How relatively simple 3D tissue models helped us to get insights into a complex disease
Organoid. This word might sound like from a sci-fi novel. However, organoids have been around for already decades and in the last one, they skyrocketed to their absolute fame. Simply put, organoids are mini versions of organs that can be cultured by the scientists in the lab. They provide a unique window into the mystery of the development and disease of organs, which are otherwise inaccessible. In the recent publication (1) by the lead author Afshan Iqbal (Emma R. Andersson lab), organoids helped us to study a liver disease called Alagille syndrome.
In newborn patients with Alagille syndrome, bile duct trees have failed to grow branches at the periphery of the liver. These normally help collecting and draining bile out of the liver. In their absence, the bile accumulates and the excessive bile damages the tissue around, often so that the patient needs a liver transplant. Curiously, some patients escape this fate because their bile ducts spontaneously regrow the missing parts later in life. Scientists know that understanding why some patients recover and some not holds the key to the treatment of this disease. But things are, as always, quite complicated.
To study bile duct tree development and regrowth, our lab has generated mice that mimic the disease (2). They too experience the onset of the disease and the recovery. When our colleagues analysed regrown bile duct trees, they realized they don’t look exactly like the healthy ones and show different patterns at the periphery and at the centre of the liver (3). This could suggest that there are also different mechanisms at play in these two liver regions.
The bile duct trees are made of cells called cholangiocytes and there might be something inherently different in their ability to respond to the surrounding environment. To study the dynamic behaviours of cells in a 3D environment, organoids are a great system. We can grow them in the lab and multiply them to get as many samples as we need or preserve them in liquid nitrogen for future use. We can observe living organoids under the microscope and test the effect of different molecules and drugs before we try to treat the mice.
For example, we know that patients and a mouse model with Alagille syndrome express less Insulin-like growth factor 1 (IGF1). Therefore, treatment with IGF1 could alleviate the disease symptoms. IGF1 is already an FDA- and EMA-approved therapy to treat growth in individuals with genetic loss of function of IGF1 (Laron syndrome).
Afshan’s idea was to study differences in at the recovered bile duct trees at the periphery and the centre of the liver. She derived organoids from bile duct branches of these liver regions and compared them to the respective regional organoids from healthy livers. To analyse the organoids, we employed various techniques. Transcriptomics analysis showed us which genes are expressed in organoids from different regions and we used microscopy to observe how happy they are, i.e. if they grow, if the cells are healthy and how they respond to IGF1 treatment.
Experiments with organoids showed that there are indeed differences in the recovered bile ducts from the periphery and centre of the livers of the Alagille syndrome mouse model and they do not respond to IGF1 treatment the same way. Organoids from the centre of the recovered livers were the most surprising to us. First of all, they did not respond to IGF1, second, they seemed to be confused in their cell identity. Among cholangiocytes, which we would expect in the organoids, we spotted another liver cell type - hepatocytes. Another look into the liver tissue confirmed the finding. This suggest that therapeutical efforts should be directed to help the cells interpret their environment correctly and choose a correct cell fate.
On the other hand, organoids from the periphery of the liver appear to be more similar to healthy ones in their cell identity, but unlike organoids from healthy cells, they grew slower and divided less. This was improved by adding IGF1, suggesting that IGF1 treatment could improve the recovery of peripheral bile ducts in Alagille syndrome livers, which we will test in coming experiments.
Organoids, seemingly simple blobs, thus helped researchers once again to get insights into the complex problems inside the tissues and generate testable hypotheses for the future research in animals.
Read the original publication here:
Other publications from the lab:
(3) DUCT reveals architectural mechanisms contributing to bile duct recovery in a mouse model for Alagille syndrome | eLife (elifesciences.org)
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