Dr Meri Huch of the Gurdon Institute explores liver's regenerative power using organoids
The human liver is a truly remarkable organ.
Like a salamander, which can regrow its limbs, our liver has a tremendous ability to regenerate.
“You can remove 70 per cent and the remaining tissue will regrow to compensate for the lost volume,” Dr Meritxell Huch tells the Cambridge Independent.
Her lab at the Wellcome/Cancer Research UK Gurdon Institute in Cambridge is interested in understanding this extraordinary power.
Dr Huch is exploring it with the aid of organoids – tiny, self-organising structures in a lab dish that mimic the development and some functions of organs.
“Understanding the mechanism by which the liver is able to regenerate so efficiently may give us the knowledge to promote regeneration in disease states of the liver, and potentially other tissues that don’t regenerate well, like the kidney or pancreas,” she says.
The regenerative power of the liver has been known since Ancient Greek times.
In Greek mythology, Zeus punished Prometheus for stealing fire by binding him to a rock and sending an eagle to feed daily on his liver, which grew back each night.
“Our liver gets injured in a constant manner from what’s in our blood – the things we eat, drink and smell. The liver is the main detoxifying organ of the body,” explains Dr Huch.
“On a day-to-day basis, the liver has the capacity to activate many different cell types. Usually hepatocytes will be the damaged cells and the remaining healthy hepatocytes will compensate.
“Sometimes if the injury is extensive, or has been very chronic, there are no more healthy hepatocytes so the liver pulls from another cell source, the ductal cells. They will proliferate and try to generate new hepatocytes that are being lost.
“But this capacity is not unlimited,” warns Dr Huch. “Sometimes, perhaps because the damage has been very extensive, chronic or acute, as in alcoholism, then the liver can only cope up to a certain point, and it installs disease – fibrosis or cancer.”
For some patients with liver cancer who still have good liver function, it is possible to carry out a tissue resection, in which a sizeable portion of the organ can be removed. The procedure relies on the liver’s capacity to regrow.
Liver transplants also make use of this restorative power.
“A donor can give part of his or her liver while still alive to a recipient because of the capacity of the liver to repopulate,” notes Dr Huch.
About 350 living donor liver transplants are carried out in the United States each year, although only a small proportion are for patients with liver cancer.
Recent research has shown that in some cases it may be possible to reverse fibrosis – the scarring of the liver – and even cirrhosis, the long-term damage of the organ in which both scarring and nodules, or irregular bumps, are present.
But we are still in the early stages of understanding this regenerative power.
“Very little is known at the molecular level about the exact detailed mechanism of how the cells sense damage and respond by proliferating and differentiating,” says Dr Huch.
“We know the liver is capable of secreting growth factors, particularly proteins, that help facilitate this proliferation. We know it is capable of recruiting other cell types, like endothelial cells, which will produce growth factors and contribute to the regeneration process.
“But there is a big gap in knowledge in this area of research, in particular in relation to human regeneration, as all studies are done in animal models.”
It is here that laboratory models of human liver tissue could prove to be a game-changer.
“Our knowledge comes from animal models, especially mouse or rat. But the mouse is not a perfect model, which is why good in vitro models for human tissue are important. It might elucidate molecules that we’ve missed from studies in mice,” says Dr Huch.
“Organoids have revolutionised the way we do biology in the lab in the last three, four or five years. They are a much more physiologically relevant in vitro system. They are complementary. It’s not that we won’t work with cell lines or animal models anymore.
“They are not perfect but they allow us to ask interesting questions that we could not address before, especially in the human context, where studying regeneration is difficult for ethical reasons.”
The study of an organ’s development and morphogenesis – how it takes on its shape – becomes more feasible with the use of organoids.
“The definition of an organoid is a three-dimensional structure that is derived either from a pluripotent stem cell or from an adult, differentiated cell or stem cell. They have the capacity to self-organise and generate a structure that recapitulates some aspects of the tissue of origin – the morphology and the function,” says Dr Huch.
Pluripotent stem cells are master cells that are able to self-renew and grow, or ‘differentiate’, into all cell types in human tissue.
“Pluripotent stem cells have been differentiated into brain organoids, retina organoids, hair follicles, inner ear – many types of tissues from all the germ layers. They mainly recapitulate the developmental process,” says Dr Huch.“It means we have, for the first time, a way to mimic human development in vitro.”
Scientists have, for example, been able to create something akin to a miniature human small intestine in a dish, and examine the processes it would undergo as an embryo in a mother’s womb, something previously beyond the reach of study.
“It has revolutionised the development of biology,” Dr Huch adds. “They self-organise very well. Brain organoids are not a brain but they recapitulate many cortical areas. They are lacking vasculature and some of the supporting cells but the neurons can fire in a very organised manner.”
The use of adult cells to create organoids has also been transformational, enabling the study of the intestines, the stomach, the liver epithelium, the pancreas epithelium and more.
“It is the first primary tissue to be expanded long-term in culture. We don’t do anything to the cells. We take them from the biopsy, put them in a dish, give them some growth factors to make them grow and that’s it. There is no genetic manipulation.”
Dr Huch has played a key role in the development of liver organoids in recent years, developing them from adult differentiated cells that activate progenitor state cells. Like stem cells, they can differentiate into specific types of cells but are at a more developed stage and cannot replicate indefinitely.
“It is progenitors that get activated in the organoid culture,” says Dr Huch. “They make a ductal epithelium very well, which is very polarised, but they don’t make hepatocytes until we change the culture conditions. So our organoids don’t have the complete structure – in our liver we have both. But they recapitulate better than anything we have had before.”
One potential long-term use of the technology is cell therapy transplantation.
“When I was a post-doc in the Netherlands, we transplanted a liver organoid into a mouse that had liver disease,” recalls Dr Huch, explaining that the aim was to answer the basic question of whether the immature hepatocyte-like cells in the organoid would be fully differentiated when placed in an actual liver.
It worked, but only one per cent of tissue had been generated. To be effective at curing disease, this would need to be expanded to 20-30 per cent.
“Hypothetically, it would be possible but it’s not ready yet. The differentiation needs to be improved significantly,” says Dr Huch.
“It’s not something I’m working on because it requires a big infrastructure. But my former mentor might work on it,” she notes.
“We use the organoids to understand the biology of tissue regeneration, the regulation, how things go wrong and the molecular mechanisms. We can do an experiment where we collect the cells from the tissue and analyse the cells as they are making the organoids.
“We know that this process mimics exactly the regenerative process. We have a lot of data in this direction. It is not published yet though, but we are working on it.
“We also use the organoids to model human disease and we’ve been very successful in modelling human liver cancer,” says Dr Huch.
“We’ve shown that by having this in vitro model we could use it for drug testing.
“The aim of my lab is not to find a therapeutic drug, but to provide the model for the world so that they can use it for that purpose.”
Dr Huch believe it will not be long before these ‘tumouroids’ are of use to drug companies looking for a cost-effective model of a human tumour.
They mimic well the genetics, the transcriptomics, or RNA molecule activity, and the histology, or microscopic structure, of a patient’s tumour.
“We’ve proved that,” says Dr Huch. “We have developed a method on how you can test the drugs on them in a relatively high throughput manner. We tested 29 drugs using a robot.
“What still needs to be proven is the predictive value of the organoid technology.”
The next step is to see if patient responses to medicines are matched by those predicted using tumouroids.
Meanwhile, Dr Huch’s lab also uses organoids to explore the pancreas.
“This is an organ that originates from the same embryonic progenitors as the liver,” says Dr Huch. “Morphologically they are very different but conceptually they are quite similar.
“Both have a ductal network that collects secretions. Both are released into the same place. Yet while the liver is excellent at regeneration, in the pancreas there is none.
“We are interested in understanding the reason. If we understand the mechanism that is different, we might be able to trigger regeneration in the pancreas, which would have implications for pancreatic disease, in particular diabetes.
“We know the human and mouse pancreas are similar but not the same, so we need to develop human models. That’s what my lab has been working on for some time.”
As our understanding of these remarkable organoids develops further, it can only deepen our understanding of human biology, and accelerate the development of new drugs and therapies.
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