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Principal Investigator: VALERIE B GOUON-EVANS
Organization: BOSTON MEDICAL CENTER
Fiscal Year: 2024
Award: $554,527
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
PROJECT SUMMARY / ABSTRACT
Liver disease affects hundreds of millions of people worldwide. Liver transplantation remains the only treatment
for end stage liver disease (ESLD); however, transplantation faces a major burden due to a shortage of liver
donors. The liver is known for a remarkable regenerative ability through hepatocyte-driven regeneration, the
proliferation of the main functional liver cell type, the hepatocyte. However, in ESLD, hepatocyte proliferation
becomes exhausted. An alternative strategy to treat ESLD would be to promote liver regeneration through biliary
epithelial cell (BEC)-driven regeneration as a novel mechanism that could be exploited as a therapeutic target.
BEC-driven liver regeneration is a process by which BECs proliferate, transition to a liver progenitor cell (LPC)
stage, a process defined as ductular reaction (DR), and differentiate into functional hepatocytes and restore liver
function. BEC-driven regeneration has been experimentally demonstrated in mouse models in which hepatocyte
proliferation was compromised and in our zebrafish models after near complete ablation of hepatocytes.
Observation of DR in virtually all chronic and acute human liver diseases and of budding hepatocytes from BECs
in human cirrhotic livers suggests that BEC-driven repair occurs in human, yet differentiation into hepatocytes is
insufficient to alleviate the liver disease. Our goal is therefore to identify and test a druggable pathway that
triggers BEC-to-hepatocyte conversion for the efficient therapeutic use of BECs to treat liver diseases. We
propose that VEGFA promotes BEC-to-hepatocyte conversion and rescues liver function in complementary
mouse and zebrafish liver injury models. Our preliminary data demonstrate that delivery of VEGFA in injured
mouse livers via the non-integrative and safe nucleoside-modified mRNA complexed with lipid nanoparticles
(mRNA-LNP) induces robust BEC-to-hepatocyte conversion and reversion of steatosis and fibrosis. Moreover,
blocking VEGFR2, the main receptor for VEGFA, or downstream mediators PI3K/AKT abrogates BEC-driven
liver regeneration in zebrafish, suggesting the key contribution of the VEGFR2/PI3K/AKT axis. Previous studies
showed that VEGFA promotes liver repair in rodents by stimulating VEGFR2 on endothelial cells (ECs) that
induce the secretion of hepatocyte mitogens and thus drives hepatocyte-driven repair. However, it has not been
reported that VEGFA directly affects BECs for BEC-driven repair, which is suggested by our preliminary data
showing VEGFR2 induction in a subset of BECs in injured mouse livers, an observation also reported by others
in injured rats. Therefore, our findings combined with studies from others lead us to test 2 hypotheses using the
complementary mouse and zebrafish liver injury models: (Aim 1) VEGFA delivery in vivo triggers BEC-to-
hepatocyte conversion to replenish the lost cell mass and restore liver functions, and that (Aim 2) VEGFA acts
directly on BECs and/or indirectly on ECs that express VEGFR2. This study may have key clinical significance
by establishing a treatment to prevent progression of the liver disease, by exploiting the alternative intrinsic
regenerative ability of the liver via BEC-driven liver regeneration using clinically safe mRNA-LNPs.
Terms: <Ablation><Acute><Affect><Albumins><Antimorphic mutation><Apoptosis><Apoptosis Pathway><Bile><Bile Juice><Bile fluid><Biliary><Bilirubin><Bilirubin IX alpha><Brachydanio rerio><CSAID-Binding Protein 1><CSAID-Binding Protein 2><CSBP2><Cause of Death><Cell Body><Cell Lineage><Cells><Chemical Models><Chemicals><Chronic><Cirrhosis><Clinical><Common Rat Strains><Complex><Cytokine-Suppressive Antiinflammatory Drug-Binding Protein 1><Cytokine-Suppressive Antiinflammatory Drug-Binding protein 2><Danio rerio><Data><Disease regression><Documentation><Dominant Negative><Dominant-Negative Mutant><Dominant-Negative Mutation><Endothelial Cells><Epithelial Cell Proliferation><Epithelial Cells><Extracellular Signal-Regulated Kinase Gene><FLK1><Face><Fibrosis><Fishes><Generations><Goals><Hepatic Cells><Hepatic Disorder><Hepatic Parenchymal Cell><Hepatic Transplantation><Hepatocyte><Human><Inflammation><Injury><Injury to Liver><Investigation><KDR gene><KO mice><Knock-out><Knock-out Mice><Knockout><Knockout Mice><Liver><Liver Cells><Liver Grafting><Liver Regeneration><Liver Stem Cell><Liver Transplant><Liver diseases><MAP Kinase Gene><MAPK><MAPK14><MAPK14 Mitogen-Activated Protein Kinase><MAPK14 gene><Maps><Mediating><Mediator><Messenger RNA><Metabolic><Mice><Mice Mammals><Mission><Mitogen-Activated Protein Kinase 14><Mitogen-Activated Protein Kinase Gene><Mitogens><Modeling><Modern Man><Molecular Mechanisms of Action><Murine><Mus><Mxi2><NIH><National Institutes of Health><Natural regeneration><Nucleosides><Null Mouse><Organ Donor><PI-3K/AKT><PI3K/AKT><Pathway interactions><Persons><Phase><Procedures><Process><Progenitor Cells><Programmed Cell Death><Proliferating><Public Health><Rat><Rats Mammals><Rattus><Reaction><Recovery><Regeneration><Reporting><Research><Rodent><Rodentia><Rodents Mammals><Role><SAPK2A><Stress-Activated Protein Kinase 2A><Testing><Therapeutic><Therapeutic Uses><Transgenic Organisms><Transplantation><United States National Institutes of Health><VEGF Receptors><VEGFA><VEGFA gene><VEGFR><VEGFR-2><VEGFR2><VPF Receptor><Vascular Endothelial Cell Growth Factor Receptor><Vascular Endothelial Growth Factor A><Vascular Endothelial Growth Factor Receptor 2><Vascular Permeability Factor Receptor><Vasculotropin><Zebra Danio><Zebra Fish><Zebrafish><acute liver injury><cell dedifferentiation><cell type><cholangiocyte><cirrhotic><clinical significance><clinically significant><disease model><disorder model><end stage liver disease><end stage liver failure><exhaust><faces><facial><genetic approach><genetic strategy><hepatic body system><hepatic cell proliferation><hepatic cellular proliferation><hepatic damage><hepatic disease><hepatic injury><hepatic organ system><hepatocyte cell proliferation><hepatocyte cellular proliferation><hepatocyte proliferation><hepatopathy><in vivo><injured><injuries><lipid based nanoparticle><lipid nanoparticle><liver cell proliferation><liver cellular proliferation><liver damage><liver disorder><liver function><liver injury><liver progenitor><liver repair><liver transplantation><mRNA><mortality><mouse model><murine model><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><novel><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><overexpress><overexpression><p38><p38 MAP Kinase><p38 MAPK Gene><p38 Mitogen Activated Protein Kinase><p38 Protein Kinase><p38 SAPK><p38-Alpha><p38Alpha><pathway><prevent><preventing><regenerate><regenerative><repair><repaired><senescence><senescent><social role><stem cells><therapeutic target><transgenic><transplant><virtual>