ArticleCell stem cell2023
VEGFA mRNA-LNP promotes biliary epithelial cell-to-hepatocyte conversion in acute and chronic liver diseases and reverses steatosis and fibrosis.
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Article in Cell stem cell, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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22citing papers in PubMed
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22 citing papers in PubMed, 44 citations in OpenAlex.
- Trial
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Authors and funding
21 authors at 4 institutions in 2 countries.
Fatima RizviCenter for Regenerative Medicine, Department of Medicine, Section of Gastroenterology, Boston University and Boston Medical Center, Boston, MA 02118, USA.
Yu-Ri LeeDepartment of Developmental Biology, Pittsburgh Liver Research Center, McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260, USA.
Ricardo Diaz-AragonDepartment of Pathology, Center for Transcriptional Medicine, Pittsburgh Liver Research Center, McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Pushpinder S BawaCenter for Regenerative Medicine, Department of Medicine, Section of Gastroenterology, Boston University and Boston Medical Center, Boston, MA 02118, USA.
Juhoon SoDepartment of Developmental Biology, Pittsburgh Liver Research Center, McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260, USA.
Rodrigo M FlorentinoDepartment of Pathology, Center for Transcriptional Medicine, Pittsburgh Liver Research Center, McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Susan WuCenter for Regenerative Medicine, Department of Medicine, Section of Gastroenterology, Boston University and Boston Medical Center, Boston, MA 02118, USA.
Arianna SarjooCenter for Regenerative Medicine, Department of Medicine, Section of Gastroenterology, Boston University and Boston Medical Center, Boston, MA 02118, USA.
Emily TruongCenter for Regenerative Medicine, Department of Medicine, Section of Gastroenterology, Boston University and Boston Medical Center, Boston, MA 02118, USA.
Anna R SmithCenter for Regenerative Medicine, Department of Medicine, Section of Gastroenterology, Boston University and Boston Medical Center, Boston, MA 02118, USA.
Feiya WangCenter for Regenerative Medicine, Department of Medicine, Section of Gastroenterology, Boston University and Boston Medical Center, Boston, MA 02118, USA.
Elissa EvertonCenter for Regenerative Medicine, Department of Medicine, Section of Gastroenterology, Boston University and Boston Medical Center, Boston, MA 02118, USA.
Alina OstrowskaDepartment of Pathology, Center for Transcriptional Medicine, Pittsburgh Liver Research Center, McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Kyounghwa JungDepartment of Developmental Biology, Pittsburgh Liver Research Center, McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260, USA.
Ying TamAcuitas Therapeutics, Vancouver, BC V6T 1Z3, Canada.
Hiromi MuramatsuDepartment of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Norbert PardiDepartment of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Drew WeissmanDepartment of Medicine, Infectious Diseases Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 10104, USA.
Alejandro Soto-GutierrezDepartment of Pathology, Center for Transcriptional Medicine, Pittsburgh Liver Research Center, McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Donghun ShinDepartment of Developmental Biology, Pittsburgh Liver Research Center, McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260, USA.
Valerie Gouon-EvansCenter for Regenerative Medicine, Department of Medicine, Section of Gastroenterology, Boston University and Boston Medical Center, Boston, MA 02118, USA. Electronic address: valerige@bu.edu.
Boston University · USUniversity of Pittsburgh · USUniversity of Pennsylvania · USAcuitas Therapeutics (Canada) · CA
Funding
Project-005UL1TR001430 · NCATS · BOSTON UNIVERSITY MEDICAL CAMPUS · PI BAIR-MERRITT, MEGAN H, CENTER, DAVID M. · 2015 to 2024
$52.3MTreating AT Deficiency with Drugs that Modulate the Proteostasis NetworkP01DK096990 · NIDDK · WASHINGTON UNIVERSITY · PI BAHAR, IVET · 2012 to 2023
$18.3MPittsburgh Liver Research CenterP30DK120531 · NIDDK · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI DAVID A GELLER · 2019 to 2026
$10.9MHarnessing human brain and liver microphysiological systems for testing therapeutics for metastatic melanomaU01TR002383 · NCATS · VANDERBILT UNIVERSITY · PI MURPHY, WILLIAM L., TAYLOR, D. LANSING · 2018 to 2022
$7.6MHuman Microphysiology Systems Disease Model of Type 2 Diabetes Starting with Liver and pancreatic IsletsUH3DK119973 · NIDDK · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI TAYLOR, D. LANSING · 2020 to 2022
$6.7MA National iPS Cell Network with Deep Phenotyping for Translational ResearchU01TR001810 · NCATS · BOSTON UNIVERSITY MEDICAL CAMPUS · PI GILAD, YOAV, KOTTON, DARRELL N. · 2016 to 2020
$4.4MNRSA Training CoreTL1TR001410 · NCATS · BOSTON UNIVERSITY MEDICAL CAMPUS · PI KOTTON, DARRELL N. · 2015 to 2024
$4.3MLipid nanoparticles as novel adjuvants inducing effective T follicular helper cell and humoral immune responsesR01AI153064 · NIAID · UNIVERSITY OF PENNSYLVANIA · PI Michela Locci, Norbert Pardi · 2020 to 2026
$4.2MElucidating the role of the FXR-PTEN-PI3K-AKT-mTOR axis in liver progenitor cell-driven liver regenerationR01DK101426 · NIDDK · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI SHIN, DONGHUN · 2014 to 2023
$3.8MMini-Livers Derived from Human IPS Cells for Modeling Steatosis and TherapyR01DK099257 · NIDDK · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI NAGRATH, DEEPAK, SOTO-GUTIERREZ, ALEJANDRO · 2014 to 2024
$3.4MInvestigation of the role of VEGFA in harnessing cholangiocyte-driven liver regenerationR01DK133404 · NIDDK · BOSTON MEDICAL CENTER · PI VALERIE B GOUON-EVANS · 2022 to 2026
$2.9MApplying a Human Liver Microphysiology System to Develop Therapeutic Strategies for Non-Alcoholic Fatty Liver Disease (NAFLD)R01DK117881 · NIDDK · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI TAYLOR, D. LANSING · 2018 to 2021
$2.7MNCATS NIH HHS TL1 TR001410NCATS NIH HHS U01 TR001810NCATS NIH HHS U01 TR002383NCATS NIH HHS UG3 TR003289NCATS NIH HHS UH3 TR003289NCATS NIH HHS UL1 TR001430NHLBI NIH HHS R24 HL123828NIAID NIH HHS R01 AI153064NIDDK NIH HHS F31 DK127606NIDDK NIH HHS P01 DK096990NIDDK NIH HHS P30 DK120531NIDDK NIH HHS R01 DK099257NIDDK NIH HHS R01 DK101426NIDDK NIH HHS R01 DK117881NIDDK NIH HHS R01 DK124361NIDDK NIH HHS R01 DK133404NIDDK NIH HHS UG3 DK119973NIDDK NIH HHS UH3 DK119973
Abstract
The liver is known for its remarkable regenerative ability through proliferation of hepatocytes. Yet, during chronic injury or severe hepatocyte death, proliferation of hepatocytes is exhausted. To overcome this hurdle, we propose vascular-endothelial-growth-factor A (VEGFA) as a therapeutic means to accelerate biliary epithelial-cell (BEC)-to-hepatocyte conversion. Investigation in zebrafish establishes that blocking VEGF receptors abrogates BEC-driven liver repair, while VEGFA overexpression promotes it. Delivery of VEGFA via nonintegrative and safe nucleoside-modified mRNA encapsulated into lipid nanoparticles (mRNA-LNPs) in acutely or chronically injured mouse livers induces robust BEC-to-hepatocyte conversion and elimination of steatosis and fibrosis. In human and murine diseased livers, we further identified VEGFA-receptor KDR-expressing BECs associated with KDR-expressing cell-derived hepatocytes. This work defines KDR-expressing cells, most likely being BECs, as facultative progenitors. This study reveals unexpected therapeutic benefits of VEGFA delivered via nucleoside-modified mRNA-LNP, whose safety is widely validated with COVID-19 vaccines, for harnessing BEC-driven repair to potentially treat liver diseases.
Indexed as
Liver DiseasesZebrafishAnimalsCOVID-19 VaccinesEpithelial CellsFibrosisHepatocytesHumansLiverLiver RegenerationMiceNucleosidesRNA, MessengerVascular Endothelial Growth Factor ACOVID-19 VaccinesNucleosidesRNA, MessengerVascular Endothelial Growth Factor AVEGFA protein, humanacute liver injuryBEC-derived intermediate liver progenitor cellsBEC-driven liver regenerationcholangiocyte-driven liver regenerationchronic liver injuryductular reactionhuman liver cirrhosisKDRmouse liver injury modelVEGFA mRNA-LNPzebrafish liver injury model
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