Human stem cells used to grow a mini-liver in mice

The researchers' liver buds growing in culture prior to transplant into an animal.

Takanori Takebe

One of the things that got people excited about stem cells was the prospect that they could be used to generate entire tissues or organs, ready to replace what's been damaged by injury or disease. But there's a big gap between the embryonic stem cells we can generate and an adult organ. If you put the stem cells into an adult body, there's no way to control how they develop. But if you control their development outside of an organism, you generally wind up with a bunch of cells, mostly of a single type, sitting in a plate. That's a far cry from the complex, integrated, three-dimensional structure of an actual organ.

Now, a team of scientists in Japan has decided to split the difference. Using stem cells from various sources, they put together the three types of tissues that normally work together to give rise to the liver in embryos. And when those were implanted into a mouse, they did what they would do in the embryo: integrate together and grow into a functional liver.

In the embryo, the liver forms from a combination of two tissues. One is called endoderm, and these are the cells that line the developing gut. Resting above that is a population of loosely packed cells called mesoderm, which envelop and integrate with the endoderm to form what's called a liver bud. At that point, blood vessels become necessary for the bud to grow and specialize into the liver.

Due to work in a number of labs, we've been able to identify stem cells for all the populations necessary to form a liver bud. Embryonic stem cells can be pushed to differentiate into endoderm cells and then be given a liver identity. Mesenchymal stem cells have been found in the bone marrow. And it's possible to isolate the cells that line blood vessels from the umbilical vein that is otherwise discarded after childbirth. Putting all three populations into a culture dish together was all that was needed; they would spontaneously aggregate to form three-dimensional structures that were reminiscent of the embryonic liver bud. The genes expressed by these clumps of cells looked very similar to the set expressed during normal liver development.

The researchers took the next step and implanted the cluster into a mouse. Within three days, the blood vessel cells had integrated with the host's blood supply, and the remainder of the cells in the cluster started proliferating. That continued for up to two months, and over that time the gene expression began to look more and more like that of a mature liver. Human albumin (a blood protein produced by the liver) appeared by day 10. At day 45, significant levels were detected in the blood of the mice.

By all measures, the small buds that were implanted began developing into something resembling an adult liver. So the authors tested its performance in a number of ways. They treated the mice with two drugs that are metabolized in the liver but handled in different ways by humans and mice. The human-specific metabolites appeared in the blood and urine of the mice. The authors then tried a drug that causes liver toxicity; survival of the mice with the implanted liver buds was just as high as in a control where the authors implanted adult liver cells.

All of this suggests that the general approachusing stem cells to re-create an embryonic organ and then letting that organ develop inside an adulthas lots of promise. But there will definitely be some challenges before it's put to wider use. The liver is a relatively easy organ to test since it only requires three cell types and is able to self-organize, even in adults. Finally, the use of three different cell sources means that there are three potential sources of rejection problems should this ever be used in a transplant.

Despite the remaining hurdles, however, it's clear that Japan hopes to move forward with the technology. Earlier this month, its government started the process to lift the banon growing human organs in other animals. Initial plans appear to use pigs, where organs can grow much larger than they are able to in mice. In the US, Congress and several states considered bans on chimeric animals (animals that are a mix of their own and human tissues) a number of times over the past decade. No federal law has been enacted so far, but a number of state restrictions have reportedly passed. Depending on their precise wording, this research or any medical applications that arise from it may not be legal.

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Human stem cells used to grow a mini-liver in mice