Functional 3D Human Liver Bud Assembled from MSC-Derived Multiple Liver Cell Lineages

Area of Science:

• Regenerative Medicine
• Stem Cell Biology
• Hepatology

Background:

• Severe shortage of donor livers necessitates alternative strategies for liver tissue replacement.
• Previous attempts to create vascularized, functional liver tissues have not successfully incorporated key cell types like hepatic stellate cells (HSCs) and liver sinusoidal endothelial cells (LSECs).

Purpose of the Study:

• To develop a reproducible protocol for self-assembling 3D human liver buds incorporating multiple cell lineages.
• To evaluate the therapeutic potential of these engineered liver buds in a preclinical model of acute liver failure.

Main Methods:

• Optimized self-assembly of three-dimensional (3D) human liver buds from mesenchymal stem cells (MSCs), MSC-derived hepatocytes, and HSC- and LSEC-like cells within 72 hours.
• Transplantation of self-assembled liver buds into a murine model of acute liver failure via mesenteric administration.

Main Results:

• The self-assembled liver buds exhibited characteristics similar to early-stage murine liver buds.
• Mesenteric transplantation of the engineered liver buds significantly improved survival rates and ameliorated liver injury in mice, outperforming splenic transplantation of hepatocytes or MSCs.
• Transplanted liver buds demonstrated maturation and adopted an adult human liver gene expression profile post-transplantation.

Conclusions:

• The developed protocol offers a viable method for generating functional 3D human liver buds from diverse MSC-derived hepatic cell lineages.
• This technique holds significant promise for clinical applications in liver transplantation and advancing regenerative medicine research.