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, Nicholas Dixon Hastie

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)

1 Citation (Scopus)
102 Downloads (Pure)

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.

Original languageEnglish
Article number4688
Number of pages18
JournalNature Communications
Volume10
Issue number1
DOIs
Publication statusPublished - 1 Dec 2019

Keywords

  • Cell lineage
  • Liver fibrosis
  • Mechanisms of disease

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