Therapeutic HNF4A mRNA attenuates liver fibrosis in a preclinical model.
Name:
Publisher version
View Source
Access full-text PDFOpen Access
View Source
Check access options
Check access options
Average rating
Cast your vote
You can rate an item by clicking the amount of stars they wish to award to this item.
When enough users have cast their vote on this item, the average rating will also be shown.
Star rating
Your vote was cast
Thank you for your feedback
Thank you for your feedback
Authors
Yang, TaihuaPoenisch, Marion
Khanal, Rajendra
Hu, Qingluan
Dai, Zhen
Li, Ruomeng
Song, Guangqi
Yuan, Qinggong
Yao, Qunyan
Shen, Xizhong
Taubert, Richard
Engel, Bastian
Jaeckel, Elmar
Vogel, Arndt
Falk, Christine S
Schambach, Axel
Gerovska, Daniela
Araúzo-Bravo, Marcos J
Vondran, Florian W R
Cantz, Tobias
Horscroft, Nigel
Balakrishnan, Asha
Chevessier, Frédéric
Ott, Michael
Sharma, Amar Deep
Issue Date
2021-08-25
Metadata
Show full item recordAbstract
Background & aims: Therapeutic targeting of injuries that require transient restoration of proteins by mRNA delivery is an attractive approach that, until recently, has remained poorly explored. In this study, we examined the therapeutic utility of mRNA delivery for liver fibrosis and cirrhosis. Specifically, we aimed to demonstrate the therapeutic efficacy of human hepatocyte nuclear factor alpha (HNF4A) mRNA in mouse models of fibrosis and cirrhosis. Methods: We investigated restoration of hepatocyte functions by HNF4A mRNA transfection in vitro, and analyzed the attenuation of liver fibrosis and cirrhosis in multiple mouse models, by delivering hepatocyte-targeted biodegradable lipid nanoparticles (LNPs) encapsulating HNF4A mRNA. To identify potential mechanisms of action, we performed microarray-based gene expression profiling, single-cell RNA sequencing, and chromatin immunoprecipitation. We used primary liver cells and human liver buds for additional functional validation. Results: Expression of HNF4A mRNA led to restoration of the metabolic activity of fibrotic primary murine and human hepatocytes in vitro. Repeated in vivo delivery of LNP-encapsulated HNF4A mRNA induced a robust inhibition of fibrogenesis in 4 independent mouse models of hepatotoxin- and cholestasis-induced liver fibrosis. Mechanistically, we discovered that paraoxonase 1 is a direct target of HNF4A and it contributes to HNF4A-mediated attenuation of liver fibrosis via modulation of liver macrophages and hepatic stellate cells. Conclusion: Collectively, our findings provide the first direct preclinical evidence of the applicability of HNF4A mRNA therapeutics for the treatment of fibrosis in the liver. Lay summary: Liver fibrosis and cirrhosis remain unmet medical needs and contribute to high mortality worldwide. Herein, we take advantage of a promising therapeutic approach to treat liver fibrosis and cirrhosis. We demonstrate that restoration of a key gene, HNF4A, via mRNA encapsulated in lipid nanoparticles decreased injury in multiple mouse models of fibrosis and cirrhosis. Our study provides proof-of-concept that mRNA therapy is a promising strategy for reversing liver fibrosis and cirrhosis.Citation
J Hepatol. 2021 Aug 25:S0168-8278(21)02006-7. doi: 10.1016/j.jhep.2021.08.011. Epub ahead of print.Affiliation
TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH,Feodor-Lynen Str. 7, 30625 Hannover, Germany.Publisher
ElsevierJournal
Journal of hepatologyPubMed ID
34453962Type
ArticleLanguage
enEISSN
1600-0641ae974a485f413a2113503eed53cd6c53
10.1016/j.jhep.2021.08.011
Scopus Count
Collections
The following license files are associated with this item:
- Creative Commons
Except where otherwise noted, this item's license is described as Attribution-NonCommercial-NoDerivatives 4.0 International
Related articles
- Identification of TAF1, HNF4A, and CALM2 as potential therapeutic target genes for liver fibrosis.
- Authors: Ji D, Chen GF, Wang JC, Cao LH, Lu F, Mu XX, Zhang XY, Lu XJ
- Issue date: 2019 Jun
- Synthetic human ABCB4 mRNA therapy rescues severe liver disease phenotype in a BALB/c.Abcb4(-/-) mouse model of PFIC3.
- Authors: Wei G, Cao J, Huang P, An P, Badlani D, Vaid KA, Zhao S, Wang DQ, Zhuo J, Yin L, Frassetto A, Markel A, Presnyak V, Gandham S, Hua S, Lukacs C, Finn PF, Giangrande PH, Martini PGV, Popov YV
- Issue date: 2021 Jun
- Hepatocyte nuclear factor 4A improves hepatic differentiation of immortalized adult human hepatocytes and improves liver function and survival.
- Authors: Hang HL, Liu XY, Wang HT, Xu N, Bian JM, Zhang JJ, Xia L, Xia Q
- Issue date: 2017 Nov 15
- Hepatic Stress Response in HCV Infection Promotes STAT3-Mediated Inhibition of HNF4A-miR-122 Feedback Loop in Liver Fibrosis and Cancer Progression.
- Authors: Aydin Y, Kurt R, Song K, Lin D, Osman H, Youngquist B, Scott JW, Shores NJ, Thevenot P, Cohen A, Dash S
- Issue date: 2019 Sep 20
- Alterations in hepatic mRNA expression of phase II enzymes and xenobiotic transporters after targeted disruption of hepatocyte nuclear factor 4 alpha.
- Authors: Lu H, Gonzalez FJ, Klaassen C
- Issue date: 2010 Dec