A three-day-old mini-liver, grown in a lab from human pluripotent stem cells
Organ transplants save lives, but in terms of human donors, demand far exceeds supply. Current research is looking into how viable animal alternatives might be, whether human organs can be grown inside living pigs and how replacements could be grown in a lab. A new breakthrough could make the latter more likely, as a team from the Cincinnati Children’s Hospital Medical Center has found a way to control how different types of cells arrange themselves during development.
Growing different types of tissue in the lab is a great way to test the effects of drugs, treatments and injuries without harming human or animal test subjects. But they aren’t perfect replicas since they’re taken out of the context in which the organ operates naturally. Miniature 3D versions of the full organs, like Brown University’s mini-brains, are closer models to the real thing, but even these can’t capture the full picture.
The long-term goal is for organs grown from stem cells to be so accurate they can be implanted into patients. But a liver is more than just liver cells: it’s a tangle of vasculature, connective tissue and hepatic cells, and any viable lab-grown replacement would need to mimic all of these components in the proper structure. Recently, the mini-brains were found to be sprouting their own vasculature, and the Cincinnati researchers wanted to find ways to control the process to grow better liver “buds”.
The team used single-cell RNA sequencing (RNA-Seq) to keep track of individual cells, and watch how they might change as the organ grows. Different types of cells send proteins back and forth constantly to drive development, and by monitoring this “molecular crosstalk”, the researchers were able to create a kind of blueprint for bioengineering better livers. For example, the signaling protein VEGF and the receptor protein KDR work together to create blood vessels and form a blood supply for the organ. This process was seen in natural mice and human liver cells, as well as the team’s bioengineered livers.
These genetic-molecular conversations drove the livers to develop in very different ways to isolated cells grown in culture. The team found that the bioengineered livers had molecular and genetic signature profiles that were very similar to the real thing.
“Our data reveals, in exquisite resolution, that the conversation between cells of different types changes the cells in a way that likely mimics what is going on during human development,” says Barbara Treutlein, one of the lead researchers on the study. “There is still a lot left to learn about how to best generate a functioning human liver tissue in a dish, nevertheless, this a big step in that direction.”
The process still isn’t perfect: where and when genes are expressed isn’t quite the same as in nature, which the researchers say is probably a result of them being grown in culture. But closing these gaps will be the focus of future study.