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Functional, if Still Tiny, Human Liver Created from Stem Cells

By Anette Breindl
Science Editor

Starting with induced pluripotent stem cells (iPSCs), scientists have created the first artificial organ – a functional liver bud, which is the precursor to the mature liver that is normally formed early in embryonic development.

When transplanted into mice, those buds were able to perform the functions of a normal liver, and extended survival of animals with liver failure.

Lead author Takanori Takebe of the Japanese Yokohama City University told reporters at a press conference that as far as transplantation goes, practical applications of his team’s discovery are likely to be a decade away. But the work provides proof of concept that it is possible to make not just individual cell types from stem cells, but functional organs composed of several different sorts of cells – a goal that has eluded scientists for decades.

The work, which was reported in the July 3, 2013, advance online issue of Nature, began as an accidental finding. While studying human embryonic stem cells, Takebe and his colleagues noticed that when such cells were co-cultured with support cells, they organized themselves into 3-dimensional structures and ultimately liver buds, which are precursor structures to the liver that form early in embryonic development.

Takebe and his team then tested whether they could make such liver buds using iPSC-derived liver cells. Success came when they combined liver cells with two types of support cells, human umbilical vein endothelial cells (HUVECs) and mesenchymal stem cells. Speaking through a translator, Takebe told reporters that “using those three together, and the interaction between them, is what causes the liver to form.”

Takebe and his team first reported that they had generated liver buds, of about half a centimeter in length, at a scientific meeting last year. In the paper, they reported on those liver buds in more detail. The buds are not miniature versions of a fully functioning liver – they do not form bile ducts, which transport bile from its synthesis in the liver to the digestive tract.

But when they were transplanted, the buds were able to connect to the blood system of the recipient mice, and blood vessels formed within the liver buds themselves. Consequently, the liver buds were able to take over metabolic functions in animals whose own livers were damaged by drug treatment. Of the animals that were transplanted with a dozen liver buds after such damage, more than 90 percent survived for 30 days, while fewer than a third of untreated control animals did.

The transplantation work is, for the time being, an early proof-of-concept study. In order for it to become clinically viable, the liver buds will have to be followed for much longer periods of time than the two months that Takebe and his colleagues reported on in their paper, both to make sure that they stay functional, and that they do not ultimately proliferate into tumors.

Then, there are the regulatory issues that will need to be addressed. A report published this week in Britain stated that regulatory issues are holding back the development of regenerative therapies. (See Monday’s edition of BioWorld Today.)

And those regulatory issues are magnified when regenerative therapies use cell sources from several different tissues, as the liver buds currently do. HUVECs would come from a different person than the iPSCs themselves. (See BioWorld Insight, May 20, 2013.)

Closer at hand are uses in drug discovery, where liver buds might be used to get a better handle on how drugs are metabolized by the human liver. Co-authors on the study are from the ADME & Tox Research Institute of Tokyo biotech firm Sekisui Medical Company Ltd. The team showed that mice with human liver buds metabolized several drugs in the way that a human liver rather than a mouse liver would. They also showed that transplanted animals produced the human versions of proteins such as albumin and alpha-1 antitrypsin.

The technique might also be useful for other organs besides the liver. Generating enough of a blood vessel network to survive has been one of the challenges in making artificial organs, and the fact that Takebe and his team managed to do so in the liver, which is one of the most heavily vascularized organs in the body, is encouraging for the method’s application to other organs. Takebe said that “several kinds of organs, such as the pancreas or kidneys or even lungs could be applicable to this basic technique. We are now trying to apply this self-organizing approach into the pancreas formation, and are so far getting good results.”