By Heather Main
Organoids are pretty big in stem cells right now. The last couple of years have attracted a lot of media attention on mini lungs, mini brains, mini kidneys, mini guts and more, giving the impression that scientists know how to specify and organise cells into mini functional organs in the lab. Organoids have become a hot topic in a stem cell environment where our understanding of disease is limited by studying only cell autonomous effects in single cells. If Thursdays ISSCR 2015 plenary is anything to go by, 2 of the 5 talks were on organoids, the first from Carla Kim on lung organoids and the second Hans Clevers on gut and liver organoids.
Carla Kim started with a seemingly irrelevant summary of the fact that just about every cell type in the lung seems to have some sort of stem cell or regenerative capacity but then continued to discuss their work on formation of lung organoids from Sca1+ BASCs (Bronchio Alveolar Stem Cells). Culture of bodies from these sorted stem cells leads to a mixed population of organoids, 20% representing bronchiolar, 60% alveolar and 20% mixed structures. Carla’s research has now shown that Tsp1 increases the proportion of alveolar organoid formation. This is relevant to an increase of Tsp1 seen due to alveolar injury and works towards defining the reactions of lung stem cells to different types of lung damage. I must say however that what caught my attention from a purely human view was Carla’s movie on unidirectional mucin flow in bronchiolar organoids, demonstrating the level of complexity of these structure but also just giving you the school yard giggle of producing snot from pluripotent cells.
Hans Clevers talk was such a mass of animation that you found yourself amazed that they have the funding for all of this and a little cheated at the same time that it is the animation that sticks in your mind rather than the data. Hans began with his gut organoids and then moved onto liver organdies (note added from Paul; see image of a liver organoid from one of the Clevers lab papers with the wonderful Meritxell Huch, Hans’ former postdoc as first author, who now has her own lab ).
It was fascinating to see that at least to some extent the gut organoids were capable integrating to gut tissue when transplanted in vivo. The animation showed the organoid splitting to expose its apical surface and then integrating into the tissue through its basal surface. It was unclear to me, but possible I just missed it, if the body was capable of integrating to normal tissue or if some type of damage was required to allow the basal surface to implant in the tissue. Hans also showed forskolin induced swelling of these bodies and rescue of swelling in CRISPR modified Cystic Fibrosis cells. As a progression Hans discussed their developments in liver organoids. These bodies were established from dissociation of liver, which left EPCAM+ bile duct cells that could be programmed to a stem cell state through Wnt and RTK regulation. These liver organoids were used to test responder behaviour of different individuals to drug treatments.
The organoid talks are always beautiful. They always have amazing staining patterns of impressive structural complexities, but what makes them any more interesting than a biopsy in understanding disease? Will they be more powerful for cellular therapies than single cell populations or transplantation of the relevant stem cell of origin? The cost of producing and culturing these organoids needs to be balanced against the benefit of the application over existing and alternative technologies. It was nice to see Hans’ application in responses to chemotherapy, which should be a field that would benefit out of such techniques. The cost to the patient of undergoing a cancer treatment that does nothing to the cancer but ravages their body is huge and will have implications in the number of other treatments that they are able to endure. Chemotherapy treatments themselves have a large financial cost not only for the drugs but the time in hospital, which would further validate the cost of organoid diagnostics.
However, it is not time to throw away autonomous cell studies. The direct effects of genetic diseases on primary affected cell types are essential to understanding the origin of disease. Treating secondary effects will not be as effective, or long-lived, as rescuing the primary effect. Organoids give a second level of understanding which will no doubt lead to increased complexity of autonomous ‘single cell’ cultures towards absolutely defining mechanisms for efficient targeting of therapeutics.
Back to the public, one may imagine that while being a little exciting these ‘mini organ’ studies also seems a little scary to the public and may make them scared of what else we are capable of if we are now growing mini functioning organs. What may need to be a little clearer, at least for the sake of the public, is that while different labs can produce structures with more or less complex hallmarks of structures within particular organs, at this stage we have very little understanding of the processes involved and thus have extremely limited control. It seems that both the starting cell and the culture conditions are important in driving the complexity of tissue formation, but the field is still quite primitive in understanding the complexity of the programs these starting cells undergo. We are also far from the public impression of growing ‘functional’ organs in the lab.