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- Title
Transient growth factor expression via mRNA in lipid nanoparticles promotes hepatocyte cell therapy in mice.
- Authors
Smith, Anna R.; Rizvi, Fatima; Everton, Elissa; Adeagbo, Anisah; Wu, Susan; Tam, Ying; Muramatsu, Hiromi; Pardi, Norbert; Weissman, Drew; Gouon-Evans, Valerie
- 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. Primary human hepatocyte (PHH) transplantation could be an alternative to liver transplantation. Here, the authors use the mRNA-LNP platform to express growth factors in the liver in a controlled manner to drastically improve PHH engraftment, thus, reducing disease burden and enhancing overall liver function.
- Subjects
HEPATOCYTE growth factor; GROWTH factors; EPIDERMAL growth factor; GENE expression; CELLULAR therapy; LIPIDS
- Publication
Nature Communications, 2024, Vol 15, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-024-49332-8