A human liver cell-based system modeling a clinical prognostic liver signature for therapeutic discovery
Name
s41467-021-25468-9.pdf
Description
Published version
Size
7.38 MB
Format
Adobe PDF
Checksum (MD5)
40e99b2090164f2686d529f7faf93d4b
Author(s)
Shalek, Alexander
Date Issued
2021
Journal
Nature Communications
Publisher
Springer Science and Business Media LLC
Citation
Shalek, Alexander. 2021. "A human liver cell-based system modeling a clinical prognostic liver signature for therapeutic discovery." Nature Communications, 12 (1).
Version
Final published version
Abstract
AbstractChronic liver disease and hepatocellular carcinoma (HCC) are life-threatening diseases with limited treatment options. The lack of clinically relevant/tractable experimental models hampers therapeutic discovery. Here, we develop a simple and robust human liver cell-based system modeling a clinical prognostic liver signature (PLS) predicting long-term liver disease progression toward HCC. Using the PLS as a readout, followed by validation in nonalcoholic steatohepatitis/fibrosis/HCC animal models and patient-derived liver spheroids, we identify nizatidine, a histamine receptor H2 (HRH2) blocker, for treatment of advanced liver disease and HCC chemoprevention. Moreover, perturbation studies combined with single cell RNA-Seq analyses of patient liver tissues uncover hepatocytes and HRH2+, CLEC5Ahigh, MARCOlow liver macrophages as potential nizatidine targets. The PLS model combined with single cell RNA-Seq of patient tissues enables discovery of urgently needed targets and therapeutics for treatment of advanced liver disease and cancer prevention.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Terms of Use
Creative Commons Attribution 4.0 International license
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DOI of Published Version
https://doi.org/10.1038/S41467-021-25468-9
