Japanese and American researchers have reported a new process to create a biologically accurate mass-production platform for bioengineering human liver tissue suitable for transplantation into humans. The process, which is described in a study published in Cell Reports, offers a new treatment for people with severe, chronic hepatitis C virus infection.
The team was led by the Cincinnati Children’s Center for Stem Cell and Organoid Medicine (CuSTOM) and Yokohama City University in Japan. Takanori Takebe, MD, the study’s lead author, is a physician/investigator at both institutions.
The new process reportedly overcomes nagging challenges for researchers working to bioengineer human organs that are safe and effective for therapeutic use, according to Dr. Takebe. With it, researchers can bioengineer single batches of up to 20,000 genetically matched, three-dimensional, and highly functional liver micro-buds.
When combined, a batch has a sufficient quantity of liver cells in a size feasible for transplanting into a person with liver failure or for testing new drugs. The liver tissues were generated entirely from human-induced pluripotent stem cells (iPSCs), which frees the process of animal feeder byproducts used to make cells for research purposes–a barrier to the cells being used therapeutically.
“Because we can now overcome these obstacles to generate highly functional, three-dimensional liver buds, our production process comes very close to complying with clinical-grade standards,” Dr. Takebe explained. “The ability to do this will eventually allow us to help many people with final-stage liver disease. We want to save the lives of children who need liver transplants by overcoming the shortage of donor livers available for this.”
The researchers stress that continued research and refinement of their process is required before initial clinical trials could begin. Dr. Takebe estimates this might occur in the next 2 to 5 years.
Dr. Takebe and colleagues published several studies that discussed the continuous progress into defining the precise genetic and molecular blueprints needed to mimic natural human development during the past 5 years. These studies enabled the researchers to develop and bioengineer functional, three-dimensional human mini-livers in the laboratory.
To help overcome the biological challenge of animal-product feeder cells, the team used their formula of genetic and molecular components to generate liver tissues in custom-designed, U-shaped bottom micro-well cell plates. The plates use a combination of chemistry techniques to form a finely structured film inside the micro-wells to nurture the developing liver buds.
Before this step, the researchers started mass production by initially using donor-derived iPSCs to grow three critical types of liver progenitor cells needed to generate healthy livers. These include hepatic endoderm cells and both endothelial and septum mesenchyme cells.
Study data show this process generates robust and highly functional progenitor cells that are placed into the custom-designed, film-coated micro-wells. The progenitor cells then engage in high levels of molecular cross-communication to form into self-organizing, three-dimensional liver buds.
The authors wrote that they generated more than 20,000 (liver) micro spots per well capable of reaching a scalable, therapeutically viable level. They then tested the functionality of the three-dimensional tissues in genetically programmed mouse models of liver disease. The animals were rescued from liver disease by the highly functional organs.
To read more about this study, click here.