Hepatocytes derived from human induced pluripotent stem cells (iPSCs) were co-cultured with some progenitor cells that were extremely important in development. The researchers confirmed that these cells can organize themselves into functional three-dimensional liver buds. The researchers found that these liver buds showed similar metabolism to human livers in some ways. When transplanted into mice, the liver buds were connected to the host circulatory system. The new research work was published in the July 3rd issue of Nature.
Stephen Duncan, director of the Regenerative Medicine Center at the University of Wisconsin School of Medicine (not involved in the study), said: "I think the quality of the work of the researchers in this paper is very high. By adding cells that can produce appropriate growth factors, they differentiate iPSCs ... ... and then these cells spontaneously formed these three-dimensional aggregates, which in turn formed a preliminary vasculature. "
Currently, there are more than 100,000 patients with end-stage organ failure worldwide waiting for organ transplantation. Due to the lack of organ donors, scientists have been trying to build transplanted organs from scratch for decades. The discovery of embryonic stem cells in 1981 brought hope to the development of customized organs in the laboratory. The discovery of iPSCs provides the possibility to generate organs derived from the patient's own undifferentiated cells, and will likely solve the problem of histocompatibility.
"If you can use iPSCs to generate a truly functional organ, then you will get an unlimited spare parts box with the parts genetically matched to the individual," Duncan said.
"Most researchers working on organogenesis research have focused on one component: the differentiation of functional cells with human iPSCs. This is not an effective method, so we have proposed a new concept of three-dimensional organogenesis , "Said akanori Takebe, a research leader and an expert in regenerative medicine at Yokohama City University in Japan.
First, the researchers used iPSCs to cultivate human hepatocytes, and then added two developmentally important cell types-human umbilical vein endothelial cells and human mesenchymal stem cells. The researchers found that within 48 hours of mixing the three cell types together, the hepatocyte mass began to self-organize to form a three-dimensional mass and generated blood vessels.
Microarray analysis of 83 genes known to be active during liver development revealed that the gene expression in iPSC-derived liver buds is more similar to human fetal liver tissue than iPSC-derived hepatocytes generated by other research groups. The researchers also found that liver buds break down certain drugs in a manner similar to human metabolism. In addition, transplanted liver buds produced higher levels of human serum albumin (an important liver metabolite) than other iPSC-derived hepatocytes.
The Takebe team also transplanted liver buds into the brains of immunodeficient mice, and they observed the tissue mass through a window implanted in the skull. Fluorescence imaging of the blood vessels in the liver buds revealed that these blood vessels formed an unimpeded connection with the mouse vasculature within 48 hours of transplantation.
Shay Soker, a bioengineering scientist at Wake Forest Medical College in the United States, believes that this research is an important technical achievement. But he also questioned whether this technology could be extended to make usable human livers.
Takebe said: "It is a very important step to make liver buds that are large enough to be transplanted into humans. The liver is composed of 10-100 billion hepatocytes. We need to establish a new automatic cultivation system to make it possible to produce Large liver buds. "
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