Embryonic mesothelial-derived hepatic lineage of quiescent and heterogenous scar-orchestrating cells defined but suppressed by WT1

Timothy James Kendall (), Catherine Mary Duff, Luke Boulter, David H. Wilson, Elisabeth Freyer, Stuart Aitken, Stuart John Forbes, John Peter Iredale and Nicholas Dixon Hastie
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Timothy James Kendall: The University of Edinburgh
Catherine Mary Duff: The University of Edinburgh
Luke Boulter: The University of Edinburgh
David H. Wilson: The University of Edinburgh
Elisabeth Freyer: The University of Edinburgh
Stuart Aitken: The University of Edinburgh
Stuart John Forbes: The University of Edinburgh
John Peter Iredale: University of Edinburgh Centre for Inflammation Research, The University of Edinburgh
Nicholas Dixon Hastie: The University of Edinburgh

Nature Communications, 2019, vol. 10, issue 1, 1-18

Abstract: Abstract Activated hepatic stellate cells (aHSCs) orchestrate scarring during liver injury, with putative quiescent precursor mesodermal derivation. Here we use lineage-tracing from development, through adult homoeostasis, to fibrosis, to define morphologically and transcriptionally discreet subpopulations of aHSCs by expression of WT1, a transcription factor controlling morphological transitions in organogenesis and adult homoeostasis. Two distinct populations of aHSCs express WT1 after injury, and both re-engage a transcriptional signature reflecting embryonic mesothelial origin of their discreet quiescent adult precursor. WT1-deletion enhances fibrogenesis after injury, through upregulated Wnt-signalling and modulation of genes central to matrix persistence in aHSCs, and augmentation of myofibroblastic transition. The mesothelial-derived lineage demonstrates punctuated phenotypic plasticity through bidirectional mesothelial-mesenchymal transitions. Our findings demonstrate functional heterogeneity of adult scar-orchestrating cells that can be whole-life traced back through specific quiescent adult precursors to differential origin in development, and define WT1 as a paradoxical regulator of aHSCs induced by injury but suppressing scarring.

Date: 2019
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DOI: 10.1038/s41467-019-12701-9

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