PUBLICATION
VEGFA mRNA-LNP promotes biliary epithelial cell-to-hepatocyte conversion in acute and chronic liver diseases and reverses steatosis and fibrosis
- Authors
- Rizvi, F., Lee, Y.R., Diaz-Aragon, R., Bawa, P.S., So, J., Florentino, R.M., Wu, S., Sarjoo, A., Truong, E., Smith, A.R., Wang, F., Everton, E., Ostrowska, A., Jung, K., Tam, Y., Muramatsu, H., Pardi, N., Weissman, D., Soto-Gutierrez, A., Shin, D., Gouon-Evans, V.
- ID
- ZDB-PUB-231130-19
- Date
- 2023
- Source
- Cell Stem Cell 30(12): 1640-1657.e8 (Journal)
- Registered Authors
- Shin, Donghun, So, Juhoon
- Keywords
- BEC-derived intermediate liver progenitor cells, BEC-driven liver regeneration, KDR, VEGFA mRNA-LNP, acute liver injury, cholangiocyte-driven liver regeneration, chronic liver injury, ductular reaction, human liver cirrhosis, mouse liver injury model, zebrafish liver injury model
- MeSH Terms
-
- Animals
- COVID-19 Vaccines
- Epithelial Cells
- Fibrosis
- Hepatocytes
- Humans
- Liver
- Liver Diseases*/pathology
- Liver Regeneration
- Mice
- Nucleosides
- RNA, Messenger/genetics
- Vascular Endothelial Growth Factor A/genetics
- Zebrafish*
- PubMed
- 38029740 Full text @ Cell Stem Cell
Citation
Rizvi, F., Lee, Y.R., Diaz-Aragon, R., Bawa, P.S., So, J., Florentino, R.M., Wu, S., Sarjoo, A., Truong, E., Smith, A.R., Wang, F., Everton, E., Ostrowska, A., Jung, K., Tam, Y., Muramatsu, H., Pardi, N., Weissman, D., Soto-Gutierrez, A., Shin, D., Gouon-Evans, V. (2023) VEGFA mRNA-LNP promotes biliary epithelial cell-to-hepatocyte conversion in acute and chronic liver diseases and reverses steatosis and fibrosis. Cell Stem Cell. 30(12):1640-1657.e8.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping