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

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  • Anna R. Smith

    (Boston University Chobanian & Avedisian School of Medicine & Boston Medical Center)

  • Fatima Rizvi

    (Boston University Chobanian & Avedisian School of Medicine & Boston Medical Center)

  • Elissa Everton

    (Boston University Chobanian & Avedisian School of Medicine & Boston Medical Center)

  • Anisah Adeagbo

    (Boston University Chobanian & Avedisian School of Medicine & Boston Medical Center)

  • Susan Wu

    (Boston University Chobanian & Avedisian School of Medicine & Boston Medical Center)

  • Ying Tam

    (Acuitas Therapeutics)

  • Hiromi Muramatsu

    (University of Pennsylvania Perelman School of Medicine)

  • Norbert Pardi

    (University of Pennsylvania Perelman School of Medicine)

  • Drew Weissman

    (University of Pennsylvania Perelman School of Medicine)

  • Valerie Gouon-Evans

    (Boston University Chobanian & Avedisian School of Medicine & Boston Medical Center)

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.

Suggested Citation

  • Anna R. Smith & Fatima Rizvi & Elissa Everton & Anisah Adeagbo & Susan Wu & Ying Tam & Hiromi Muramatsu & Norbert Pardi & Drew Weissman & Valerie Gouon-Evans, 2024. "Transient growth factor expression via mRNA in lipid nanoparticles promotes hepatocyte cell therapy in mice," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49332-8
    DOI: 10.1038/s41467-024-49332-8
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    as
    1. Alexander Raven & Wei-Yu Lu & Tak Yung Man & Sofia Ferreira-Gonzalez & Eoghan O’Duibhir & Benjamin J. Dwyer & John P. Thomson & Richard R. Meehan & Roman Bogorad & Victor Koteliansky & Yuri Kotelevtse, 2017. "Cholangiocytes act as facultative liver stem cells during impaired hepatocyte regeneration," Nature, Nature, vol. 547(7663), pages 350-354, July.
    2. Fatima Rizvi & Elissa Everton & Anna R. Smith & Hua Liu & Elizabeth Osota & Mitchell Beattie & Ying Tam & Norbert Pardi & Drew Weissman & Valerie Gouon-Evans, 2021. "Murine liver repair via transient activation of regenerative pathways in hepatocytes using lipid nanoparticle-complexed nucleoside-modified mRNA," Nature Communications, Nature, vol. 12(1), pages 1-10, December.
    3. Fatima Rizvi & Elissa Everton & Anna R. Smith & Hua Liu & Elizabeth Osota & Mitchell Beattie & Ying Tam & Norbert Pardi & Drew Weissman & Valerie Gouon-Evans, 2021. "Author Correction: Murine liver repair via transient activation of regenerative pathways in hepatocytes using lipid nanoparticle-complexed nucleoside-modified mRNA," Nature Communications, Nature, vol. 12(1), pages 1-1, December.
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