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Murine liver repair via transient activation of regenerative pathways in hepatocytes using lipid nanoparticle-complexed nucleoside-modified mRNA

Author

Listed:
  • Fatima Rizvi

    (Center for Regenerative Medicine and the Section of Gastroenterology of Boston University and Boston Medical Center)

  • Elissa Everton

    (Center for Regenerative Medicine and the Section of Gastroenterology of Boston University and Boston Medical Center)

  • Anna R. Smith

    (Center for Regenerative Medicine and the Section of Gastroenterology of Boston University and Boston Medical Center)

  • Hua Liu

    (Center for Regenerative Medicine and the Section of Gastroenterology of Boston University and Boston Medical Center)

  • Elizabeth Osota

    (Center for Regenerative Medicine and the Section of Gastroenterology of Boston University and Boston Medical Center)

  • Mitchell Beattie

    (Acuitas Therapeutics)

  • Ying Tam

    (Acuitas Therapeutics)

  • Norbert Pardi

    (Department of Medicine, University of Pennsylvania)

  • Drew Weissman

    (Department of Medicine, University of Pennsylvania)

  • Valerie Gouon-Evans

    (Center for Regenerative Medicine and the Section of Gastroenterology of Boston University and Boston Medical Center)

Abstract

Induction of intrinsic liver regeneration is an unmet need that can be achieved by temporally activating key hepatocyte regenerative pathways. Here, we establish an efficient, safe, non-integrative method to transiently express hepatocyte-growth-factor (HGF) and epidermal-growth-factor (EGF) in hepatocytes via nucleoside-modified, lipid-nanoparticle-encapsulated mRNA (mRNA-LNP) delivery in mice. We confirm specific hepatotropism of mRNA-LNP via intravenous injection of firefly luciferase encoding mRNA-LNP, with protein expression lasting about 3 days. In the liver, virtually all hepatocytes are transfected along with a subpopulation of endothelial and Kupffer cells. In homeostasis, HGF mRNA-LNP efficiently induce hepatocyte proliferation. In a chronic liver injury mouse model recapitulating non-alcoholic fatty liver disease, injections of both HGF and EGF mRNA-LNP sharply reverse steatosis and accelerate restoration of liver function. Likewise, HGF and EGF mRNA-LNP accelerate liver regeneration after acetaminophen-induced acute liver injury with rapid return to baseline ALT levels. This study introduces mRNA-LNP as a potentially translatable safe therapeutic intervention to harness liver regeneration via controlled expression of endogenous mitogens in vivo.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-20903-3
    DOI: 10.1038/s41467-021-20903-3
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    Cited by:

    1. Sebastian Castillo-Hair & Stephen Fedak & Ban Wang & Johannes Linder & Kyle Havens & Michael Certo & Georg Seelig, 2024. "Optimizing 5’UTRs for mRNA-delivered gene editing using deep learning," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    2. 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.

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