From iPSCs to Organs
What is Human ipsc?
Human induced pluripotent stem cells (Human-iPSCs) are cells that can be found mainly in the umbilical cord or bone marrow. They can be reprogrammed back to embryonic stem cells, which have the unique ability to develop into any type of human cell. For example, they can become nerve cells, liver cells, or blood cells. Human-IPSCs are widely used for disease modeling, drug development, and regenerative medicine.
Why generate organs from Human-ipsc?
With the shortage of organ donation and increased cases of organ failure, finding a replacement for a human organ became an interesting topic for scientists in both the medical and engineering field. As mentioned above, human ipsc can be used to differentiate into cells with different functions. But how to make human ipsc differentiate into a functional organ to transplant is a question that needs to be solved.
Now let’s look at how two researchers are using human ipsc to generate a functional liver.
In vivo refers to experiments of research conducted with living organisms, such as mice and animal models. In vitro refers to experiments that were conducted outside of living organisms, performing experiments on cell cultures instead.
Vivo Experiment-Yokohama City University (2013 Japan)
In 2013, scientists in regenerative medicine at Yokohama City University (Japan) generated a functional, three-dimensional human organ. The Human-ipsc derived tissue structure can perform liver functions such as protein production and drug metabolism. A liver bud is vascularized from hepatic cells tissue mass. The three dimensional liver bud was formed by hepatic endoderm cells with antithetical cells (HUVECS) and human mesenchymal stem cells (MSCs). The tri-lineage mix tissue forms a human ipsc-HEs which can self organize into a three dimensional liver bud tissue structure 48 hours after seeding in cell culture. Through PCR analysis on early hepatic marker genes, an increase of marker genes was observed in Human-iPSC HEs. FGF and BMP pathways are signals activated during development. It was observed in the co-culture of Human-iPSC and stromal cells. This observation with other supplemental loss and gain function experiments indicated the three dimensional Human-iPSCs liver bud tissue formation is stromal cell dependent. The derived bud structure was transplanted into a mice model. Functional vessel was formed between the transplanted organ and host vessel. The functional verral formation was able to deliver nutrients, oxygen and establish an instructive vascular niche which stimulated liver organogenesis. Functional maturation of human iPSC- liver bud was compared with human adult hepatocytes and have shown significant hepatic maturation. The Human iPSC-liver bud was also tested for drug metabolism activity with 222 metabolites. For clinical usage, they further transplant Human iPSC delivered liver bud into liver failure disease model mice and have shown an increase in survival.
Vitro-Massachusetts Institute of Technology (2016 U.S.)
In 2016, Bioengineers in Massachusetts Institution of Technology used Human-IPSC and bioengineering skills to generate a tissue with liver-bud-like phenotype in two weeks. This research focuses on the transcription factors GATA6 that guide cell fate from Human-iPSC to endodermal and mesodermal lineage. Previous research has shown the expression of GATA6 can influence liver development and expression of BMP4 growth factor. GATA6 can also regulate hepatic cell fate. Scientists engineered a wide range of GATA6 expression levels in iPSC cells and direct cell fate. Through generating co-differentiate events to deliver a complex tissue with epithelial and stromal cell types. GATA driven endodermal cells can induce wild type cells into mesoderm fate. GATA induction can form reproductive and stable tissue.The generated tissue has liver phenotype and key features. This experiment approach has the advantage of a short time period, and more controllable oxygen, nutrients exchange. The development process of tissue can be regulated and visualized more clearly compared to animal models.
Applications
These findings are meaningful for future organ transplantation. Although we are not able to generate a whole adult organ , the human-ipsc derived cells and tissue are useful for other scientists to study related diseases. The generated functional liver tissue can even be used for drug development. Overally, this is a good start and lends hope to the idea that one day we can create organs from stem cells.