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

Nat Commun. 2019 Oct 15;10(1):4688. doi: 10.1038/s41467-019-12701-9.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Lineage
  • Cicatrix / genetics*
  • Cicatrix / metabolism
  • Epithelium / embryology*
  • Hepatic Stellate Cells / cytology*
  • Hepatic Stellate Cells / metabolism
  • Liver / embryology*
  • Liver Cirrhosis / genetics*
  • Liver Cirrhosis / metabolism
  • Mice
  • Myofibroblasts / cytology*
  • Myofibroblasts / metabolism
  • WT1 Proteins / genetics*
  • WT1 Proteins / metabolism

Substances

  • WT1 Proteins
  • WT1 protein, mouse