Hypoimmunogenic iPSC-derived hepatic organoids featuring a functional vascular network

Area of Science:

• Regenerative Medicine
• Stem Cell Biology
• Tissue Engineering

Background:

• End-stage liver disease management relies on transplantation, limited by donor scarcity and immune rejection.
• Induced pluripotent stem cells (iPSCs) offer a renewable source for cell therapies, with potential for immune compatibility.
• Developing complex, functional liver tissues from stem cells remains a challenge.

Purpose of the Study:

• To engineer off-the-shelf hepatic organoids using hypoimmunogenic iPSC technology and tissue engineering.
• To create organoids that recapitulate the native liver microenvironment by integrating multiple liver cell types.
• To advance cell-based therapies for liver diseases and metabolic disorders.

Main Methods:

• Combined tissue engineering with hypoimmunogenic iPSC technology.
• Integrated parenchymal (hepatocytes, cholangiocytes) and non-parenchymal cells (hepatic stellate cells, Kupffer cells, endothelial cells).
• Validated lineage identity and organoid complexity using gene/protein expression, electron microscopy, and single-cell RNA sequencing.

Main Results:

• Successfully generated hepatic organoids with a complex microenvironment mimicking native liver composition.
• Validated the presence and identity of multiple integrated cell types within the organoids.
• Demonstrated hepatic maturation through secretion of liver-specific proteins (albumin, apolipoproteins) and formation of a functional endothelial network.

Conclusions:

• Engineered hepatic organoids represent a significant step towards universal cell therapies for liver diseases.
• The developed organoids show potential for treating hepatic metabolic disorders.
• This approach overcomes limitations of donor scarcity and immune rejection associated with liver transplantation.