Is the future of disease modeling in organoids?


Graphical abstract. Credit: DOI: 10.1016/j.stemcr.2019.08.007
Graphical abstract. Credit: DOI: 10.1016/j.stemcr.2019.08.007

Organoid technologies have emerged as a strong new tool for modeling liver disorders, medication screening, and tailored therapy. Assoc. Prof. Tamer Önder of Koç University and his colleagues developed and described a hepatic organoid culture system using human induced pluripotent stem cells (iPS) as a bridge.


Developing a therapy for certain disorders is incredibly difficult for a variety of reasons, leaving the medical community helpless. However, with organoids, it is now conceivable to achieve several things that were previously considered "impracticable," and Assoc. Dr. Tamer Önder of Koç University School of Medicine and his colleagues are among the scientists working in this area.


There are around 20–25 hereditary illnesses that disrupt liver metabolism and can be deadly or result in permanent damage. When such a disease is discovered in a newborn, there is no method to work on the sick organ because there is no means to collect liver tissue from a baby. Furthermore, if the disease is a rare form, the difficulty is multiplied because there is less knowledge about it. As a result, in order to develop medications against such diseases or understand the biochemical basis of liver disease, cells that can be worked within the lab are required.

Dr. Tamer Önder and his team are working hard to overcome this obstacle. A study they are conducting in collaboration with the zmir Biomedicine and Genome Center (BG) as part of the TÜBTAK 1003 Project aims to replicate diseases that damage the liver or are extremely rare. According to the article published in Stem Cell Reports, the team uses the Cellular Reprogramming Method to turn a skin cell sample into a pluripotent stem cell (iPS).


They first expanded the iPS cells to a specific level before changing them into hepatocyte progenitor cells and placing them in a medium that allows them to grow in three dimensions. These lab-made human liver cells were then tagged with a green fluorescent protein before being injected intravenously into mice with damaged livers. Cells appeared to adhere to and proliferate in damaged sections of mouse livers.


The scientists discovered that the enzyme ASS1 had no function in sick cells during these tests, and they were able to reintroduce the enzyme into the cell using viral vectors. As a result, they were able to introduce a normal copy of this gene into organoids. They were able to see that ammonia levels fell once the cells acquired a normal copy of their defective genes, which caused the release of excess ammonia when the urea balance was disrupted. In other words, gene therapy allowed them to mend the cell.


They implanted this treated organoid into mice with damaged livers. The next step is to examine the treated organoid performing its function in the liver into which it was transplanted, verifying that the urea cycle is successfully completed.


Journal Information: Soheil Akbari et al, Robust, Long-Term Culture of Endoderm-Derived Hepatic Organoids for Disease Modeling, Stem Cell Reports (2019). DOI: 10.1016/j.stemcr.2019.08.007

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