Developing Bioengineered Human Livers

The current treatment for end-stage Human livers disease is a liver transplant. The number of livers available from recently dead donors is less. To overcome situations major goal in regenerative medicine is to attain self-organizing human tissues. In which cells experience a series of coordinated molecular events precisely timed and spaced to form functioning three dimensional liver buds. The organ"s developmental processes greatly advancing efforts to generate healthy and usable human liver tissue from human pluripotent stem cells.

The bioengineered human liver tissues need additional rounds of molecular fine tuning before testing in clinical trials. The research was led by Takanori Takebe, MD, a physician/investigator at Cincinnati Children"s Hospital Medical Center (Division of Gastroenterology, Hepatology & Nutrition) in the United States, and Barbara Treutlein, PhD, Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany.

More detailed understanding of the intercellular communication between developing liver cells shows we can produce human liver buds. But remarkably close to recapitulating fetal cells from natural human development.

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Genetic Blueprint

In the current study the researchers used single-cell RNA sequencing (RNA-Seq). To monitor how individual cells change when they are combined in a three-dimensional (3D) microenvironment. This is where vascular cells, connective tissue cells and hepatic cells engage in a complex communication. The main advantage of using single-cell RNA-Seq technology is it provides a blueprint of gene activity in each and every cell type. The researchers zeroed in on developing a complete blueprint of active transcription factors. The signaling molecules and receptors in each of the different cells before and after they come together to form liver tissue. Observing dramatic change in the genetic-molecular conversations and how the cells behave when they all develop together in a 3D microenvironment.

Single-cell RNA-Seq analysis also helped researchers benchmark the engineered 3D liver tissues. Generated from stem cells against naturally occurring human fetal and adult liver cells. Researchers observed that the lab-grown liver buds have molecular and genetic signature profiles. Where very closely resemble those found in naturally developing human liver cells.

In particular they highlight molecular crosstalk between a signaling protein that cells produce to stimulate formation of blood vessels (VEGF). Also protein and receptor that communicates with VEGF to help trigger formation of a blood supply to the developing liver (KDR). The current study shows the communication between VEGF and KDR is critical to instructing the development and maturation of liver tissues. Researchers indicate they observed this crosstalk during development of mouse liver cells. Also natural human liver cells and in their bioengineered livers.

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Natural vs. Bioengineered

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. Inspite caused by the unique microenvironment of cells developing 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. For further improve liver bud organoids and precisely recapitulate differentiation of all cell types in fetal human development.