accurate means of toxicity prediction. Encouragingly, kidney organoids have been shown to recapitulate the nephrotoxic effects of cisplatin and gentamicin. The use of organoids has undeniably been more prevalent in real-life applications. For example, the Food and Drug Administration (FDA) has recently started testing three-dimensional “liver-on-a-chip” constructs to screen for the hepatic toxicity of compounds used in food additives, nutritional supplements, and cosmetics.





Tissue Architecture of Organoids



Organoid cultures rely on self-organisation that sometimes results in abnormal tissue architectures. These may be improved by providing a scaffold made of biomaterials or printed with bioinks, which has been used to print three-dimensional renal proximal tubules in a perfusable tissue chip. Such organ chip systems that combine microfluidics and organoids provide precise control over biomechanical variables and the delivery of bioactive molecules. However, such real-time monitoring capabilities are generally lacking in current studies of organoids. The development of such techniques will require close collaboration between engineers and developmental biologists. In the future, the pace of discovery may be accelerated by commercial platforms for biomaterials and bioprinting. Organoid technology has also been effectively integrated with other cutting edge technologies, shown above.


References

https://www.drugtargetreview.com/article/48244/what-are-the-pros-and-cons-of-using-organoids/

https://www.nejm.org/doi/full/10.1056/NEJMra1806175

Fig1: https://www.ddw-online.com/hts-a-strategy-for-drug-discovery-900-200008/

Fig 2: https://www.genengnews.com/insights/biobanking-can-boost-scientific-productivity/


Joyce Ong



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