Hello everyone and welcome to this week's blog post. In this article, I will be discussing organoids. I will first explain what organoids are and how they are made, before moving on to explain their use in biomedical research.
What are organoids?
According to the Harvard Stem Cell Institute, organoids are complex, small, 3D tissues which are constructed from stem cells in vitro. These structures can be constructed to mimic most of the complex biochemical reactions that occur in an organ. Alternatively, organoids can be created that focus on one particular type of cell found in the organ.
The process by which organoids are manufactured significantly impacts their complexity and their usage. Organoids are grown from stem cells. Under the right conditions in a laboratory or in the body, these stem cells can be induced to differentiate into other, specialised cells. By manipulating the division of these stem cells, structures such as tissues and miniature organs can be grown. This in turn then affects the complexity of the structure produced.
One method to produce organoids begins by harvesting pluripotent stem cells. These are stem cells which have to ability to divide an unlimited number of times to form many different types of cell. The pluripotent stem cells are then provided nutrients and the necessary conditions for growth before being given simple instructions to divide. This allows the cells to organise themselves into the correct structure.
Scientists can also use existing knowledge of the structure of organs to stimulate cellular growth in certain areas. For example, according to Nature America, organoids that represent specific regions of the brain can be produced by stimulating stem cells to form these specific structures.
These methods can be enhanced by using a three-dimensional medium, including extracellular matrix gels such as Matrigel. Since these 3D mediums are rich in laminin (a protein found in the extracellular matrix), they help growth to occur. Additionally, they also allow stem cells to be embedded in the material, providing structure for the organoid to develop around.
What are some examples of how organoids are used?
Many different types of organoid have been created, each with differing levels of complexity. For instance, human pluripotent stem cells have been used to create cerebral organoids, which closely mimic certain aspects of brain function.
Brain organoids have many uses in biomedical research. For example, in 2019, scientists were able to use these models to determine how the La Crosse encephalitis virus (LACV) infects the human brain. LACV is a viral disease spread by mosquitoes, which is endemic to parts of the United States. While cases of the disease are rare, with around 100 cases reported in the USA each year, this is likely because many infected people will not experience significant symptoms and thus not seek medical attention.
LACV primarily affects children, causing inflammation in the brain and neural cell death. By using cerebral organoids which contained many different cell types, scientists discovered that the virus was more likely to cause cell death in neurons than other brain cells. They also discovered that if the cerebral organoids were treated with interferon (a type of cytokine secreted by infected cells to stimulate an immune response), then the neurons were protected from damage. The authors of this paper hope that this information may help in the treatment of this disease in the future.
The creation of cerebral organoids does raise some ethical concerns, however, as if these organoids become sufficiently advanced, then they may acquire sentience. Consequently, any development of brain organoids needs to be overseen by ethical committees and must be conducted with rigorous oversight to ensure that ethical guidelines are followed.
In addition, organoids have also been created to resemble physiology of the tongue. In 2016, these organoids were used to observe how the tongue's stem cells differentiate and mature to produce the tongue, as well as how this process can go wrong and form tumours. Organoids are incredibly useful for this, as they provide the closest replicas to human anatomy.
Furthermore, organoids have also been created to resemble parts of the gut (including the stomach and intestines), as well as the thyroid, kidney, liver, lungs, heart and eyes (to name a few).
What are some of the challenges of using organoids?
One of the biggest challenges with producing organoids is their complexity. Organoids are more complex than models researchers have been using so far, forcing them to recalibrate their testing methods. Additionally, organoids are much simpler than real organs. Consequently, while tests using organoids should be more accurate than current models, they are still not fully accurate.
Furthermore, organoids usually lack specific structures, such as blood vessels and immune cells. As a result, organoids do not currently allow us to study diseases that affect these structures. In addition, the absence of these structures also means that organoids can't grow very large without dying.
In stark contrast to 2D models, which use a single layer of differentiated stem cells, organoids have much more variability in their structure. This is because they are 3D and are much more complex. Thus, before organoids can be used to test pharmaceuticals and other medications, researchers must be able to reproduce organoids consistently. Otherwise, with such a great degree of variability, results obtained from studies using organoids will not be reliable.
To combat this, researchers have suggested that bioscaffolds can be used. These are artificial structures, which are manufactured from biological materials. When used in the production of organoids, studies have suggested that bioscaffolds provide a structure for the tissues to grow around, producing better and more consistent organoids.
What is the future of organoids?
For organoids to become used more widely in biomedical research, the variability in their structures needs to be reduced. I would contend that this is possible, provided that biomedical researchers work with engineers to overcome these challenges.
In addition, research should be conducted into whether blood vessels and immune cells can be constructed. This would remove the main restriction on the size of organoids, allowing bigger organoids to be produced.
Ultimately, if big organoids that closely mimic the functions of real organs could be produced consistently, then this would revolutionise medicine. Not only would this provide an abundant source of organs which could be used for testing pharmaceuticals and medical devices, but this could also provide organs for transplantation. This would dramatically reduce waiting times for patients to receive a life-saving transplant, thus significantly improving life expectancy.
Sources:
Hisha H., Ueno H. (2016) Organoid Culture of Lingual Epithelial Cells in a Three-Dimensional Matrix. In: Turksen K. (eds) Organoids. Methods in Molecular Biology, vol 1576. Humana, New York, NY. https://doi.org/10.1007/7651_2016_3
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