Specification of fetal liver endothelial progenitors to functional zonated adult sinusoids requires c-Maf induction

Jesus Maria Gómez-Salinero, Franco Izzo, Yang Lin, Sean Houghton, Tomer Itkin, Fuqiang Geng, Yaron Bram, Robert P. Adelson, Tyler M. Lu, Giorgio Inghirami, Jenny Zhaoying Xiang, Raphael Lis, David Redmond, Ryan Schreiner, Sina Y. Rabbany, Dan A. Landau, Robert E. Schwartz, Shahin Rafii

Research output: Contribution to journalArticlepeer-review


The liver vascular network is patterned by sinusoidal and hepatocyte co-zonation. How intra-liver vessels acquire their hierarchical specialized functions is unknown. We study heterogeneity of hepatic vascular cells during mouse development through functional and single-cell RNA-sequencing. The acquisition of sinusoidal endothelial cell identity is initiated during early development and completed postnatally, originating from a pool of undifferentiated vascular progenitors at E12. The peri-natal induction of the transcription factor c-Maf is a critical switch for the sinusoidal identity determination. Endothelium-restricted deletion of c-Maf disrupts liver sinusoidal development, aberrantly expands postnatal liver hematopoiesis, promotes excessive postnatal sinusoidal proliferation, and aggravates liver pro-fibrotic sensitivity to chemical insult. Enforced c-Maf overexpression in generic human endothelial cells switches on a liver sinusoidal transcriptional program that maintains hepatocyte function. c-Maf represents an inducible intra-organotypic and niche-responsive molecular determinant of hepatic sinusoidal cell identity and lays the foundation for the strategies for vasculature-driven liver repair.

Original languageEnglish
Pages (from-to)593-609.e7
JournalCell Stem Cell
Issue number4
StatePublished - 7 Apr 2022
Externally publishedYes


  • c-Maf
  • development
  • endothelial cell reprogramming
  • endothelial cell specification
  • fibrosis
  • hepatic angiocrine factors
  • liver sinusoidal endothelial cells
  • postnatal maturation
  • single-cell RNAseq
  • single-cell molecular profiling
  • vascular heterogeneity

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Genetics
  • Cell Biology


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