Ongoing advances in stem cell research and genetic technologies have led to important breakthroughs in organoid technology, which holds great promise for aiding in drug development, disease modeling and, ultimately, precision medicine applications, according to Hans Clevers, MD, PhD, Group Leader at the Hubrecht Institute for Developmental Biology and Stem Cell Research and Professor of Molecular Genetics at the University Medical Center Utrecht and Utrecht University in The Netherlands.
During Monday’s Hans Popper Basic Science State-of-the-Art Lecture, “Hepatocyte and Bile Duct Organoids As Models for Liver Research,” Dr. Clevers will describe his groundbreaking research in the development of organoid technology and how it can be applied to liver and biliary disease.
Dr. Clevers’ lab was the first to demonstrate that organ-specific stem cells harvested and grown in vitro have the ability to differentiate and become organoids, or “mini versions” of their organ of origin. His lecture will focus on organoids developed from bile duct cells and hepatocytes, as well as applications for disease modeling in cancer, hereditary disease and regenerative medicine strategies.
“We showed a long time ago that the most active stem cells are in the gut and that Wnt proteins are the crucial drivers of the activity,” Dr. Clevers said. “That led to a long line of research where we found that this same principle holds in other organs, which led us to identify a number of novel stem cells, first in the gut and then in the liver, the pancreas, the lung and other organs.”
Dr. Clevers and his research team then developed the technology to take a single stem cell from any of those organs, first in mouse then in man, and grow them in the lab into a large amount of tissue.
“Our intention originally was to just make many stem cells out of one and manipulate them genetically or use them in mouse experiments, but much to our surprise, we observed that these stem cells didn’t just make more stem cells, but they had a strong tendency to create a small version of their originating organs,” Dr. Clevers said. “This started with a mini gut in 2009 and since then we have steadily optimized the technology for human tissues.”
In the liver, Dr. Clevers and his colleagues recently showed that cholangiocytes taken from patients with alpha-1 antitrypsin deficiency, a common hereditary liver disease, can be expanded in vitro, allowing the researchers to recreate the disease model in a petri dish. Additionally, in an upcoming paper to be published in the journal Cell, Dr. Clevers and his colleagues report that they have successfully created large amounts of fully functional hepatocytes in the lab, which he said could have great importance in the study of hepatitis B or C infections.
“In the long run, and we know that it works in principle, we may be able to take a small sample from a healthy donor, grow it into a large amount of tissue in the lab, freeze the samples, essentially creating a liver organoid bank,” Dr. Clevers said. “Then, whenever the patient might need healthy liver cells or a new healthy liver, rather than wait for terminal disease or for a donor liver, you could actually inject these stem cells into the diseased liver early on and let them repair the liver. It has worked on animals in many labs and, maybe not in the near, but in the somewhat distant future, should be feasible.”