Fatima Rizvi, Yu-Ri Lee, Ricardo Diaz-Aragon, Pushpinder S Bawa, Juhoon So, Rodrigo M Florentino, Susan Wu, Arianna Sarjoo, Emily Truong, Anna R Smith, Feiya Wang, Elissa Everton, Alina Ostrowska, Kyounghwa Jung, Ying Tam, Hiromi Muramatsu, Norbert Pardi, Drew Weissman, Alejandro Soto-Gutierrez, Donghun Shin, Valerie Gouon-Evans
{"title":"VEGFA mRNA-LNP在急性和慢性肝病中促进胆道上皮细胞向肝细胞的转化,并逆转脂肪变性和纤维化。","authors":"Fatima Rizvi, Yu-Ri Lee, Ricardo Diaz-Aragon, Pushpinder S Bawa, Juhoon So, Rodrigo M Florentino, Susan Wu, Arianna Sarjoo, Emily Truong, Anna R Smith, Feiya Wang, Elissa Everton, Alina Ostrowska, Kyounghwa Jung, Ying Tam, Hiromi Muramatsu, Norbert Pardi, Drew Weissman, Alejandro Soto-Gutierrez, Donghun Shin, Valerie Gouon-Evans","doi":"10.1016/j.stem.2023.10.008","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p>","PeriodicalId":93928,"journal":{"name":"Cell stem cell","volume":" ","pages":"1640-1657.e8"},"PeriodicalIF":0.0000,"publicationDate":"2023-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10843608/pdf/","citationCount":"0","resultStr":"{\"title\":\"VEGFA mRNA-LNP promotes biliary epithelial cell-to-hepatocyte conversion in acute and chronic liver diseases and reverses steatosis and fibrosis.\",\"authors\":\"Fatima Rizvi, Yu-Ri Lee, Ricardo Diaz-Aragon, Pushpinder S Bawa, Juhoon So, Rodrigo M Florentino, Susan Wu, Arianna Sarjoo, Emily Truong, Anna R Smith, Feiya Wang, Elissa Everton, Alina Ostrowska, Kyounghwa Jung, Ying Tam, Hiromi Muramatsu, Norbert Pardi, Drew Weissman, Alejandro Soto-Gutierrez, Donghun Shin, Valerie Gouon-Evans\",\"doi\":\"10.1016/j.stem.2023.10.008\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>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.</p>\",\"PeriodicalId\":93928,\"journal\":{\"name\":\"Cell stem cell\",\"volume\":\" \",\"pages\":\"1640-1657.e8\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2023-12-07\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10843608/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cell stem cell\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1016/j.stem.2023.10.008\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2023/11/28 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell stem cell","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1016/j.stem.2023.10.008","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2023/11/28 0:00:00","PubModel":"Epub","JCR":"","JCRName":"","Score":null,"Total":0}
VEGFA mRNA-LNP promotes biliary epithelial cell-to-hepatocyte conversion in acute and chronic liver diseases and reverses steatosis and fibrosis.
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.