Liver cells derived from human induced pluripotent stem cells (iPSCs) and cultured with developmentally important progenitor cells self-organize into functional, three-dimensional liver buds, according to new research published today (July 3) in Nature. The liver buds exhibited metabolisms that, in some aspects, resembled that of human livers, the researchers found, and when transplanted into mice, the buds connected with the host circulatory system.
“I think the quality of the work in the paper is very high,” said Stephen Duncan, the director of the Regenerative Medicine Center at the Medical College of Wisconsin, who did not participate in the research. “They got iPSCs to differentiate by adding cells that produce the right growth factors . . . and then the cells spontaneously formed these three-dimensional aggregates that were able to form a rudimentary vasculature.”
There are currently more than 100,000 people around the globe with end-stage organ failure awaiting organ transplants. With no end to the shortage of organ donors in sight, scientists have for decades attempted to build organs for transplantation from the ground up. The discovery of embryonic stem cells in 1981 offered promise that custom-made organs could be grown in the lab. Later, the discovery of iPSCs offered the possibility of making organs from patient’s own undifferentiated cells, which would circumvent compatibility concerns.
“If you could use iPSCs to generate a truly functioning organ, then you would have this unlimited suitcase of spare parts that would be genetically matched to individuals,” said Duncan.
“Most researchers working on generating organs focus on one component: functional cell differentiation from human iPSCs,” said study lead Takanori Takebe, a regenerative medicine specialist at the Yokohama City University in Japan. “But that is not an efficient approach, so we established a new concept for three-dimensional organ generation.”
During natural liver development, sheets of liver cells cleave off of gut endodermal cells—the cells that make up the innermost germ cell layer of the embryo—and form a liver bud, a mass of condensed tissue that quickly becomes vascularized. To recapitulate liver development, Takebe’s team cultured the human hepatocytes, or liver cells, derived from iPSCs with two other developmentally important cell types—human umbilical vein endothelial cells and human mesenchymal stem cells. Within 48 hours of combining these three cell types, the mass of liver cells self-organized into three-dimensional clusters and formed blood vessels.
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