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Cited by 18Liver physiology and pathologyRNA Interference and Gene DeliveryTissue Engineering and Regenerative Medicine

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

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Smith, Anna R., Rizvi, Fatima, Everton, Elissa, Adeagbo, Anisah, Wu, Susan, Tam, Ying, Muramatsu, Hiromi, Pardi, Norbert +2 more·2024·Nature Communications
DOI 10.1038/s41467-024-49332-8PMC PMC11169405
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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.

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  • Evaluating chronic liver damage has traditionally relied on animal models.

    “While several cellular models have been established to investigate acute hepatotoxicity, evaluating chronic liver damage has traditionally relied on animal models (Smith, 2024; Ma, 2009).”

    From A 3D bioengineered human liver for the study of acute and chronic drug-induced hepatotoxicity and fibrosis (2026) · cites this paper as Smith, 2024

    The Methods section (‘Chronic and acute liver injury mouse models’; page not provided) describes using NSG-PiZ mice to model chronic liver injury, and the Introduction describes prior preclinical mouse models. The paper therefore supports the use of animal models, but it does not establish that evaluation of chronic liver damage has traditionally relied on them rather than cellular models. (LLM, conf=0.84)

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Cited by

Sorted by citations

Authors
Smith, A. R., Rizvi, F., Everton, E., Adeagbo, A., Wu, S., Tam, Y., Muramatsu, H., Pardi, N., Weissman, D., & Gouon-Evans, V.
Affiliations
  • Boston University (US)
  • Acuitas Therapeutics (Canada) (CA)
  • University of Pennsylvania (US)
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2024-06-12
Volume
15
Issue
1
Pages
5010-5010
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-024-49332-8
PMC
PMC11169405
OpenAlex
W4399576605
Cited by
18
References
4
Citations by year
2026: 7 · 2025: 10 · 2024: 1
FWCI
4.71
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institutes of Health (U01TR001810, TL1TR001410)
  • National Heart, Lung, and Blood Institute (R24HL123828)
  • National Institute of Diabetes and Digestive and Kidney Diseases (F31DK135378, R01DK124361)
  • National Center for Advancing Translational Sciences
Topics
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
  • Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
Keywords
hepatocyte engraftment, hepatocyte growth factor, epidermal growth factor, lipid nanoparticles, mRNA delivery, nucleoside-modified mRNA, liver disease, hepatocyte proliferation, cell therapy, liver regeneration
MeSH terms
COVID-19, SARS-CoV-2, Animals, Disease Models, Animal, Epidermal Growth Factor, Humans, Liposomes, Liver, Liver Diseases, Male, RNA, Messenger, Hepatocyte Growth Factor, Hepatocytes, Cell Proliferation, Mice, Nanoparticles, Cell- and Tissue-Based Therapy

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