Mouse liver repopulation with hepatocytes generated from human fibroblasts.

Area of Science:

• Hepatology and Regenerative Medicine
• Stem Cell Biology
• Cell Therapy

Background:

• Human induced pluripotent stem cells (iPSCs) offer potential for liver disease research and therapy.
• Current iPSC-derived hepatocytes (iPSC-Heps) lack extensive in vivo proliferation, limiting their therapeutic application.
• Extensive post-transplant cell expansion is crucial for effective liver cell therapy, as seen in adult hepatocyte trials.

Purpose of the Study:

• To develop a novel source of human hepatocytes capable of extensive in vivo proliferation for liver regeneration.
• To overcome the limitations of current iPSC-derived hepatocytes in terms of proliferative capacity.
• To establish a feasible model for autologous liver cell therapy and in vivo disease modeling.

Main Methods:

• Generated induced multipotent progenitor cells (iMPCs) by truncating the reprogramming of human fibroblasts to pluripotency.
• Differentiated iMPCs into hepatocytes (iMPC-Heps) using small molecules that promote endoderm and hepatocyte development without affecting proliferation.
• Transplanted iMPC-Heps into an immune-deficient mouse model of human liver failure.

Main Results:

• Transplanted iMPC-Heps demonstrated extensive proliferation in mouse livers, successfully repopulating the organ.
• iMPC-Heps achieved hepatocyte function comparable to adult primary hepatocytes (aHeps).
• Transplanted iMPC-Heps did not form tumors, likely due to the absence of a pluripotent state.

Conclusions:

• Successfully generated human hepatocytes from fibroblasts that can extensively repopulate mouse livers in vivo.
• This approach bypasses the pluripotent state, enhancing safety and potentially enabling effective autologous liver cell therapy.
• The findings remove a significant barrier for developing in vitro-derived hepatocytes for clinical applications in liver disease.