Researchers from the Max Planck Institute and the Technical University of Munich (TUM) have created mini-livers from stem cells. The breakthrough, which was published in the journal nature, offers a potential treatment for the end-stage liver disease.
So far the only treatment for the end-stage liver disease is a liver transplant, and the number of livers available from deceased donors is very limited. Regenerative medicine, which offers an alternative solution to organ transplants, allows us to understand how human tissues develop and organize themselves on a molecular level. By learning how cells interact with each other, especially from the embryonic stage where livers form, we can eventually create bioengineer transplantable livers that can save thousands of lives.
“Our data gives us a new, detailed understanding of the inter-cellular communication between developing liver cells, and shows that we can produce human liver buds that come remarkably close to recapitulating fetal cells from natural human development.” said Takanori Takebe, physician and investigator at Cincinnati Children’s Hospital Medical Center and Yokohama City University.
In order to create the mini-livers, researchers first studied the molecular mechanisms that are involved in forming a liver. They used single-cell RNA sequencing (RNA-Seq) to monitor how individual cells change when they are combined in a three-dimensional (3D) microenvironment where vascular cells, connective tissue cells and hepatic cells (liver cells) engage in a complex communication. “The main advantage of using single-cell RNA-Seq technology is it gives us a map of gene activity in each and every cell type, allowing us to eavesdrop on the conversation”, says Keisuke Sekine from Yokohama City University, Japan, co-first author of the study.
The researchers zeroed in on developing a complete blueprint of active transcription factors (genes that tell other genes what to do), signalling molecules and receptors in each of the different types of cells before and after the cells come together to form the liver bud tissue. The authors observed that there is a dramatic change in the conversation and how the cells behave when all of the cells develop together in 3D.
“It was exciting to see, for the first time, how individual cells are reacting to each other when put into the same context within the liver bud. It’s a bit like people-watching at a party,” says Gray Camp of the Max Planck Institute for Evolutionary Anthropology, the study’s other co-first author.
The lab-grown liver buds displayed molecular and genetic signature profiles that very closely resemble those found in naturally developing human liver cells. Credit: J. Gray Camp et al.
Single-cell RNA-Seq analysis also helped the researchers to benchmark the engineered 3D liver tissues generated from stem cells in the lab against naturally occurring human fetal and adult liver cells. Researchers observed that their lab-grown liver buds have molecular and genetic signature profiles that very closely resemble those found in naturally developing human liver cells. “Our data reveals, in exquisite resolution, that the conversation between cells of different types changes the cells in a way that likely mimics what is going on during human liver development”, says Barbara Treutlein from the TUM.
In particular they highlight molecular crosstalk between a signaling protein that cells produce to stimulate formation of blood vessels (VEGF) and a protein and receptor that communicates with VEGF to help trigger formation of a blood supply to the developing liver (KDR), which the current study shows is critical to instructing the development and maturation of liver tissues. Researchers observed this crosstalk during the development of mouse liver cells, natural human liver cells and in their bioengineered livers.
The authors also noticed the gene expression landscape in the generated liver buds – such as precisely where and when genes express themselves – did not completely match natural human liver cells. The remaining gaps between natural and bioengineered tissues may come from different developmental cues caused by the unique microenvironment of cells developing in a petri dish versus that of cells developing in a person or animal. The new cellular and molecular data uncovered in the current study will be “exploited in the future to further improve liver bud organoids” and “precisely recapitulate differentiation of all cell types” in fetal human development, the authors write. “There is still a lot left to learn about how to best generate a functioning human liver tissue in a dish”, concludes Treutlein. “Nevertheless, this is a big step in that direction”.
Source:
https://sciencr.com/scientists-have-created-bioengineered-mini-livers-from-stem-cells/
