Transient growth factor expression via mRNA in lipid nanoparticles promotes hepatocyte cell therapy in mice

Anna R. Smith, Fatima Rizvi, Elissa Everton, Anisah Adeagbo, Susan Wu, Ying Tam, Hiromi Muramatsu, Norbert Pardi, Drew Weissman, Valerie Gouon-Evans

Research output: Contribution to journalArticlepeer-review

Abstract

Primary human hepatocyte (PHH) transplantation is a promising alternative to liver transplantation, whereby liver function could be restored by partial repopulation of the diseased organ with healthy cells. However, currently PHH engraftment efficiency is low and benefits are not maintained long-term. Here we refine two male mouse models of human chronic and acute liver diseases to recapitulate compromised hepatocyte proliferation observed in nearly all human liver diseases by overexpression of p21 in hepatocytes. In these clinically relevant contexts, we demonstrate that transient, yet robust expression of human hepatocyte growth factor and epidermal growth factor in the liver via nucleoside-modified mRNA in lipid nanoparticles, whose safety was validated with mRNA-based COVID-19 vaccines, drastically improves PHH engraftment, reduces disease burden, and improves overall liver function. This strategy may overcome the critical barriers to clinical translation of cell therapies with primary or stem cell-derived hepatocytes for the treatment of liver diseases.

Original languageEnglish
Article number5010
JournalNature Communications
Volume15
Issue number1
DOIs
StatePublished - Dec 2024
Externally publishedYes

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