Poster abstracts
Poster number 69 submitted by Ullas Valiya Chembazhi
Cellular plasticity balances the metabolic and proliferation dynamics of a regenerating liver
Ullas Valiya Chembazhi (Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL), Sushant Bangru (Department of Biochemistry, Cancer Center@Illinois), Mikel Hernaez (Carl R. Woese Institute for Genomic Biology, University of Illinois, Urbana-Champaign, IL, United States. 4 Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Navarra, Spain.), Auinash Kalsotra (Department of Biochemistry, Cancer Center@Illinois)
Abstract:
The adult liver has exceptional ability to regenerate and can replenish up to 70% of the lost tissue
mass and functionality within weeks after surgical resection. Accumulating evidence suggest that
injury provokes adult livers to re-acquire fetal-like characteristics that facilitate regeneration (1-3).
Recently, we showed that chronic liver injury induces major expression changes in RNA binding
proteins like ESRP2, to re-activate the neonatal splicing and transcriptional programs in adult
hepatocytes (2,4). However, mechanisms that enable sustenance of normal metabolic activities
during regeneration remains unclear. Here, we use partial hepatectomy (PHx) in tandem with
single-cell transcriptomics to track cellular transitions and heterogeneities of ~22,000 liver cells
through the initiation, progression, and termination phases of mouse liver regeneration. Our
results reveal that following PHx, a subset of hepatocytes transiently reactivates an earlypostnatal-like gene expression program to proliferate, while a distinct population of metabolically hyperactive cells appears to compensate for any temporary deficits in liver function. Importantly, through combined analysis of gene regulatory networks and cell-cell interaction maps, we find that regenerating hepatocytes redeploy key developmental gene regulons, which are guided by
extensive ligand-receptor mediated signaling events between hepatocytes and non-parenchymal
cells. Altogether, our study offers a detailed blueprint of the intercellular crosstalk and cellular
reprogramming that balances the metabolic and proliferation requirements of a regenerating
liver (5).
References:
1 Hyun, J. et al. Epithelial splicing regulatory protein 2-mediated alternative splicing reprograms
hepatocytes in severe alcoholic hepatitis. J Clin Invest 130, 2129-2145, doi:10.1172/JCI132691
(2020).
2 Bangru, S. et al. Alternative splicing rewires Hippo signaling pathway in hepatocytes to promote
liver regeneration. Nat Struct Mol Biol 25, 928-939, doi:10.1038/s41594-018-0129-2 (2018).
3 Hyun, J. et al. Dysregulated activation of fetal liver programme in acute liver failure. Gut 68, 1076-
1087, doi:10.1136/gutjnl-2018-317603 (2019).
4 Bhate, A. et al. ESRP2 controls an adult splicing programme in hepatocytes to support postnatal
liver maturation. Nat Commun 6, 8768, doi:10.1038/ncomms9768 (2015).
5 Chembazhi, U. V., Bangru, S., Hernaez, M. & Kalsotra, A. Cellular plasticity balances the metabolic
and proliferation dynamics of a regenerating liver. 2020.2005.2029.124263,
doi:10.1101/2020.05.29.124263 %J bioRxiv (2020).
Keywords: Liver regeneration